bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross-sectional study on the effect of dietary zinc intake on the relationship between serum vitamin D3 and HOMA-IR
Authors: Hu Biao , Lin Zheng-yang , Cai Yuan , Sun Yue-xin , Yang Shu-qi , Guo Jiang-long , Zhang Shi , Sun Dong-lin
Published: October 2022

Introduction

Serum vitamin D3 concentration is associated with the risk of insulin resistance. Zinc has also been reported to be associated with a lower risk of insulin resistance. In addition, zinc is an essential cofactor in the activation of vitamin D3. However, the effect of dietary zinc intake on the relationship between vitamin D3 and insulin resistance risk has not been fully studied. Therefore, we designed this cross-sectional study to assess the impact of changes in zinc intake on the relationship between vitamin D3 and insulin resistance risk.

Study design and methods

This study analyzed data from the national Health and Nutrition Examination Survey (NHANES) from 2005 to 2018, involving 9,545 participants. Participants were stratified by zinc intake category (low zinc intake <9.58 mg/ day; High zinc intake: ≥9.58 mg/ day).

Results

In this cross-sectional study, serum vitamin D3 levels were independently associated with the risk of insulin resistance in both the low and high Zinc intakes (β: −0.26, 95%Cl: −0.56~0.04 vs. β: −0.56, 95%Cl: −1.01~-0.11). In addition, this association was influenced by different dietary zinc intakes (interaction P < 0.05).

Conclusions

Our results suggest that zinc intake may influence the association between serum vitamin D3 and the risk of insulin resistance. Further randomized controlled trials are needed to provide more evidence of this finding.
Gallbladder cancer during pregnancy treated with surgery and adjuvant gemcitabine: A case report and review of the literature
Authors: Diciolla A. , Gianoni M. , Fleury M. , Szturz P. , Demartines N. , Peters S. , Duran R. , Desseauve D. , Panchaud Monnat A. , Fasquelle F. , Digklia A.
Published: October 2022

Background

Gallbladder cancer (GBC) represents the most common biliary tract cancer. Prognosis remains poor with 5-year overall survival rates less than 5% in advanced stages. GBCs are diagnosed more frequently in women, supposedly due to endocrine factors.

Case

A 35-year-old woman, diagnosed with a non-metastatic GBC in the 22nd week of gestation, underwent a complete surgical resection 5 weeks later. Adjuvant gemcitabine was administered without complications, temporarily discontinued in the 32nd week to allow childbirth. The patient was disease-free for more than 3 years with ongoing remission at the last visit in July 2022. During the follow-up period, the child had no developmental, cognitive, or other health issues.

Conclusion

Malignant tumors occur in about 0.1% of pregnant women, many are treated with chemotherapy. In oncology, the need to deliver optimal treatment in these patients represents a major concern. Both surgery and adjuvant chemotherapy of locally advanced GBC can be performed safely, with certain considerations, in the second trimester of pregnancy.
A novel diagnostic model for differentiation of lung metastasis from primary lung cancer in patients with colorectal cancer
Authors: Guo Rui , Yan Shi , Wang Fei , Su Hua , Xie Qing , Zhao Wei , Yang Zhi , Li Nan , Yu Jiangyuan
Published: October 2022

Objective

This study aimed to evaluate the 18F-FDG PET/CT in differentiating lung metastasis(LM) from primary lung cancer(LC) in patients with colorectal cancer (CRC).

Methods

A total of 120 CRC patients (80 male, 40 female) who underwent 18F-FDG PET/CT were included. The diagnosis of primary lung cancer or lung metastasis was based on histopathology The patients were divided into a training cohort and a validation cohort randomized 1:1. Independent risk factors were extracted through the clinical information and 18F-FDG PET/CT imaging characteristics of patients in the validation cohort, and then a diagnostic model was constructed and a nomograms was made. ROC curve, calibration curve, cutoff, sensitivity, specificity, and accuracy were used to evaluate the prediction performance of the diagnostic model.

Results

One hundred and twenty Indeterminate lung lesions (ILLs) (77 lung metastasis, 43 primary lung cancer) were analyzed. No significant difference in clinical characteristics and imaging features between the training and the validation cohorts (P > 0. 05). Using uni-/multivariate analysis, pleural tags and contour were identified as independent predictors. These independent predictors were used to establish a diagnostic model with areas under the receiver operating characteristic curves (AUCs) of 0.92 and 0.89 in the primary and validation cohorts, respectively. The accuracy rate of the diagnostic model for differentiating LM from LC were higher than that of subjective diagnosis (P < 0.05).

Conclusions

Pleural tags and contour were identified as independent predictors. The diagnostic model of ILLs in patients with CRC could help differentiate between LM and LC.
Bevacizumab increases the risk of anastomosis site leakage in metastatic colorectal cancer
Authors: Kim Seijong , Shin Jung Kyong , Park Yoonah , Huh Jung Wook , Kim Hee Cheol , Yun Seong Hyeon , Lee Woo Yong , Cho Yong Beom
Published: October 2022

Background

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor and is used in combination with first-line chemotherapy in the treatment of metastatic colorectal cancer. One of the side effects of bevacizumab is gastrointestinal perforation. This study was designed to identify the effect of bevacizumab in intestinal anastomosis site healing.

Methods

From January 2010 to December 2020, patients diagnosed with stage IV colorectal cancer treated with palliative chemotherapy or chemoradiotherapy followed by radical surgery were retrospectively reviewed. Clinical signs or symptoms and computed tomography were tools used for diagnosing anastomosis site leakage. The patients were divided into two groups, the bevacizumab group (n = 136) and the non-bevacizumab group (n = 124).

Results

Among the 260 patients 14 (5.4%) patients were diagnosed with anastomosis site leakage. In the bevacizumab group, 13 (9.6%) patients were diagnosed with anastomotic leakage. In the non-bevacizumab group, 1 (0.8%) patient was diagnosed with anastomotic leakage. Anastomosis site leakage was significantly higher in the bevacizumab treatment group (P < 0.001). In the bevacizumab group, period of drug discontinuation before surgery was factor associated with anastomosis site leakage in multivariable analysis (P = 0.031).

Conclusion

Stage IV colorectal patients treated with bevacizumab before radical surgery for primary cancer should be carefully observed of anastomosis site leakage after surgery, and the period of drug discontinuation before surgery should be longer than 5 weeks to avoid anastomosis site leakage.
Neoadjuvant immunotherapy combined with chemotherapy significantly improved patients’ overall survival when compared with neoadjuvant chemotherapy in non-small cell lung cancer: A cohort study
Authors: Dai Fuqiang , Wu Xiaoli , Wang Xintian , Li Kunkun , Wang Yingjian , Shen Cheng , Zhou Jinghai , Niu Huijun , Deng Bo , Tan Qunyou , Wang Ruwen , Guo Wei
Published: October 2022

Background

Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors displayed considerable advantages in neoadjuvant therapy of non-small cell lung cancer (NSCLC), but the specific application of neoadjuvant immunotherapy has not been well determined, and the long-term prognostic data of neoadjuvant immunochemotherapy combined with surgical resection of NSCLC remains limited. In this study, we intended to assess the efficacy of the neoadjuvant therapy of the PD-1 inhibitor and long-term prognosis in patients with resectable NSCLC.

Methods

We retrospectively analyzed NSCLC surgical patients treated with neoadjuvant therapy in our hospital, and divided them into a neoadjuvant chemotherapy group and a neoadjuvant immunotherapy combined with chemotherapy group. The propensity score matching method was used to evaluate the effectiveness of immunotherapy combined with chemotherapy in the treatment of resectable lung cancer, and the long-term prognosis of these two groups was compared.

Results

A total of 62 cases were enrolled, including 20 patients (20/62, 32.26%) in the immunotherapy group and 42 patients (42/62, 67.74%) in the chemotherapy group. The clinical baseline data of these two groups were balanced. In the immunotherapy group, all patients had tumor regression in imaging finding (tumor regression ratio: 11.88% - 75.00%). In the chemotherapy group, 30 patients had tumor regression (tumor regression ratio: 2.70% - 58.97%). The R0 removal rates of cancers were comparable between the immunotherapy group and chemotherapy group (19/20, 95.00% vs. 39/42, 92.86%, P=1.000). The two groups were balanced in complete minimally invasive surgery, pneumonectomy, operative duration, blood loss, postoperative complications, and hospital stay. The immunotherapy group had more sleeve resection (36.84% vs. 10.26%, p=0.039) including bronchial sleeve and vascular sleeve, higher pathological complete response (pCR) rate (57.89% vs. 5.13%, P<0.001) and major pathologic response (MPR) rate (78.95% vs. 10.26%, P<0.001). There were no differences in survival curves for: smoker and non-smoker, squamous cell carcinoma and adenocarcinoma, or right lung cancer and left lung cancer. Moreover, patients who achieved MPR (including pCR) had significantly better overall survival (OS) and disease-free survival (DFS). Patients in immunotherapy group had significantly better OS and longer DFS than those in chemotherapy group.

Conclusions

In conclusion, neoadjuvant immunotherapy combined with chemotherapy can provide better OS and DFS and improving pCR and MPR rates by shrinking tumors.

This study has been registered in the Chinese Clinical Trial Registry, number ChiCTR2200060433. http://www.chictr.org.cn/edit.aspx?pid=170157&htm=4.
Expression of basement membrane genes and their prognostic significance in clear cell renal cell carcinoma patients
Authors: Tao Junyue , Li Xiao , Liang Chaozhao , Liu Yi , Zhou Jun
Published: October 2022

Background

Clear cell renal cell carcinoma (ccRCC) is a malignant tumor with limited treatment options. A recent study confirmed the involvement of basement membrane (BM) genes in the progression of many cancers. Therefore, we studied the role and prognostic significance of BM genes in ccRCC.

Methods

Co-expression analysis of ccRCC-related information deposited in The Cancer Genome Atlas database and a BM geneset from a recent study was conducted. The differentially expressed BM genes were validated using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Least absolute shrinkage and selection operator regression and univariate Cox regression analyses were performed to identify a BM gene signature with prognostic significance for ccRCC. Multivariate Cox regression, time-dependent receiver operating characteristic, Kaplan–Meier, and nomogram analyses were implemented to appraise the prognostic ability of the signature and the findings were further verified using a Gene Expression Omnibus dataset. Additionally, immune cell infiltration and and pathway enrichment analyses were performed using ImmuCellAI and Gene Set Enrichment Analysis (GSEA), respectively. Finally, the DSIGDB dataset was used to screen small-molecule therapeutic drugs that may be useful in treating ccRCC patients.

Results

We identified 108 BM genes exhibiting different expression levels compared to that in normal kidney tissues, among which 32 genes had prognostic values. The qRT-PCR analyses confirmed that the expression patterns of four of the ten selected genes were the same as the predicted ones. Additionally, we successfully established and validated a ccRCC patient prediction model based on 16 BM genes and observed that the model function is an independent predictor. GSEA revealed that differentially expressed BM genes mainly displayed significant enrichment of tumor and metabolic signaling cascades. The BM gene signature was also associated with immune cell infiltration and checkpoints. Eight small-molecule drugs may have therapeutic effects on ccRCC patients.

Conclusion

This study explored the function of BM genes in ccRCC for the first time. Reliable prognostic biomarkers that affect the survival of ccRCC patients were determined, and a BM gene-based prognostic model was established.
The clinical outcomes of extended resections in patients with IV stage gallbladder cancers: A retrospective study from a large tertiary center
Authors: Zhang Kecheng , Liu Hu , Zhao Yongyang , Zhang Baohua
Published: October 2022

Background and aim

The role of extended resections in patients with clinical stage IV gallbladder cancer (GBC) remains unclear. This study retrospectively analyzed the clinical outcomes of patients who underwent extended resections for IV GBC.

Methods

Patients who were diagnosed with IV stage GBCs and underwent extended resections in Eastern Hepatobiliary Surgery Hospital, Shanghai, China, were retrospectively included in our study. Extended resection was defined as a major hepatectomy (resection of ≥3 liver segments), a pancreatoduodenectomy, or both. The clinical outcomes (baseline characteristics, preoperative variables, intraoperative variables, pathological outcomes, and follow-up data) were obtained and analyzed. The factors associated with major postoperative complications and long-term survival were analyzed by logistic regression analyses.

Results

From January 2011 to June 2017, 74 patients were included in our study. There were 33 (44.6%) males and the median age was 62.5 years (interquartile range [IQR], 56.0-67.0 years). According to pathological specimens, the median tumor size was 7cm (IQR, 6-8cm), 73(98.6%) of them received R0 resection and 72 (97.2%) of them were IV A stage GBC. Three perioperative deaths (5.4%) occurred, and major postoperative complications occurred for 15 patients (20.3%). Among them, 61 patients (82.4%) experienced recurrence and 17 patients (23.0%) were still alive after a median follow-up period of 52 months. The disease free survival time was 9 months (95% confidence interval [CI], 7.8-10.2 months) and the overall survival was 18.0 months (95% CI, 15.2-20.8 months). Longer hospital stay days [odds ratio, (OR)=1.979, 95%CI:1.038-1.193, P=0.003), initial symptoms with abdominal pain (OR=21.489, 95%CI=1.22-37.57, P=0.036), more blood transfusion volume during hospitalization (OR=1.036, 95%CI:1.021-1.058, P=0.005), and intraoperative hemorrhage (OR=18.56, 95%C:3.54-47.65, P=0.001) were independently associated with postoperative complications. Moreover, locally recurrence (OR=1.65, 95%CI:1.17-1.96, P=0.015), and more adjuvant chemotherapy cycles (OR=1.46, 95%CI:1.13-1.76, P=0.026) were independently associated with long-term survival.

Conclusion

Our retrospective study identified that extended resections can be safely and efficaciously performed on stage IV GBC patients in selected cases and performed by experienced surgeons.
Combining metformin with lactate transport inhibitors as a treatment modality for cancer - recommendation proposal
Authors: Benjamin Don , Hall Michael N.
Published: October 2022

Highly glycolytic cancer cells excrete lactate to maintain cellular homeostasis. Inhibiting lactate export by pharmacological targeting of plasma membrane lactate transporters is being pursued as an anti-cancer therapy. Work from many laboratories show that the simultaneous inhibition of lactate export and mitochondrial respiration elicits strong synthetic lethality. The mitochondrial inhibitor, metformin, has been the subject of numerous clinical trials as an anti-cancer agent. We propose that, in future clinical trials, metformin be combined with lactate transport inhibitors to exploit this synergistic interaction.
Determination of a DNA repair-related gene signature with potential implications for prognosis and therapeutic response in pancreatic adenocarcinoma
Authors: Lai Jinzhi , Chen Weijie , Zhao Aiyue , Huang Jingshan
Published: October 2022

Background

Pancreatic adenocarcinoma (PAAD) is one of the leading causes of cancer death worldwide. Alterations in DNA repair-related genes (DRGs) are observed in a variety of cancers and have been shown to affect the development and treatment of cancers. The aim of this study was to develop a DRG-related signature for predicting prognosis and therapeutic response in PAAD.

Methods

We constructed a DRG signature using least absolute shrinkage and selection operator (LASSO) Cox regression analysis in the TCGA training set. GEO datasets were used as the validation set. A predictive nomogram was constructed based on multivariate Cox regression. Calibration curve and decision curve analysis (DCA) were applied to validate the performance of the nomogram. The CIBERSORT and ssGSEA algorithms were utilized to explore the relationship between the prognostic signature and immune cell infiltration. The pRRophetic algorithm was used to estimate sensitivity to chemotherapeutic agents. The CellMiner database and PAAD cell lines were used to investigate the relationship between DRG expression and therapeutic response.

Results

We developed a DRG signature consisting of three DRGs (RECQL, POLQ, and RAD17) that can predict prognosis in PAAD patients. A prognostic nomogram combining the risk score and clinical factors was developed for prognostic prediction. The DCA curve and the calibration curve demonstrated that the nomogram has a higher net benefit than the risk score and TNM staging system. Immune infiltration analysis demonstrated that the risk score was positively correlated with the proportions of activated NK cells and monocytes. Drug sensitivity analysis indicated that the signature has potential predictive value for chemotherapy. Analyses utilizing the CellMiner database showed that RAD17 expression is correlated with oxaliplatin. The dynamic changes in three DRGs in response to oxaliplatin were examined by RT-qPCR, and the results show that RAD17 is upregulated in response to oxaliplatin in PAAD cell lines.

Conclusion

We constructed and validated a novel DRG signature for prediction of the prognosis and drug sensitivity of patients with PAAD. Our study provides a theoretical basis for further unraveling the molecular pathogenesis of PAAD and helps clinicians tailor systemic therapies within the framework of individualized treatment.
A domain knowledge enhanced yield based deep learning classifier identifies perineural invasion in oral cavity squamous cell carcinoma
Authors: Lee Li-Yu , Yang Cheng-Han , Lin Yu-Chieh , Hsieh Yu-Han , Chen Yung-An , Chang Margaret Dah-Tsyr , Lin Yen-Yin , Liao Chun-Ta
Published: October 2022

Background

Perineural invasion (PNI), a form of local invasion defined as the ability of cancer cells to invade in, around, and through nerves, has a negative prognostic impact in oral cavity squamous cell carcinoma (OCSCC). Unfortunately, the diagnosis of PNI suffers from a significant degree of intra- and interobserver variability. The aim of this pilot study was to develop a deep learning-based human-enhanced tool, termed domain knowledge enhanced yield (Domain-KEY) algorithm, for identifying PNI in digital slides.

Methods

Hematoxylin and eosin (H&E)-stained whole-slide images (WSIs, n = 85) were obtained from 80 patients with OCSCC. The model structure consisted of two parts to simulate human decision-making skills in diagnostic pathology. To this aim, two semantic segmentation models were constructed (i.e., identification of nerve fibers followed by the diagnosis of PNI). The inferred results were subsequently subjected to post-processing of generated decision rules for diagnostic labeling. Ten H&E-stained WSIs not previously used in the study were read and labeled by the Domain-KEY algorithm. Thereafter, labeling correctness was visually inspected by two independent pathologists.

Results

The Domain-KEY algorithm was found to outperform the ResnetV2_50 classifier for the detection of PNI (diagnostic accuracy: 89.01% and 61.94%, respectively). On analyzing WSIs, the algorithm achieved a mean diagnostic accuracy as high as 97.50% versus traditional pathology. The observed accuracy in a validation dataset of 25 WSIs obtained from seven patients with oropharyngeal (cancer of the tongue base, n = 1; tonsil cancer, n = 1; soft palate cancer, n = 1) and hypopharyngeal (cancer of posterior wall, n = 2; pyriform sinus cancer, n = 2) malignancies was 96%. Notably, the algorithm was successfully applied in the analysis of WSIs to shorten the time required to reach a diagnosis. The addition of the hybrid intelligence model decreased the mean time required to reach a diagnosis by 15.0% and 23.7% for the first and second pathologists, respectively. On analyzing digital slides, the tool was effective in supporting human diagnostic thinking.

Conclusions

The Domain-KEY algorithm successfully mimicked human decision-making skills and supported expert pathologists in the routine diagnosis of PNI.
Contrastive learning–guided multi-meta attention network for breast ultrasound video diagnosis
Authors: Huang Xiaoyang , Lin Zhi , Huang Shaohui , Wang Fu Lee , Chan Moon-Tong , Wang Liansheng
Published: October 2022

Breast cancer is the most common cause of cancer death in women. Early screening and treatment can effectively improve the success rate of treatment. Ultrasound imaging technology, as the preferred modality for breast cancer screening, provides an essential reference for early diagnosis. Existing computer-aided ultrasound imaging diagnostic techniques mainly rely on the selected key frames for breast cancer lesion diagnosis. In this paper, we first collected and annotated a dataset of ultrasound video sequences of 268 cases of breast lesions. Moreover, we propose a contrastive learning–guided multi-meta attention network (CLMAN) by combining a deformed feature extraction module and a multi-meta attention module to address breast lesion diagnosis in ultrasound sequence. The proposed feature extraction module can autonomously acquire key information of the feature map in the spatial dimension, whereas the designed multi-meta attention module is dedicated to effective information aggregation in the temporal dimension. In addition, we utilize a contrast learning strategy to alleviate the problem of high imaging variability within ultrasound lesion videos. The experimental results on our collected dataset show that our CLMAN significantly outperforms existing advanced methods for video classification.
Awareness of prostate cancer and its associated factors among men 40 years of age and older in Mizan Aman town, Bench Sheko zone, Southern Nations, Nationalities, and Peoples’ Region, South West Ethiopia, 2019
Authors: Assefa Ashenafi , Germossa Gugsa Nemera , Ayenew Mengistu , Bedada Gadisa Bekele
Published: October 2022

Background

Prostate cancer is a common cause of morbidity and mortality among men aged 40 years and older. Evidence has shown that awareness of prostate cancer plays a greater role in the early detection of prostate cancer. However, there is a paucity of information regarding prostate cancer awareness levels in Ethiopia in general and in Mizan Aman town in particular.

Objectives

To assess the awareness of prostate cancer and its associated factors among men aged 40 years and older in Mizan Aman, Bench Sheko zone, Southern Nations, Nationalities, and Peoples’ Region, South West Ethiopia, 2019.

Methods

A community-based cross-sectional study was conducted from 1 to 30 April 2021 in Mizan Aman town. A total of 322 study subjects were selected from a total population of 1,242 in Mizan Aman town by using the simple random sampling method. Data were collected through a face-to-face interview using a structured questionnaire. Data were entered into EpiData version 3.1 and analyzed by Statistical Package for Social Science version 20. Descriptive statistics were used to summarize sociodemographic characteristics and personal history. Bivariate and multivariate regression analyses were used to explore further variables that were associated with the level of awareness. Significant associations were declared at a p-value of <0.05. The results were presented in text, tables, and charts.

Results

The magnitude of prostate cancer awareness was 64%. Participants who were between 40 and 55 years of age (adjusted odd ratio = 6.16, 95% confidence interval = 2.62–14.47), who were government employees (adjusted odd ratio = 4.684, 95% confidence interval = 1.56–13.97), and whose monthly income level is greater than 5,000 birr (adjusted odd ratio = 12.45, 95% confidence interval = 3.2–47.77) were significantly associated with the level of awareness.

Conclusion and recommendation

This study revealed that more than half of the men residing in Mizan Aman town had a high level of prostate cancer awareness. First-category age, better economic status, and employment were significantly associated with awareness of prostate cancer. This indicates the need for a collective effort to enhance the awareness of men regarding prostate cancer.
The effect of a video tutorial to improve patients’ keratoconus knowledge – a randomized controlled trial and meta-analysis of published reports
Authors: Sommer Chiara , Bachmann Lucas M. , Handzic Armin , Iselin Katja C. , Sanak Frantisek , Pfaeffli Oliver , Kaufmann Claude , Thiel Michael A. , Baenninger Philipp B.
Published: October 2022

Objective

To investigate whether a video tutorial, highlighting important aspects of keratoconus provided prior to a scheduled follow-up consultation, has a specific effect on patients’ knowledge after the consultation.

Methods and Analysis

Single center, randomized controlled trial registered on ISRCTN registry (number ISCTN75317089, https://doi.org/10.1186/ISRCTN75317089). Consenting eligible keratoconus patients were randomly assigned to either receive a conventional face-to-face consultation (control group) or to an additional video tutorial (interventional group) on definition, risk factors and treatment options provided prior to the consultation. The main outcome measure was the difference of knowledge assessed by a questionnaire after the consultation. Of each participant, clinical characteristics, highest educational level and medical background were obtained. We also performed a meta-analysis of published reports assessing knowledge improvement by video-based patient education.

Results

We assigned 22 patients to the interventional and 21 patients to the control group. Mean age was 29.0 years (SD 11.6), 8/43 (18.6%) were female and median disease duration was 2.5 years (interquartile range: 2-5years). Compared to the control group, knowledge was 12.0% (95%CI: 5.8%-18.2%; p<0.001) higher in the interventional group. Subjects with a university degree scored 6.8% (95%CI: 3.8%-13.3%; p=0.038) higher. There was no interaction between video information and university degree. Other parameters were not associated with patient knowledge. The meta-analysis of 566 subjects enrolled in 6 studies revealed a standardized mean difference in favor of video-based education of 0.47 (95% CI: 0.30-0.64; p<0.004)

Conclusion

The results suggest that supplementary video information embedded in the clinical management of keratoconus, helps conveying relevant disease knowledge.
Chaigui granule exerts anti-depressant effects by regulating the synthesis of Estradiol and the downstream of CYP19A1-E2-ERKs signaling pathway in CUMS-induced depressed rats
Authors: Tian Jun-sheng , Qin Peng-fei , Xu Teng , Gao Yao , Zhou Yu-zhi , Gao Xiao-xia , Qin Xue-mei , Ren Yan
Published: October 2022

Background: There is a significant gender difference in the prevalence of depression. Recent studies have shown that estrogen plays a crucial role in depression. Therefore, studying the specific mechanism of estrogen’s role in depression can provide new ideas to address the treatment of depression. Chaigui granule has been shown to have exact antidepressant efficacy, and the contents of saikosaponin (a, b1, b2, d) and paeoniflorin in Chaigui granule are about 0.737% and 0.641%, respectively. Some studies have found that they can improve depression-induced decrease in testosterone (T) levels (∼36.99% decrease compared to control). However, whether Chaigui granule can exert antidepressant efficacy by regulating estrogen is still unclear. This study aimed to elucidate the regulation of estrogen levels by Chaigui granule and the underlying mechanism of its anti-depressant effect.

Methods: Eighty-four male Sprague-Dawley (SD) rats were modeled using a chronic unpredictable mild stress (CUMS) procedure. The administration method was traditional oral gavage administration, and behavioral indicators were used to evaluate the anti-depressant effect of Chaigui granule. Enzyme-linked immunosorbent assay (ELISA) was adopted to assess the modulating impact of Chaigui granule on sex hormones. Then, reverse transcription-quantitative PCR (RT-qPCR), and Western blot (WB) techniques were employed to detect extracellular regulated protein kinases (ERK) signaling-related molecules downstream of estradiol in the hippocampus tissue.

Results: The administration of Chaigui granule significantly alleviated the desperate behavior of CUMS-induced depressed rats. According to the results, we found that Chaigui granule could upregulate the level of estradiol (E2) in the serum (∼46.56% increase compared to model) and hippocampus (∼26.03% increase compared to model) of CUMS rats and increase the levels of CYP19A1 gene and protein, which was the key enzyme regulating the synthesis of T into E2 in the hippocampus. Chaigui granule was also found to have a significant back-regulatory effect on the gene and protein levels of ERβ, ERK1, and ERK2.

Conclusion: Chaigui granule can increase the synthesis of E2 in the hippocampus of CUMS-induced depressed rats and further exert antidepressant effects by activating the CYP19A1-E2-ERKs signaling pathway.
Integrated network pharmacology and metabolomics to reveal the mechanism of QiShenYiQi Dripping Pills against cardiac structural and functional abnormalities
Authors: Zhang Jun , Yang Zunyuan , Jia Xue , Li Xinxin , Wang Xiangyang , Rong Hua , Liang Yinan , Zeng Wen , Jia Wei , Ma Xiaohui
Published: October 2022

Background: Heart failure (HF), the final stage of cardiovascular diseases, is a clinical syndrome of cardiac structural or functional abnormalities. QiShenYiQi Dripping Pills, short for QSYQ, showed effectiveness and safety in the treatment of HF according to modern pharmacological research and clinical studies, but the mechanism remains unclear. This study aims to clarify the mechanism of QSYQ in treating heart failure through the analysis to critical biomarkers, targets and pathways.

Materials and Methods: In this study, the efficacies of QSYQ in non-human primates and rodents were evaluated, and the mechanism was demonstrated by integrating network pharmacology and metabolomics analysis. Furthermore, the targets from network pharmacology and the metabolites from targeted metabolomics were jointly analyzed to screen the critical pathways.

Results: In rhesus monkeys with spontaneous chronic heart failure, nasogastric administration of QSYQ for 12 weeks caused profound improvement of systolic and diastolic function as evidenced by echocardiography detection. Consistently, QSYQ administration especially with higher dose lowered the blood pressure and improved the ventricular remodeling, collagen deposition and fibrosis markedly in Spontaneous Hypertension Rats (SHR) model. Computational prediction showed that QSYQ exhibited anti-HF effects possibly through HIF-1 signaling pathway, FoxO signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway and other enriched paths. Metabolomics analysis obtained 23 significantly altered metabolites, revealing that QSYQ significantly regulated the abnormal levels of fatty acids, carnitines, organic acids pyridines, nucleosides, which were mostly involved in myocardial energy metabolism related pathways.

Conclusion: Based on serum and myocardium metabolomics and network pharmacology, the present study revealed that the actions of QSYQ in treating HF depend on multi-components, multi-targets and multi-pathways.
Potential cardiotoxicity induced by Euodiae Fructus: In vivo and in vitro experiments and untargeted metabolomics research
Authors: Zhang Dan , Lü Jintao , Ren Zhixin , Zhang Xiaomeng , Wu Huanzhang , Sa Rina , Wang Xiaofang , Wang Yu , Lin Zhijian , Zhang Bing
Published: October 2022

Background:Euodiae Fructus, a well-known herbal medicine, is widely used in Asia and has also gained in popularity in Western countries over the last decades. It has known side effects, which have been observed in clinical settings, but few studies have reported on its cardiotoxicity.

Methods:In the present study, experiments using techniques of untargeted metabolomics clarify the hazardous effects of Euodiae Fructus on cardiac function and metabolism in rats in situations of overdosage and unsuitable syndrome differentiation.In vitroassays are conducted to observe the toxic effects of evodiamine and rutaecarpine, two main chemical constituents of Euodiae Fructus, in H9c2 and neonatal rat cardiomyocytes (NRCMs), with their signaling mechanisms analyzed accordingly.

Results:The cardiac cytotoxicity of evodiamine and rutaecarpine inin vivoexperiments is associated with remarkable alterations in lactate dehydrogenase, creatine kinase, and mitochondrial membrane potential; also with increased intensity of calcium fluorescence, decreased protein expression of the cGMP-PKG pathway in H9c2 cells, and frequency of spontaneous beat in NRCMs. Additionally, the results in rats with Yin deficiency receiving a high-dosage of Euodiae Fructus suggest obvious cardiac physiological dysfunction, abnormal electrocardiogram, pathological injuries, and decreased expression of PKG protein. At the level of endogenous metabolites, the cardiac side effects of overdose and irrational usage of Euodiae Fructus relate to 34 differential metabolites and 10 metabolic pathways involving among others, the purine metabolism, the glycerophospholipid metabolism, the glycerolipid metabolism, and the sphingolipid metabolism.

Conclusion:These findings shed new light on the cardiotoxicity induced by Euodiae Fructus, which might be associated with overdose and unsuitable syndrome differentiation, that comes from modulating the cGMP-PKG pathway and disturbing the metabolic pathways of purine, lipid, and amino acid. Continuing research is needed to ensure pharmacovigilance for the safe administration of Chinese herbs in the future.
Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes
Authors: Wang Xiaokang , Rao Jiaoyu , Tan Zhiyi , Xun Tianrong , Zhao Jingqian , Yang Xixiao
Published: October 2022

Cytochrome P450 (CYP450) enzymes are membrane-bound blood proteins that are vital to drug detoxification, cell metabolism, and homeostasis. CYP450s belonging to CYP families 1–3 are responsible for nearly 80% of oxidative metabolism and complete elimination of approximately 50% of all common clinical drugs in humans liver hepatocytes. CYP450s can affect the body’s response to drugs by altering the reaction, safety, bioavailability, and toxicity. They can also regulate metabolic organs and the body’s local action sites to produce drug resistance through altered drug metabolism. Genetic polymorphisms in the CYP gene alone do not explain ethnic and individual differences in drug efficacy in the context of complex diseases. The purpose of this review is to summarize the impact of new inflammatory-response signaling pathways on the activity and expression of CYP drug-metabolizing enzymes. Included is a summary of recent studies that have identified drugs with the potential to regulate drug-metabolizing enzyme activity. Our goal is to inspire the development of clinical drug treatment processes that consider the impact of the inflammatory environment on drug treatment, as well as provide research targets for those studying drug metabolism.
Impact of Ninjin’yoeito on frailty and short life in klotho-hypomorphic (kl/kl) mice
Authors: Amitani Haruka , Chiba Shigeki , Amitani Marie , Michihara Seiwa , Takemoto Risa , Han Likun , Fujita Nina , Takahashi Ryuji , Inui Akio
Published: October 2022

With the recent aging of society, the prevention of frailty has become an important issue because people desire both a long and healthy lifespan. Klotho-hypomorphic (kl/kl) mice are known to show phenotypes of premature aging. Ninjin’yoeito (NYT) is a traditional Japanese Kampo medicine used to treat patients with vulnerable constitution, fatigue or physical exhaustion caused by aging and illness. Recent studies have reported the potential efficacy of NYT against frailty. We therefore evaluated the effect of NYT on the gait function, activity, the histopathological status of organs and survival using kl/kl mice as a model of aging-related frailty. Two sets of 28-day-old male kl/kl mice were assigned to the vehicle (non-treated; NT), 3% or 5% NYT dietary groups. One set of groups (NT, n = 18; 3% NYT, n = 11; 5% NYT, n = 11) was subjected to the analysis of free walking, rotarod, and spontaneous activity tests at approximately 58 days old. Thereafter, we measured triceps surae muscles weight and myofiber cross-sectional area (CSA), and quantified its telomere content. In addition, we evaluated bone strength and performed histopathological examinations of organs. Survival was measured in the second set of groups (NT, 3% NYT and 5% NYT group, n = 8 each). In the walking test, several indicators such as gait velocity were improved in the NYT 3% group. Similar results were obtained for the latency to fall in the rotarod test and spontaneous motor activity. Triceps muscle mass, CSA and its telomere content were significantly improved in the NYT 3% group. Bone density, pulmonary alveolus destruction and testicular atrophy were also significantly improved in the NYT 3% group. Survival rate and body weight were both significantly improved in the NYT3% group compared with those in the NT group. Continuous administration of NYT from the early stage of aging improved not only gait performance, but also the survival in the aging-related frailty model. This effect may be associated with the improvements in aging-related organ changes such as muscle atrophy. Intervention with NYT against the progression of frailty may contribute to a longer, healthier life span among the elderly individuals.
A new non-entangled quantum secret sharing protocol among different nodes in further quantum networks
Authors: Fu Si-Jia , Zhang Ke-Jia , Zhang Long , Hou Kun-Chi
Published: October 2022

As an important branch of quantum secure multi-party computation, quantum secret sharing (QSS) can distribute secret information among dishonest network nodes without revealing the secrets. In this study, a new four-party QSS protocol based on locally indistinguishable orthogonal product (LIOP) states is first proposed for quantum network communication. Then, the general multiparty QSS model based on LIOP states will be expanded. Combined with the property of LIOP states and obfuscating operation, the source node can send the secrets to different destination nodes in the quantum network. Accordingly, it is proven that the destination nodes have to work together to recover the shared secrets against some existing attacks. Furthermore, no entangled resources and complicated operations are required in the presented protocol. We hope the results could make positive effects to the development of quantum secure communication in the future.
Alterations in hepatic mitotic and cell cycle transcriptional networks during the metabolic switch in broiler chicks
Authors: Hicks Julie A. , Pike Brandon E. , Liu Hsiao-Ching
Published: October 2022

During embryonic life, chicks mainly derive energy from hepatic oxidation of yolk lipids. After hatch, chicks must rely on carbohydrate-rich feed to obtain energy. This requires an abrupt and intensive switch of metabolic processes, particularly in the liver. We recently identified a number of transcriptional and post-transcriptional regulatory networks that work concordantly to tune metabolic processes during the metabolic switch. Here, we used delayed feeding post-hatch (48 h) to impede the metabolic switch in broilers. We used RNA-seq to identify hepatic transcriptome differences between late stage embryos (E18) and two-day-old chicks (D2), which were either fed-from-hatch (FED) or not fed (DLY). Between FED and E18, 2,430 genes were differentially expressed (fold-change≥ 2; FDR p-value 0.05), of these 1,237 were downregulated in FED birds and 1,193 were upregulated. Between DLY and E18, 1979 genes were differentially expressed, of these 1,043 were downregulated and 936 were upregulated in DLY birds. Between DLY and FED, 880 genes were differentially expressed, of these 543 were downregulated and 337 were upregulated in DLY birds. We found that in addition to disturbances in a number of metabolic pathways, unfed chicks had a widespread suppression of gene networks associated with cell proliferation, cell cycle progression and mitosis. Expression patterns suggest that hepatocytes of delayed-fed birds have abnormal mitosis and increased polyploidization. This suggests that post-hatch feed consumption maintains the rate and integrity of liver growth immediately, which in turn, likely helps facilitate the appropriate programming of hepatic metabolic networks.
Premature atrial contractions: A predictor of atrial fibrillation and a relevant marker of atrial cardiomyopathy
Authors: Guichard Jean-Baptiste , Guasch Eduard , Roche Frederic , Da Costa Antoine , Mont Lluís
Published: October 2022

An increased burden of premature atrial contractions (PACs) has long been considered a benign phenomenon. However, strong evidence of their involvement in the occurrence of atrial fibrillation (AF), ischemic stroke, and excess mortality suggests the need for management. The central question to be resolved is whether increased ectopic atrial rhythm is only a predictor of AF or whether it is a marker of atrial cardiomyopathy and therefore of ischemic stroke. After reviewing the pathophysiology of PACs and its impact on patient prognosis, this mini-review proposes to 1) detail the physiological and clinical elements linking PACs and AF, 2) present the evidence in favor of supraventricular ectopic activity as a marker of cardiomyopathy, and 3) outline the current limitations of this concept and the potential future clinical implications.
Rice iron storage protein ferritin 2 (OsFER2) positively regulates ferroptotic cell death and defense responses against Magnaporthe oryzae
Authors: Nguyen Nam Khoa , Wang Juan , Liu Dongping , Hwang Byung Kook , Jwa Nam-Soo
Published: October 2022

Ferritin is a ubiquitous iron storage protein that regulates iron homeostasis and oxidative stress in plants. Iron plays an important role in ferroptotic cell death response of rice (Oryza sativa) to Magnaporthe oryzae infection. Here, we report that rice ferritin 2, OsFER2, is required for iron- and reactive oxygen species (ROS)-dependent ferroptotic cell death and defense response against the avirulent M. oryzae INA168. The full-length ferritin OsFER2 and its transit peptide were localized to the chloroplast, the most Fe-rich organelle for photosynthesis. This suggests that the transit peptide acts as a signal peptide for the rice ferritin OsFER2 to move into chloroplasts. OsFER2 expression is involved in rice resistance to M. oryzae infection. OsFER2 knock-out in wild-type rice HY did not induce ROS and ferric ion (Fe3+) accumulation, lipid peroxidation and hypersensitive response (HR) cell death, and also downregulated the defense-related genes OsPAL1, OsPR1-b, OsRbohB, OsNADP-ME2-3, OsMEK2 and OsMPK1, and vacuolar membrane transporter OsVIT2 expression. OsFER2 complementation in ΔOsfer2 knock-out mutants restored ROS and iron accumulation and HR cell death phenotypes during infection. The iron chelator deferoxamine, the lipid-ROS scavenger ferrostatin-1, the actin microfilament polymerization inhibitor cytochalasin E and the redox inhibitor diphenyleneiodonium suppressed ROS and iron accumulation and HR cell death in rice leaf sheaths. However, the small-molecule inducer erastin did not trigger iron-dependent ROS accumulation and HR cell death induction in ΔOsfer2 mutants. These combined results suggest that OsFER2 expression positively regulates iron- and ROS-dependent ferroptotic cell death and defense response in rice–M. oryzae interactions.
Fluopyram activates systemic resistance in soybean
Authors: Rocha Leonardo F. , Subedi Arjun , Pimentel Mirian F. , Bond Jason P. , Fakhoury Ahmad M.
Published: October 2022

The soybean cyst nematode (SCN) (Heterodera glycines Ichinohe) is a significant yield-limiting factor in soybean production in the Midwestern US. Several management practices are implemented to mitigate yield losses caused by SCN, including using SDHI (succinate dehydrogenase inhibitors) fungicides delivered as seed treatments. A set of studies was conducted to evaluate the effect of two seed-applied succinate dehydrogenase inhibitors (SDHI) compounds, fluopyram and pydiflumetofen, on SCN population densities, plant injury, and plant growth. Cyst counts in untreated control and pydiflumetofen treated plants were 3.44 and 3.59 times higher than fluopyram, respectively, while egg counts were 8.25 and 7.06 times higher in control and pydiflumetofen. Next-generation sequencing was later employed to identify transcriptomic shifts in gene expression profiles in fluopyram and pydiflumetofen -treated seedlings. RNA expression patterns of seed treatments clustered by sampling time (5 DAP vs. 10 DAP); therefore, downstream analysis was conducted by timepoint. At 5 DAP, 10,870 and 325 differentially expressed genes (DEG) were identified in fluopyram and pydiflumetofen, respectively. These same treatments generated 219 and 2 DEGs at 10 DAP. Multiple DEGs identified in soybean seedlings treated with fluopyram are linked to systemic resistance, suggesting a potential role of systemic resistance in the suppression of SCN by fluopyram, in addition to the known nematicidal activity. The non-target inhibition of soybean succinate dehydrogenase genes by fluopyram may be the origin of the phytotoxicity symptoms observed and potentially the source of the systemic resistance activation reported in the current study. This work helps to elucidate the mechanisms of suppression of SCN by fluopyram.