bluuebunny/crossref_metadata_2025 huggingface dataset:
Galactooligosaccharide Treatment Alleviates DSS-Induced Colonic Inflammation in Caco-2 Cell Model
Authors: Roselli Marianna , Maruszak Aleksandra , Grimaldi Roberta , Harthoorn Lucien , Finamore Alberto
Published: April 2022

The biological activities of dietary bioactive polysaccharides have been largely explored. Studies on the immunomodulating effects of oligosaccharides and polysaccharides have shown that they are able to modulate innate immunity. Prebiotics are a class of poorly digested carbohydrates that are mainly produced from dietary fibers, which are carbohydrate polymers with ten or more monomeric units as defined by the Codex Alimentarius Commission in 2009. Considering the capacity of prebiotics in reducing gut inflammation, the aim of this study was to investigate the anti-inflammatory activity of galactooligosaccharide (Bimuno® GOS) in an in vitro model of ulcerative colitis (UC)-like inflamed intestinal cells. Differentiated Caco-2 cells were exposed to 2 % dextran-sulfate-sodium salt (DSS) to induce inflammation, and then with different concentrations of Bimuno GOS (1–1,000 μg/ml). Cell monolayer permeability, tight- and adherent junction protein distribution, pro-inflammatory cytokine secretion, and NF-kB cascade were assessed. Bimuno GOS at different concentrations, while not affecting cell monolayer permeability, was shown to counteract UC-like intestinal inflammatory responses and damages induced by DSS. Indeed, Bimuno GOS was able to counteract the detrimental effects of DSS on cell permeability, determined by transepithelial electrical resistance, phenol red apparent permeability, and tight- and adherent junction protein distribution. Furthermore, Bimuno GOS inhibited the DSS-induced NF-kB nuclear translocation and pro-inflammatory cytokine secretion. Further analyses showed that Bimuno GOS was able to revert the expression levels of most of the proteins involved in the NF-kB cascade to control levels. Thus, the prebiotic Bimuno GOS can be a safe and effective way to modulate the gut inflammatory state through NF-kB pathway modulation, and could possibly further improve efficacy in inducing remission of UC.
Evaluation of Volatile Profile and In Vitro Antioxidant Activity of Fermented Green Tea Infusion With Pleurotus sajor-caju (Oyster Mushroom)
Authors: Su Wei-Ying , Gao Shu-Yi , Zhan Si-Jia , Wu Qi , Chen Gui-Mei , Han Jin-Zhi , Lv Xu-Cong , Rao Ping-Fan , Ni Li
Published: April 2022

Green tea has distinct astringency, bitter taste, and typical green flavor because of its post-harvest treatment without withering and enzymatic oxidation. Microbial fermentation has been identified as a promising strategy that could give green tea infusion a special taste flavor. This might be linked to the metabolic transformation ability of microorganisms. In this study, starter culture of edible mushroom Pleurotus sajor-caju (oyster mushroom) was used for submerged fermentation of green tea infusion in order to improve its flavor and taste quality. The volatile profile determined by headspace solid-phase microextraction, coupled with gas chromatography mass spectrometry, showed that the contents of (Z)-2-penten-1-ol and methyl heptadienone in green tea infusion were decreased significantly by the fermentation with the basidiomycete P. sajor-caju (p < 0.01), which would alleviate the herbal and grass flavor of green tea infusion to a certain extent. Meanwhile, the contents of linalool and geraniol were increased 9.3 and 11.3 times, respectively, whereas methyl salicylate was newly produced after fermentation by P. sajor-caju, endowing the fermented tea infusion with a pleasant flower and fruit aroma. In addition, the polyphenol profile was determined using high-performance liquid chromatography equipped with ion trap mass spectrometry, and the results indicated that the contents of most polyphenols in green tea infusion decreased significantly after fermentation by P. sajor-caju. The reduction of catechins and anthocyanins in fermented green tea infusion alleviated the astringency and bitterness. Moreover, the antioxidant activity of fermented green tea infusion was obviously decreased, especially the DPPH-free radical-scavenging ability and the ferric-reducing power. However, it is noteworthy that the ABTS-free radical scavenging ability was improved compared with the unfermented one, indicating that the increased tea pigments and volatile metabolites (such as linalool and geraniol) after fermentation with P. sajor-caju may also contribute to the antioxidant capacity of fermented green tea infusion. Overall, the innovative approach driven by P. sajor-caju fermentation has achieved promising potential to manipulate the green tea flavor.
Construction of a Microfluidic Platform With Core-Shell CdSSe@ZnS Quantum Dot-Encoded Superparamagnetic Iron Oxide Microspheres for Screening and Locating Matrix Metalloproteinase-2 Inhibitors From Fruits of Rosa roxburghii
Authors: Tao Yi , Pan Meiling , Zhu Fei , Liu Qing , Wang Ping
Published: April 2022

The microfluidic platform is a versatile tool for screening and locating bioactive molecules from functional foods. Here, a layer-by-layer assembly approach was used to fabricate core-shell CdSSe@ZnS quantum dot encoded superparamagnetic iron oxide microspheres, which served as a carrier for matrix metalloproteinase-2. The matrix metalloproteinase-2 camouflaged magnetic microspheres was further incorporated into a homemade microfluidic platform and incubated with extracts of fruits of Rosa roxburghii. The flow rate of the microfluidic platform was tuned. The major influencing parameters on ligand binding, such as dissociate solvents, incubation pH, ion strength, temperature, and incubation time were also optimized by using ellagic acid as a model compound. The specific binding ligands were sent for structure elucidation by mass spectrometry. The absolute recovery of ellagic acid ranged from 101.14 to 102.40% in the extract of R. roxburghii under the optimal extraction conditions. The linearity was pretty well in the range of 0.009–1.00 mg·ml−1 (R2 = 0.9995). The limit of detection was 0.003 mg·ml−1. The relative SDs of within-day and between-day precision were <1.91%. A total of thirteen ligands were screened out from fruits of R. roxburghii, which were validated for their inhibitory effect by enzyme assay. Of note, eleven new matrix metalloproteinase-2 inhibitors were identified, which may account for the antitumor effect of fruits of R. roxburghii.
Lactobacillus rhamnosus Encapsulated in Alginate/Chitosan Microgels Manipulates the Gut Microbiome to Ameliorate Salt-Induced Hepatorenal Injury
Authors: Zhang Zheng , Liu Jiajian , Li Mengjie , Yang Binbin , Liu Wei , Chu Zhuangzhuang , Cui Bo , Chen Xiao
Published: April 2022

As the essential regulator of intestinal bacterial diversity, probiotics are a potential treatment for chronic high-salt diet (HSD)–induced metabolic dysfunction. Probiotic cells entrapped in microgels have been confirmed as being more effective than free cells in protecting bacteria against unfavorable conditions, that is, enhancing their stress resistance. This study explored the physiological mechanism by which probiotic microgels relieve HSD–induced hepatorenal injury. Herein, Lactobacillus rhamnosus was encapsulated in alginate-chitosan microgels which the percentage of alginate/chitosan was applied 1.5:0.5 (w/w) in this system, and the encapsulation significantly improved the probiotic viability in simulated gastrointestinal conditions. Mice were fed an HSD with L. rhamnosus (SDL) or L. rhamnosus microgels (SDEL). After 8 weeks of administration, dietary sodium was confirmed as inducing the hepatic and renal damages in mice, based on indicators, including serum biomarker levels, histopathological features of tissues, and pro-inflammatory cytokine contents in blood levels. However, the serum levels of urea nitrogen, creatinine, uric acid, glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, and alkaline phosphatase in the SDL and SDEL-fed mice were significantly lowered compared to the HSD-fed mice, especially in the SDEL group. HSD increased the abundances of Anaeroplasma, Enterorhabdus, Parvibacter, and Bacteroides, while the microgels increased the abundances of Lactobacillus, Bifidobacterium, Mucispirillum, and Faecalibaculum. Significant variations of fecal metabolome were validated for SDEL-treated mice, containing those linked to entero-hepatic circulation (e.g., cholic acid), carbohydrate metabolism (i.e., L-lactic acid), and increased antioxidants including citric acid. Furthermore, the probiotic microgels ameliorated intestinal damage by improving barrier and absorption functions. These results augmented existing knowledge on probiotic application for salt toxicity.
A Two-Stage Enzymolysis Method and Its Application in Exerting Antioxidant Activity of Walnut Protein
Authors: Liu Dandan , Chen Min , Zhu Junsong , Tian Weijie , Guo Yiting , Ma Haile
Published: April 2022

Traditional enzymolysis method for producing bioactive peptides does not consider the utilization of digestive enzymes in the human gastrointestinal tract, leading to the possibility of excessive hydrolysis and higher production cost. Therefore, a two-stage enzymolysis method was established in this study based on in vitro limited enzymolysis and gastrointestinal digestion, and applied it to the research of walnut protein (WP) in exerting antioxidant activity. Results showed that WP could be well-digested by pepsin and pancreatin. WP with limited enzymolysis degree of 0% could achieve high antioxidant activity after the simulated gastrointestinal digestion, and the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging activity and reducing power were 66.53% and 8.55 μmoL TE/mL, respectively. In vivo experimental results also exhibited that both WP and WP hydrolysate (WPH) could alleviate the oxidative damage induced by D-galactose in SD rats to some extent. Considering the digestive function of human body, in vitro limited enzymolysis, in vitro simulated gastrointestinal digestion and in vivo validation are necessary processes for the production of bioactive peptides.
SRSF3 Expression Serves as a Potential Biomarker for Prognostic and Immune Response in Pan-Cancer
Authors: Li Zihua , Huang Hui , Wu Xinbo , Yu Tao , Xiao Fajiao , Zhou Haichao , Shang Anquan , Yang Yunfeng
Published: April 2022

Serine-rich splicing factor3 (SRSF3) plays an essential role in cell proliferation and inducing and maintaining of cancers as a proto-oncogene. However, the mechanisms of SRSF3 in pan-cancers are still unknown. In our study, a visualized prognostic landscape of SRSF3 in pan-cancer was investigated and the relationship between SRSF3 expression and immune infiltration was also investigated. The expression pattern and prognostic worth of SRSF3 among pan-cancers were explored through different databases, namely, the TCGA and Kaplan–Meier Plotter. Moreover, the survival analysis including Kaplan-Meier method for evaluating between groups was conducted. Further analyses including the correlation between expression SRSF expression and immune infiltration including tumor mutation burden (TMB), microsatellite instability (MSI) was investigated using Spearman test. In ACC, KIRP and UCEC cancer, upregulated expression of SRSF3 was associated with worse disease-free interval (DFI), representing a mechanism in promoting progression of tumor. Our results showed that SRSF3 expression was positively correlated immune cell infiltration, TMB, MSI in certain cancer types, indicating SRSF3 expression to potential value of therapy response. Additionally, we explored the functional characteristics of SRSF in vitro through western blot detecting the expression level of the apoptosis-related proteins in SW480 and 786-O cells. SRSF3 expression was upregulated in pan-cancer tissue compared with normal tissue, which confirmed by immunohistochemistry and its expression indicated poor overall survival and death-specific survival. Therefore, SRSF3 was found to be a possible biomarker for prognostic and therapeutic assessment through bioinformatic analysis. SRSF3 is expressed in various cancers and its high expression correlated to poor survival and disease progression. In summary, SRSF3 expression can be considered as a prognostic biomarker in pan-cancer and therapeutic evaluation.
Imaging Strategies in Proton Therapy for Thoracic Tumors: A Mini Review
Authors: Algranati Carlo , Strigari Lidia
Published: April 2022

Proton beam therapy (PBT) is often more attractive for its high gradient dose distributions than other treatment modalities with external photon beams. However, in thoracic lesions treated particularly with pencil beam scanning (PBS) proton beams, several dosimetric issues are addressed. The PBS approach may lead to large hot or cold spots in dose distributions delivered to the patients, potentially affecting the tumor control and/or increasing normal tissue side effects. This delivery method particularly benefits image-guided approaches. Our paper aims at reviewing imaging strategies and their technological trends for PBT in thoracic lesions. The focus is on the use of imaging strategies in simulation, planning, positioning, adaptation, monitoring, and delivery of treatment and how changes in the anatomy of thoracic tumors are handled with the available tools and devices in PBT. Starting from bibliographic research over the past 5 years, retrieving 174 papers, major key questions, and implemented solutions were identified and discussed; the results aggregated and presented following the methodology of analysis of expert interviews.
A Deep Learning Model for the Automatic Recognition of Aplastic Anemia, Myelodysplastic Syndromes, and Acute Myeloid Leukemia Based on Bone Marrow Smear
Authors: Wang Meifang , Dong Chunxia , Gao Yan , Li Jianlan , Han Mengru , Wang Lijun
Published: April 2022

Aim

Bone marrow biopsy is essential and necessary for the diagnosis of patients with aplastic anemia (AA), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). However, the convolutional neural networks (CNN) model that automatically distinguished AA, MDS, and AML based on bone marrow smears has not been reported.

Methods

Image-net pretrained model of CNN was used to construct the recognition model. Data extracted from the American Society of Hematology (ASH) Image Bank were utilized to develop the model and data extracted from the clinic were used for external validation. The model had two output layers: whether the patient was MDS (two-classification) and which of AA, MDS, and AML the patient was (three-classification). Different outcome weights (two-classification/three-classification = 5:5, 2:8, 1:9) and epochs (30, 50, 200) were used to select the optimal model. The model performance was evaluated by the Accuracy-Loss curves and calculating the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results

A total of 115 bone marrow smears from the ASH Image Bank and 432 bone marrow smears from the clinic were included in this study. The results of Accuracy-Loss curves showed that the best model training effect was observed in the model with the outcome weight and epoch of 1:9 and 200. Similarly, this model also performed well performances in the two-classification of MDS and the three-classification of AA, MDS, AML. The AUC, accuracy and sensitivity of the MDS two-classification model in the testing set were 0.985 [95% confidence interval (CI), 0.979-0.991], 0.914 (95%CI, 0.895-0.934), and 0.992 (95%CI, 0.980-1.000), respectively. The AUC, accuracy and sensitivity of the AA, MDS, AML three-classification model in the testing set were 0.968 (95%CI, 0.960-0.976), 0.929 (95%CI, 0.916-0.941), and 0.857 (95%CI, 0.828-0.886), respectively.

Conclusion

The image-net pretrained model was able to obtain high accuracy AA, MDS, AML distinction, and may provide clinicians with a convenient tool to distinguish AA, MDS, and AML.
Analysis of Tryptophan and Its Main Metabolite Kynurenine and the Risk of Multiple Cancers Based on the Bidirectional Mendelian Randomization Analysis
Authors: Li Ran , Wang Xuanyang , Zhang Yuntao , Xu Xiaoqing , Wang Lulu , Wei Chunbo , Liu Lin , Wang Ziqi , Li Ying
Published: April 2022

Background

Tryptophan and its metabolites have been found related to various cancers, but the direction of this relationship is still unclear. The purpose of this study is to explore the causal associations of tryptophan and kynurenine with multiple cancers based on the bidirectional Mendelian randomization analysis.

Methods

The data of a genome-wide association study meta-analysis on 7,824 individuals was used to explore the genetic variants strongly associated with tryptophan and kynurenine. Genetic instruments of four specific cancers were obtained from available summary-level data of 323,590 European participants. Bidirectional Mendelian randomization analysis was conducted to examine possible causality. Sensitivity analysis was performed to test heterogeneity and horizontal pleiotropy. COX regression analysis was conducted to explore associations between dietary tryptophan and cancer mortality in NHANES 1988-1994.

Results

No evidence of any causal association of tryptophan and kynurenine with the risk of four specific cancers was shown, except for weak correlations were suggested between lung or prostate cancer and kynurenine. Multiple sensitivity analyses generated similar results. Our findings from COX regression analysis were consistent with the above results.

Conclusions

Our study did not find any causal relationship between tryptophan and kynurenine and multiple cancers. The associations still need further research.
Breast Cancer Molecular Subtype Prediction on Pathological Images with Discriminative Patch Selection and Multi-Instance Learning
Authors: Liu Hong , Xu Wen-Dong , Shang Zi-Hao , Wang Xiang-Dong , Zhou Hai-Yan , Ma Ke-Wen , Zhou Huan , Qi Jia-Lin , Jiang Jia-Rui , Tan Li-Lan , Zeng Hui-Min , Cai Hui-Juan , Wang Kuan-Song , Qian Yue-Liang
Published: April 2022

Molecular subtypes of breast cancer are important references to personalized clinical treatment. For cost and labor savings, only one of the patient’s paraffin blocks is usually selected for subsequent immunohistochemistry (IHC) to obtain molecular subtypes. Inevitable block sampling error is risky due to the tumor heterogeneity and could result in a delay in treatment. Molecular subtype prediction from conventional H&E pathological whole slide images (WSI) using the AI method is useful and critical to assist pathologists to pre-screen proper paraffin block for IHC. It is a challenging task since only WSI-level labels of molecular subtypes from IHC can be obtained without detailed local region information. Gigapixel WSIs are divided into a huge amount of patches to be computationally feasible for deep learning, while with coarse slide-level labels, patch-based methods may suffer from abundant noise patches, such as folds, overstained regions, or non-tumor tissues. A weakly supervised learning framework based on discriminative patch selection and multi-instance learning was proposed for breast cancer molecular subtype prediction from H&E WSIs. Firstly, co-teaching strategy using two networks was adopted to learn molecular subtype representations and filter out some noise patches. Then, a balanced sampling strategy was used to handle the imbalance in subtypes in the dataset. In addition, a noise patch filtering algorithm that used local outlier factor based on cluster centers was proposed to further select discriminative patches. Finally, a loss function integrating local patch with global slide constraint information was used to fine-tune MIL framework on obtained discriminative patches and further improve the prediction performance of molecular subtyping. The experimental results confirmed the effectiveness of the proposed AI method and our models outperformed even senior pathologists, which has the potential to assist pathologists to pre-screen paraffin blocks for IHC in clinic.
Prognostic Value of Heterogeneity Index Derived from Baseline 18F-FDG PET/CT in Mantle Cell Lymphoma
Authors: Liu Fei , Gu Bingxin , Li Nan , Pan Herong , Chen Wen , Qiao Ying , Song Shaoli , Liu Xiaosheng
Published: April 2022

Objectives

Mantle cell lymphoma (MCL) represents a group of highly heterogeneous tumors, leading to a poor prognosis. Early prognosis prediction may guide the choice of therapeutic regimen. Thus, the purpose of this study was to investigate the potential application value of heterogeneity index (HI) in predicting the prognosis of MCL.

Methods

A total of 83 patients with histologically proven MCL who underwent baseline fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) were retrospectively enrolled. The clinicopathologic index and PET/CT metabolic parameters containing maximum and mean standard uptake value (SUVmax and SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and HI were evaluated. Receiver operating characteristic (ROC) curve analyses were performed to determine the optimal cutoff values of the parameters for progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox regression were used to assess relationships between risk factors and recurrence. Kaplan–Meier plots were applied for survival analyses.

Results

In univariate analyses, age [HR = 2.51, 95% CI = 1.20–5.24, p = 0.041 for body weight (BW)] and HI-BW (HR = 4.17, 95% CI = 1.00–17.38, p = 0.050) were significantly correlated with PFS. In multivariate analyses, age (HR = 2.61, 95% CI = 1.25–5.47, p = 0.011 for BW) and HI-BW (HR = 4.41, 95% CI = 1.06–18.41, p = 0.042) were independent predictors for PFS, but not for OS. B symptoms (HR = 5.00, 95% CI = 1.16–21.65, p = 0.031 for BW) were an independent prognostic factor for OS, but not for PFS. The other clinicopathologic index and PET/CT metabolic parameters were not related to outcome survival in MCL.

Conclusion

The age and HI derived from baseline PET/CT parameters were significantly correlated with PFS in MCL patients.
Olaparib Combined With Dacomitinib in Osimertinib-Resistant Brain and Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Report and Systematic Review
Authors: Zhang Hui , Wang Yong , Wu Huaguo , Zhou Shizhen , Li Shuo , Meng Xiangji , Tao Rongjie , Yu Jinming
Published: April 2022

Lung cancer patients with brain and leptomeningeal metastases usually have poor prognosis. For those patients with EGFR mutations, osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is the first choice of treatment. However, drug resistance to osimertinib frequently occurs; and to date, the available follow-up treatment strategies have limited efficacy. In this case study, we report that treatments with olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, combined with dacomitinib, a second-generation EGFR TKI, benefited a lung cancer patient with osimertinib-resistant brain and leptomeningeal metastases. This 55-year-old male patient was found to have a pL858R mutation on EGFR exon 21 combined with TP53 and ERBB2 mutations after developing drug resistance to osimertinib treatment. Based on the genetic testing results, he was treated with olaparib and dacomitinib, and obtained 6 months of progression-free survival (PFS) and 13 months of overall survival (OS) after the diagnosis of leptomeningeal metastasis. This case report represents the first study applying PARP inhibitor in combination with dacomitinib in the treatment of leptomeningeal metastases after osimertinib resistance.
TIM-3 Expression Level on AML Blasts Correlates With Presence of Core Binding Factor Translocations Rather Than Clinical Outcomes
Authors: Hong Jian , Xia Leiming , Huang Zhenqi , Yuan Xiaodong , Liang Xinglin , Dai Jifei , Wu Zhonghui , Liang Li , Ruan Min , Long Zhangbiao , Cheng Xin , Chen Xiaowen , Ni Jing , Ge Jian , Li Qingsheng , Zeng Qingshu , Xia Ruixiang , Wang Yi , Yang Mingzhen
Published: April 2022

Background

T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) expresses on leukemic stem and progenitor populations of non-M3 acute myeloid leukemia (AML) as well as T lymphocytes. TIM-3 is thought to be involved in the self-renewal of leukemic stem cells and the immune escape of AML cells, however its correlation with AML prognosis is still controversial and worthy of further investigation.

Methods

we simultaneously assessed TIM-3 expression levels of leukemic blasts and T lymphocytes in the bone marrow of de novo AML patients using flow cytometry. The correlations of TIM-3 expression between leukemic blasts and T lymphocytes and the correlations of TIM-3 expression with various patient parameters were analyzed. In addition, the Cancer Genome Atlas (TCGA) data of AML patients were acquired and analyzed to verify the results.

Results

TIM-3 expression of CD34+ leukemic blasts (R2 = 0.95, p<0.0001) and CD34+CD38- leukemic stem cells (R2 = 0.75, p<0.0001) were significantly and positively correlated with that of the whole population of leukemic blasts. In addition, TIM-3 expression level of leukemic blasts correlated significantly and positively with that of CD8+ (R2 = 0.44, p<0.0001) and CD4+ (R2 = 0.16, p=0.0181) lymphocytes, and higher TIM-3 expression of leukemic blasts was significantly associated with a greater proportion of peripheral CD8+ T lymphocytes (R2 = 0.24, p=0.0092), indicating that TIM-3 on leukemic blasts might alter adaptive immunity of AML patients. Regarding clinical data, the presence of core binding factor (CBF) translocations was significantly correlated with higher TIM-3 expression of leukemic blasts (CBF versus non-CBF, median 22.78% versus 1.28%, p=0.0012), while TIM-3 expression levels of leukemic blasts were not significantly associated with the remission status after induction chemotherapy (p=0.9799), overall survival (p=0.4201) or event-free survival (p=0.9873). Similar to our results, TCGA data showed that patients with CBF translocations had significantly higher mRNA expression level of HAVCR2 (the gene encoding TIM-3) (median, 9.81 versus 8.69, p<0.0001), and as all patients in the cohort were divided into two groups based on the median HAVCR2 expression level, 5-year overall survivals were not significantly different (low versus high, 24.95% versus 24.54%, p=0.6660).

Conclusion

TIM-3 expression level on AML blasts correlates with presence of CBF translocations rather than clinical outcomes.
Insights From the Analysis of Clinicopathological and Prognostic Factors in Patients With Gallbladder Cancer
Authors: Wu Di , Jin Wenjian , Zhang Yue , An Yong , Chen Xuemin , Chen Weibo
Published: April 2022

Aims

To investigate the clinical efficacy and prognostic factors of primary gallbladder cancer (GBC) treated by radical surgery.

Methods

The clinical and pathological data of 168 patients with primary gallbladder cancer admitted and treated in the Third Affiliated Hospital of Soochow University from January 1st, 2010 to December 31st, 2018 were analyzed retrospectively. Kaplan Meier method was used to draw the survival curve and evaluate the survival rate. Chi-square test was used for univariate analysis and binary logistic regression was used for multivariate analysis.

Results

94 cases showed symptoms of abdominal pain and abdominal distension. 7 cases showed symptoms of fatigue and weight loss. Jaundice occurred in 10 patients. Fever occurred in 6 patients. 51 patients had no symptoms at all. The median survival time of 168 patients was 35.0 (1.0 ~ 142.0) months. The overall 1-, 2- and 3-year cumulative survival rates were 69.6%, 55.4% and 48.8% respectively. The univariate analysis indicated that preoperative bilirubin, tumor size, tumor location, pathological type, degree of differentiation, liver invasion, nerve invasion, vascular invasion, surgical margin, filtration depth and N staging were significant factors influencing prognosis of patients with primary GBC (P<0.05). The results of multivariate analysis demonstrated that degree of differentiation, nerve invasion, filtration depth and N staging were independent risk factors for prognosis of patients with primary GBC (P<0.05).

Conclusion

Patients with risk factors of gallbladder cancer should be more active in early cholecystectomy to avoid the malignant transformation of benign diseases. Degree of differentiation, nerve invasion, filtration depth and N staging were important factors for poor prognosis of patients with primary GBC. For T4 staging patients, preoperative evaluation should be more comprehensive, and patients and surgeons should be more prudent in adopting appropriate clinical treatment. The primary purpose should be prolonging the survival time and improving the quality of life.
Chronic Neutrophilic Leukemia: A Comprehensive Review of Clinical Characteristics, Genetic Landscape and Management
Authors: Thomopoulos Thomas P. , Symeonidis Argiris , Kourakli Alexandra , Papageorgiou Sotirios G. , Pappa Vasiliki
Published: April 2022

Chronic neutrophilic leukemia (CNL) represents a rare disease, that has been classified among the BCR/ABL-negative myeloproliferative neoplasms. The disease is characterized by marked leukocytosis with absolute neutrophilia and its clinical presentation may vary from asymptomatic to highly symptomatic with massive splenomegaly and constitutional symptoms. CNL prognosis remains relatively poor, as most patients succumb to disease complications or transform to acute myeloid leukemia. Recent studies have demonstrated that CSF3R mutations drive the disease, albeit the presence of other secondary mutations perplex the genetic landscape of the disease. Notably, the presence of CSF3R mutations has been adopted as a criterion for diagnosis of CNL. Despite the vigorous research, the management of the disease remains suboptimal. Allogeneic stem cell transplantation represents the only treatment that could lead to cure; however, it is accompanied by high rates of treatment-related mortality. Recently, ruxolitinib has shown significant responses in patients with CNL; however, emergence of resistance might perturbate long-term management of the disease. The aim of this review is to summarize the clinical course and laboratory findings of CNL, highlight its pathogenesis and complex genetic landscape, and provide the context for the appropriate management of patients with CNL.
Changes in the Epidemiology and Causative Pathogens of Meningitis in Children After the Outbreak of the Coronavirus Disease 2019: A Multicenter Database Study
Authors: Lee Jooyoung , Choi Arum , Kim Kyunghoon , Bin Joong Hyun , Eom Tae Hoon , Yoo Il Han , Yoon Da Hye , Kim Sukil , Kim Young Hoon
Published: April 2022

Background

With the outbreak of the COVID-19 pandemic, non-pharmaceutical interventions such as social distancing have been implemented worldwide, and a decrease in other infectious diseases has been reported as an unexpected benefit. However, to date, studies are lacking regarding the effects of the COVID-19 pandemic on neuroinfectious diseases; therefore, we aimed to determine the effects of the COVID-19 pandemic on the incidence of meningitis, which is the most common infectious disease in children.

Methods

This retrospective study used electronic medical record data from five university hospitals located in the metropolitan cities in Korea. This study included patients aged <18 years who were diagnosed with meningitis between January 2017 and December 2020. We analyzed the clinical characteristics of patients with meningitis and changes in the incidence and causative pathogens of meningitis before and after the COVID-19 outbreak.

Results

The study included 677 patients with meningitis. Following the outbreak of COVID-19 in Korea in January 2020, the incidence of childhood meningitis significantly decreased and seasonal changes noted yearly disappeared. There was a difference in the age distribution of patients with meningitis. The incidence of meningitis decreased significantly in children aged >5 years, and the incidence in children <5 years of age relatively increased (p < 0.001). In addition, there was a notable decrease in the cases of suspected meningitis (p < 0.001). The incidence of enteroviral meningitis, the most common cause of meningitis, significantly decreased.

Conclusion

After the COVID-19 outbreak, the incidence of childhood meningitis significantly decreased with the implementation of non-pharmaceutical interventions. Absence of enteroviral meningitis and decrease in the proportion of patients aged ≥5 years with meningitis having mild symptoms were noted. Consequently, it can be concluded that the non-pharmaceutical interventions (NPIs) instituted to prevent the spread of COVID-19 had some effect on reducing the incidence of meningitis.
Circulating FGF21 and GDF15 as Biomarkers for Screening, Diagnosis, and Severity Assessment of Primary Mitochondrial Disorders in Children
Authors: Li Yi , Li Shengrui , Qiu Yinfeng , Zhou Maobin , Chen Min , Hu Yue , Hong Siqi , Jiang Li , Guo Yi
Published: April 2022

Background

Primary mitochondrial disorders (PMDs) are a diagnostic challenge for paediatricians, and identification of reliable and easily measurable biomarkers has become a high priority. This study aimed to investigate the role of serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) in children with PMDs.

Methods

We analysed serum FGF21 and GDF15 concentrations by enzyme-linked immunosorbent assay (ELISA) in children with PMDs, patients with non-mitochondrial neuromuscular disorders (NMDs), and aged-matched healthy children, and compared them with serum lactate and ratio of lactate and pyruvate (L/P). We also evaluated correlations between these biomarkers and the phenotype, genotype, and severity of PMDs.

Results

The median serum GDF15 and FGF21 concentrations were significantly elevated in fifty-one patients with PMDs (919.46 pg/ml and 281.3 pg/ml) compared with those of thirty patients with NMDs (294.86 pg/ml and 140.51 pg/ml, both P < 0.05) and fifty healthy controls (221.21 pg/ml and 85.02 pg/ml, both P < 0.05). The area under the curve of GDF15 for the diagnosis of PMDs was 0.891, which was higher than that of the other biomarkers, including FGF21 (0.814), lactate (0.863) and L/P ratio (0.671). Calculated by the maximum Youden index, the critical value of GDF15 was 606.369 pg/ml, and corresponding sensitivity and specificity were 74.5and 100%. In the PMD group, FGF21 was significantly correlated with International Paediatric Mitochondrial Disease Scale (IPMDS) score. The levels of GDF15 and FGF21 were positively correlated with age, critical illness condition, and multisystem involvement but were not correlated with syndromic/non-syndromic PMDs, different mitochondrial syndromes, nuclear DNA/mitochondrial DNA pathogenic variants, gene functions, or different organ/system involvement.

Conclusion

Regardless of clinical phenotype and genotype, circulating GDF15 and FGF21 are reliable biomarkers for children with PMDs. GDF15 can serve as a screening biomarker for diagnosis, and FGF21 can serve as a severity biomarker for monitoring.
Lung Ultrasound for the Diagnosis and Management of Neonatal Respiratory Distress Syndrome: A Minireview
Authors: Guo Bin-Bin , Pang Lin , Yang Bo , Zhang Cong , Chen Xiao-Ya , OuYang Jia-Bao , Wu Chang-Jun
Published: April 2022

Lung ultrasound (LUS) is useful for diagnosis of respiratory distress syndrome in neonates. Recently, it has been proved to play an important role in the management of neonatal respiratory distress syndrome (RDS). It is feasible to grade RDS and select therapeutic modalities accordingly by LUS. The treatment also should be adjusted with the change in ultrasound images. In conclusion, LUS is valuable for the diagnosis and management of neonatal respiratory distress syndrome.
What Have We Learnt About the Treatment of Juvenile-Onset Systemic Lupus Erythematous Since Development of the SHARE Recommendations 2012?
Authors: Gallagher Kathy L. , Patel Pallavi , Beresford Michael W. , Smith Eve Mary Dorothy
Published: April 2022

Introduction

Juvenile-onset systemic lupus erythematous (JSLE) is a rare multisystem autoimmune disorder. In 2012, the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative developed recommendations for the diagnosis/management of JSLE, lupus nephritis (LN) and childhood-onset anti-phospholipid syndrome (APS). These recommendations were based upon available evidence informing international expert consensus meetings.

Objective

To review new evidence published since 2012 relating to the management of JSLE, LN and APS in children, since the original literature searches informing the SHARE recommendations were performed.

Method

MEDLINE, EMBASE and CINAHL were systematically searched for relevant literature (2012-2021) using the following criteria: (1) English language studies; (2) original research studies regarding management of JSLE, LN, APS in children; (3) adult studies with 3 or more patients <18-years old, or where the lower limit of age range ≤16-years and the mean/median age is ≤30-years; (4) randomized controlled trials (RCTs), cohort studies, case control studies, observational studies, case-series with >3 patients. Three reviewers independently screened all titles/abstracts against predefined inclusion/exclusion criteria. All relevant manuscripts were reviewed independently by at least two reviewers. Data extraction, assessment of the level of evidence/methodological quality of the manuscripts was undertaken in-line with the original SHARE processes. Specific PUBMED literature searches were also performed to identify new evidence relating to each existing SHARE treatment recommendation.

Results

Six publications met the inclusion/exclusion criteria for JSLE: three RCTs, one feasibility trial, one case series. For LN, 16 publications met the inclusion/exclusion criteria: eight randomized trials, three open label prospective clinical trials, five observational/cohort studies. For APS, no publications met the inclusion criteria. The study with the highest evidence was an RCT comparing belimumab vs. placebo, including 93 JSLE patients. Whilst the primary-endpoint was not met, a significantly higher proportion of belimumab-treated patients met the PRINTO/ACR cSLE response to therapy criteria. New evidence specifically addressing each SHARE recommendation remains limited.

Conclusion

Since the original SHARE literature searches, undertaken >10-years ago, the main advance in JSLE treatment evidence relates to belimumab. Additional studies are urgently needed to test new/existing agents, and assess their long-term safety profile in JSLE, to facilitate evidence-based practice.
Major Bleeding Risk in Atrial Fibrillation Patients Co-Medicated With Non-Vitamin K Oral Anticoagulants and Antipsychotics
Authors: Chen Chiung-Mei , Chang Kuo-Hsuan , Wang Chun-Li , Tu Hui-Tzu , Huang Yu-Tung , Wu Hsiu-Chuan , Chang Chien-Hung , Chang Shang-Hung
Published: April 2022

Major bleeding risks associated with non-vitamin K oral anticoagulants (NOACs) used with and without concurrent antipsychotics in patients with non-valvular atrial fibrillation (AF) were assessed. A total of 98,863 patients with non-valvular AF receiving at least one NOAC prescription from Taiwan’s National Health Insurance database were enrolled. Major bleeding was defined as a primary diagnosis of intracranial or gastrointestinal hemorrhage or bleeding at other sites. The adjusted incidence rate difference (AIRD) per 1,000 person-years and adjusted rate ratio of major bleeding were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. A total of 8,037 major bleeding events occurred during 705,521 person-quarters with NOAC prescriptions. Antipsychotics were used in 26.35% of NOAC-exposed patients. Compared to using NOAC alone, co-medication of either typical (AIRD: 79.18, 95% confidence interval [CI]: 70.63–87.72) or atypical (AIRD: 40.5, 95% CI: 33.64–47.35) antipsychotic with NOAC had a significant increase in the adjusted incidence rate per 1,000 person-years of major bleeding. The concomitant use of a NOAC with chlorpromazine (AIRD: 103.87, 95% CI: 51.22–156.52), haloperidol (AIRD: 149.52, 95% CI: 125.03–174.00), prochlorperazine (AIRD: 90.43, 95% CI: 78.55–102.32), quetiapine (AIRD: 44.6, 95% CI: 37.11–52.09), or risperidone (AIRD: 41.55, 95% CI: 22.86–60.24) (All p < 0.01) showed a higher adjusted incidence rate of major bleeding than using NOACs alone. The concomitant use of typical (chlorpromazine, haloperidol, or prochlorperazine) or atypical (quetiapine or risperidone) antipsychotic with NOACs was associated with a significantly increased risk of major bleeding.
ING4 Promotes Stemness Enrichment of Human Renal Cell Carcinoma Cells Through Inhibiting DUSP4 Expression to Activate the p38 MAPK/type I IFN-Stimulated Gene Signaling Pathway
Authors: Tang Yu , Yang Xinyue , Wang Qing , Huang Haoyu , Wang Qinzhi , Jiang Min , Yuan Chunluan , Huang Yefei , Chen Yansu
Published: April 2022

Renal cell carcinoma (RCC) recurs frequently due to high metastatic spread, resulting in a high mortality. Cancer stem cells play a critical role in initiating the tumor metastasis. Inhibitor of growth 4 (ING4) is a member of the ING family, but its impact on cancer stem cells in RCC is still unknown. In this study, we found that ING4 significantly promoted the sphere-forming size and number of RCC cells under an ultralow-attachment culture condition in vitro, tumor growth and metastasis in vivo, and the expression of some stem-like or pluripotent biomarkers CD44, MYC, OCT4, and NANOG, indicating that ING4 increased the stemness enrichment of RCC cells. Mechanistically, the ING4-activated p38 MAPK pathway possibly upregulated the expression of type I IFN-stimulated genes to promote the formation of RCC stem cells. ING4 could inhibit the expression of DUSP4 to activate p38 MAPK. In addition, selective pharmacological p38 MAPK inhibitors could significantly inhibit stemness enrichment only in ING4-overexpressed RCC cells, suggesting that the p38 MAPK inhibitors might be effective in patients with high ING4 expression in RCC tissue. Taken together, our findings proposed that ING4 might serve as a potential therapeutic target for metastatic RCC, particularly RCC stem cells.
Efficacy and Safety of Lithium Treatment in SARS-CoV-2 Infected Patients
Authors: Spuch Carlos , López-García Marta , Rivera-Baltanás Tania , Cabrera-Alvargonzález J. J , Gadh Sudhir , Rodrigues-Amorim Daniela , Álvarez-Estévez Tania , Mora Almudena , Iglesias-Martínez-Almeida Marta , Freiría-Martínez Luis , Pérez-Rodríguez Maite , Pérez-González Alexandre , López-Domínguez Ana , Longueira-Suarez María Rebeca , Sousa-Domínguez Adrián , Araújo-Ameijeiras Alejandro , Mosquera-Rodríguez David , Crespo Manuel , Vila-Fernández Dolores , Regueiro Benito , Olivares Jose Manuel
Published: April 2022

At the beginning of the pandemic, we observed that lithium carbonate had a positive effect on the recovery of severely ill patients with COVID-19. Lithium is able to inhibit the replication of several types of viruses, some of which are similar to the SARS-CoV-2 virus, increase the immune response and reduce inflammation by preventing or reducing the cytokine storm. Previously, we published an article with data from six patients with severe COVID-19 infection, where we proposed that lithium carbonate could be used as a potential treatment for COVID-19. Now, we set out to conduct a randomized clinical trial number EudraCT 2020–002008–37 to evaluate the efficacy and safety of lithium treatment in patients infected with severe SARS-CoV-2. We showed that lithium was able to reduce the number of days of hospital and intensive care unit admission as well as the risk of death, reduces inflammatory cytokine levels by preventing cytokine storms, and also reduced the long COVID syndromes. We propose that lithium carbonate can be used to reduce the severity of COVID-19.
Network Pharmacology and Molecular Docking to Elucidate the Potential Mechanism of Ligusticum Chuanxiong Against Osteoarthritis
Authors: Xiang Cheng , Liao Yilin , Chen Zhuoyuan , Xiao Bo , Zhao Ziyue , Li Aoyu , Xia Yu , Wang Pingxiao , Li Hui , Xiao Tao
Published: April 2022

Background: Osteoarthritis (OA) is a degenerative disease which serious affects patients. Ligusticum chuanxiong (CX) has been shown to have a certain curative effect on osteoarthritis in traditional Chinese medicine therapy. This study is based on network pharmacology and molecular docking technology to explore the potential mechanism of CX.

Methods: Components of CX to treat osteoarthritis were screened in the TCMSP database and targets were predicted by the PharmMapper database, the osteoarthritis targets were collected from the GeneCards database, and intersection genes were found to be the possible targets of CX anti-OA. The STRING database and Cytoscape software were utilized for protein-protein interaction analysis and further screening of core targets. The Metascape database was used for KEGG and GO enrichment analyses. Then, the top 10 pathways were selected to construct “drug-compound-target-pathway-disease” network analysis. Finally, molecular docking was used to analyze the binding affinity of seven compounds with core targets and TNF-α.

Results: Seven compounds with 253 non-repetitive targets of CX were screened from the TCMSP database and 60 potential intersection targets of CX anti-OA were found. PPI network analysis showed that the core targets were ALB, AKT1, IGF1, CASP3, MAPK1, ANXA5, and MAPK14, while GO and KEGG pathway enrichment analyses showed that the relevant biological processes involved in the treatment of osteoarthritis by CX might include the MAPK cascade and reactive oxygen species metabolic process. The KEGG pathway analysis result was mainly associated with the MAPK signaling pathway and PI3K-AKT signaling pathway. We further docked seven ingredients with MAPK1 and MAPK14 enriched in the MAPK pathway, and TNF-α as the typical inflammatory cytokine. The results also showed good binding affinity, especially FA, which may be the most important component of CX anti-OA.

Conclusion: Our research revealed the potential mechanism of CX in the treatment of OA, and our findings can also pave the way for subsequent basic experimental verification and a new research direction.
Amyloid-β Induces Cdh1-Mediated Rock2 Stabilization Causing Neurodegeneration
Authors: Lapresa Rebeca , Agulla Jesus , Gonzalez-Guerrero Sonia , Bolaños Juan P. , Almeida Angeles
Published: April 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, which is causally related to the accumulation of abnormally folded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein aggregates. The dendritic spine regulator Rho protein kinase 2 (Rock2) accumulates in the brain at the earliest stages of AD and remains increased during disease progression. However, the molecular mechanism that upregulates Rock2 in AD, and its role in the disease progression, are unknown. Here, we found that oligomers of the amyloidogenic fragment 25–35 of the Aβ peptide (Aβ25-35) trigger Rock2 accumulation and activation in mouse cortical neurons in primary culture and in mouse hippocampus in vivo. Neuronal apoptotic death and memory impairment caused by Aβ25-35 administration were rescued by genetic and pharmacological inhibition of Rock2 activity. Mechanistically, Aβ25-35 elicited cyclin dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1, a cofactor that is essential for the activity of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) in neurons. Notably, phosphorylated Cdh1 was disassembled from the APC/C complex, causing its inactivation and subsequent Rock2 protein stabilization and activation. Moreover, Aβ25-35-induced neuronal apoptosis was prevented by expressing a phosphodefective form of Cdh1, but not by a phosphomimetic Cdh1. Finally, Cdh1 inactivation, using both genetic and pharmacological approaches, enhanced Aβ25-35-mediated neuronal death through a mechanism that was prevented by inhibition of Rock2 activity. These results indicate that the Cdk5-Cdh1 signaling pathway accounts for the increased Rock2 activity by amyloidogenic Aβ peptides and that this mechanism may contribute to neurodegeneration and memory loss in AD.