bluuebunny/crossref_metadata_2025 huggingface dataset:
Heightened metabolic responses in NK cells from patients with neuroblastoma suggests increased potential for immunotherapy
Authors: Slattery Karen , Breheny Megan , Woods Elena , Keating Sinead , Brennan Kiva , Rooney Caroline , Augustine Sindhu , Ryan Aishling , Owens Cormac , Gardiner Clair M.
Published: October 2022

High risk neuroblastoma is responsible for 15% of deaths in pediatric cancer patients. The introduction of anti-GD2 immunotherapy has significantly improved outcomes but there is still only approximately a 50% 5 year event-free-survival for these children and improvements in treatments are urgently required. Anti-GD2 immunotherapy uses the patients’ own immune system to kill cancer cells. In particular, Natural Killer (NK) cells kill antibody coated tumor cells by a process called antibody dependent cellular cytotoxicity (ADCC). However, our previous work has highlighted metabolic exhaustion of NK cells in circulating blood of adult cancer patients, identifying this as a potential therapeutic target. In this study, we investigated circulating NK cells in patients newly diagnosed with neuroblastoma. We found evidence of activation of NK cells in vivo by the cancer itself. While some evidence of NK cell dysfunction was observed in terms of IFNγ production, most results indicated that the NK cell compartment remained relatively intact. In fact, some aspects of metabolic and functional activities were actually increased in patients compared to controls. Glycolytic responses, which we show are crucial for ADCC, were actually enhanced in patients and CD16, the NK cell receptor that mediates ADCC, was also expressed at high levels in some patients. Overall, the data suggest that patient NK cells could be harvested at diagnosis for subsequent beneficial autologous use during immunotherapy. Enhancing glycolytic capacity of cell therapies could also be a strategic goal of future cell therapies for patients with neuroblastoma and indeed other cancers.
Development of a novel autophagy-related gene model for gastric cancer prognostic prediction
Authors: Xu Haifeng , Xu Bing , Hu Jiayu , Xia Jun , Tong Le , Zhang Ping , Yang Lei , Tang Lusheng , Chen Sufeng , Du Jing , Wang Ying , Li Yanchun
Published: October 2022

Gastric cancer (GC) is a major global health issue and one of the leading causes of tumor-associated mortality worldwide. Autophagy is thought to play a critical role in the development and progression of GC, and this process is controlled by a set of conserved regulators termed autophagy-related genes (ATGs). However, the complex contribution of autophagy to cancers is not completely understood. Accordingly, we aimed to develop a prognostic model based on the specific role of ATGs in GC to improve the prediction of GC outcomes. First, we screened 148 differentially expressed ATGs between GC and normal tissues in The Cancer Genome Atlas (TCGA) cohort. Consensus clustering in these ATGs was performed, and based on that, 343 patients were grouped into two clusters. According to Kaplan–Meier survival analysis, cluster C2 had a worse prognosis than cluster C1. Then, a disease risk model incorporating nine differentially expressed ATGs was constructed based on the least absolute shrinkage and selection operator (LASSO) regression analysis, and the ability of this model to stratify patients into high- and low-risk groups was verified. The predictive value of the model was confirmed using both training and validation cohorts. In addition, the results of functional enrichment analysis suggested that GC risk is correlated with immune status. Moreover, autophagy inhibition increased sensitivity to cisplatin and exacerbated reactive oxygen species accumulation in GC cell lines. Collectively, the results indicated that this novel constructed risk model is an effective and reliable tool for predicting GC outcomes and could help with individual treatment through ATG targeting.
Circulating plasma exosomal long non-coding RNAs LINC00265, LINC00467, UCA1, and SNHG1 as biomarkers for diagnosis and treatment monitoring of acute myeloid leukemia
Authors: Xiao Qiaoling , Lin Can , Peng Meixi , Ren Jun , Jing Yipei , Lei Li , Tao Yonghong , Huang Junpeng , Yang Jing , Sun Minghui , Wu Jing , Yang Zailin , Yang Zesong , Zhang Ling
Published: October 2022

Exosomal long non-coding RNAs (lncRNAs) have emerged as a cell-free biomarker for clinical evaluation of cancers. However, the potential clinical applications of exosomal lncRNAs in acute myeloid leukemia (AML) remain unclear. Herein, we attempted to identify plasma exosomal lncRNAs as prospective biomarkers for AML. In this study, plasma exosomes were first successfully extracted from AML patients and healthy donors (HD). Subsequently, the downregulated plasma exosomal lncRNAs (LINC00265, LINC00467, and UCA1) and the upregulated plasma exosomal lncRNA (SNHG1) were identified in AML patients (n=65) compared to HD (n=20). Notably, individual exosomal LINC00265, LINC00467, UCA1, or SNHG1 had a capability for discriminating AML patients from HD, and their combination displayed better efficiency. Furthermore, exosomal LINC00265 and LINC00467 were increased expressed in patients achieving complete remission after chemotherapy. Importantly, there was upregulation of exosomal LINC00265 and downregulation of exosomal SNHG1 upon allogeneic hematopoietic stem cell transplantation. Additionally, these lncRNAs were high stability in plasma exosomes. Exosomal LINC00265, LINC00467, UCA1, and SNHG1 may act as promising cell-free biomarkers for AML diagnosis and treatment monitoring and provide a new frontier of liquid biopsy for this type of cancer.
A population-based predictive model identifying optimal candidates for primary and metastasis resection in patients with colorectal cancer with liver metastatic
Authors: Jin Xin , Wu Yibin , Feng Yun , Lin Zhenhai , Zhang Ning , Yu Bingran , Mao Anrong , Zhang Ti , Zhu Weiping , Wang Lu
Published: October 2022

Background

The survival benefit of primary and metastatic resection for patients with colorectal cancer with liver metastasis (CRLM) has been observed, but methods for discriminating which individuals would benefit from surgery have been poorly defined. Herein, a predictive model was developed to stratify patients into sub-population based on their response to surgery.

Methods

We assessed the survival benefits for adults diagnosed with colorectal liver metastasis by comparing patients with curative surgery vs. those without surgery. CRLM patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015 were identified for model construction. Other data including CRLM patients from our center were obtained for external validation. Calibration plots, the area under the curve (AUC), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram compared with the tumor–node–metastasis (TNM) classification. The Kaplan–Meier analysis was performed to examine whether this model would distinguish patients who could benefit from surgery.

Results

A total of 1,220 eligible patients were identified, and 881 (72.2%) underwent colorectal and liver resection. Cancer-specific survival (CSS) for the surgery group was significantly better than that for the no-surgery group (41 vs. 14 months, p < 0.001). Five factors were found associated with CSS and adopted to build the nomograms, i.e., age, T stage, N stage, neoadjuvant chemotherapy, and primary tumor position. The AUC of the CRLM nomogram showed a better performance in identifying patients who could obtain benefits in the surgical treatment, compared with TNM classification (training set, 0.826 [95% CI, 0.786–0.866] vs. 0.649 [95% CI, 0.598–0.701]; internal validation set, 0.820 [95% CI, 0.741–0.899] vs. 0.635 [95% CI, 0.539–0.731]; external validation set, 0.763 [95% CI, 0.691–0.836] vs. 0.626 [95% CI, 0.542–0.710]). The calibration curves revealed excellent agreement between the predicted and actual survival outcomes. The DCA showed that the nomogram exhibited more clinical benefits than the TNM staging system. The beneficial and surgery group survived longer significantly than the non-beneficial and surgery group (HR = 0.21, 95% CI, 0.17–0.27, p < 0.001), but no difference was observed between the non-beneficial and surgery and non-surgery groups (HR = 0.89, 95% CI, 0.71–1.13, p = 0.344).

Conclusions

An accurate and easy-to-use CRLM nomogram has been developed and can be applied to identify optimal candidates for the resection of primary and metastatic lesions among CRLM patients.
Deep learning for real-time auxiliary diagnosis of pancreatic cancer in endoscopic ultrasonography
Authors: Tian Guo , Xu Danxia , He Yinghua , Chai Weilu , Deng Zhuang , Cheng Chao , Jin Xinyan , Wei Guyue , Zhao Qiyu , Jiang Tianan
Published: October 2022

In recent year, many deep learning have been playing an important role in the detection of cancers. This study aimed to real-timely differentiate a pancreatic cancer (PC) or a non-pancreatic cancer (NPC) lesion via endoscopic ultrasonography (EUS) image. A total of 1213 EUS images from 157 patients (99 male, 58 female) with pancreatic disease were used for training, validation and test groups. Before model training, regions of interest (ROIs) were manually drawn to mark the PC and NPC lesions using Labelimage software. Yolov5m was used as the algorithm model to automatically distinguish the presence of pancreatic lesion. After training the model based on EUS images using YOLOv5, the parameters achieved convergence within 300 rounds (GIoU Loss: 0.01532, Objectness Loss: 0.01247, precision: 0.713 and recall: 0.825). For the validation group, the mAP0.5 was 0.831, and mAP@.5:.95 was 0.512. In addition, the receiver operating characteristic (ROC) curve analysis showed this model seemed to have a trend of more AUC of 0.85 (0.665 to 0.956) than the area under the curve (AUC) of 0.838 (0.65 to 0.949) generated by physicians using EUS detection without puncture, although pairwise comparison of ROC curves showed that the AUC between the two groups was not significant (z= 0.15, p = 0.8804). This study suggested that the YOLOv5m would generate attractive results and allow for the real-time decision support for distinction of a PC or a NPC lesion.
Association between red blood cell distribution width and mortality in patients with metastatic brain tumors: A retrospective single-center cohort study
Authors: Sim Ji-Hoon , Park Yong-Seok , Ha Seungil , Kim Sung-Hoon , Kim Joung Uk
Published: October 2022

Metastatic brain tumor has been associated with high mortality and poor prognosis. However, information on indicators predicting surgical prognosis in patients with brain metastases is limited. This study aimed to investigate the association between preoperative red blood cell distribution width (RDW) and mortality in patients who underwent surgery for metastatic brain tumors. This study analyzed 282 patients who underwent metastatic brain tumor surgery between August 1999 and March 2020. Patients were divided into two groups based on preoperative RDW cut-off values (<13.2 and ≥13.2). The surgical outcomes were compared between the two groups. Additionally, we performed Cox regression analysis to assess the association between preoperative RDW and 1-year and overall mortality. There were significant differences in 180-day mortality (6.2% vs. 28.7%, P<0.001), 1-year mortality (23.8% vs. 46.7%, P<0.001), and overall mortality (75.0% vs. 87.7%, P=0.012) between the two groups. In the Cox regression analysis, RDW ≥ 13.2 was significantly associated with higher 1-year mortality (adjusted hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.38–3.30; P<0.001) and overall mortality (HR, 1.44; 95% CI, 1.09–1.90; P=0.010). Preoperative RDW is strongly associated with high mortality in metastatic brain tumor surgery.
EPDR1 levels and tumor budding predict and affect the prognosis of bladder carcinoma
Authors: Yang Yue , Xu Hong , Zhu Han , Yuan Dan , Zhang Hanchao , Liu Zhengdao , Zhao Faliang , Liang Guobiao
Published: October 2022

Background

Bladder carcinoma is a common malignancy of the urinary system. The previous study showed that EPDR1 expression was significantly related to the carcinogenesis and progression of bladder carcinoma

Methods

We retrospectively reviewed the records of 621 patients who were newly diagnosed with bladder carcinoma between January 2018 and August 2020 at The Affiliated Hospital of Zunyi Medical University. We conducted immunohistochemistry of EPDR1 in tumor tissues. Meanwhile, tumor budding evaluation was also carried out by 2 independent experienced pathologists.

Results

80 patients were included in this study with a median age of 66 years (range; 42–88 years). 45% of the patients (36/80) were non-muscle-invasive bladder carcinoma patients, while 55% of muscle-invasive bladder carcinoma(44/80). The follow-up time was from 6 months to 36 months. We found that there were significant differences in expression of EPDR1 in the tumor pT stages(p<0.05), pM stages(p<0.05), and pN stages(p<0.05). Meanwhile, a higher expression of EPDR1 indicated a worse outcome for the patient(p<0.05). A tendency toward a worse status of the patient was accompanied by a high positive rate (p<0.001). Moreover, the IOD of EPDR1 had a positive relationship with TB (p<0.05). Furthermore, we found that EPDR1 and tumor budding could be crucial factors for affecting the prognosis of bladder carcinoma, even better than pTMN(Riskscore=(0.724)* pT_stage +(4.960) *EPDR1+(4.312)*TB).

Conclusion

In conclusion, bladder cancer patients with higher expression levels of EPDR1 had worse survival outcomes. The combination of TB and EPDR1 levels could predict the prognosis for muscle-invasive bladder cancer patients.
A multifaceted and feasible prognostic model of amino acid metabolism-related genes in the immune response and tumor microenvironment of head and neck squamous cell carcinomas
Authors: Li Wei , Zou Zhefei , An Ning , Wang Mingwei , Liu Xiguo , Mei Zhidan
Published: October 2022

We investigated the role of amino acid metabolism (AAM) in head and neck squamous cell carcinoma (HNSCC) tissues to explore its prognostic value and potential therapeutic strategies. A risk score based on four AAM-related genes (AMG) was constructed that could predict the prognosis of HNSCC. These four genes were up-regulated in HNSCC tissues and might act as oncogenes. Internal validation in The Cancer Genome Atlas (TCGA) by bootstrapping showed that patients with high-risk scores had a poorer prognosis than patients with low-risk scores, and this was confirmed in the Gene Expression Omnibus (GEO) cohort. There were also differences between the high-risk and low-risk groups in clinical information and different anatomical sites such as age, sex, TNM stage, grade stage, surgery or no surgery, chemotherapy, radiotherapy, no radiotherapy, neck lymph node dissection or not, and neck lymphovascular invasion, larynx, overlapping lesion of lip, and oral cavity and pharynx tonsil of overall survival (OS). Immune-related characteristics, tumor microenvironment (TME) characteristics, and immunotherapy response were significantly different between high- and low-risk groups. The four AMGs were also found to be associated with the expression of markers of various immune cell subpopulations. Therefore, our comprehensive approach revealed the characterization of AAM in HNSCC to predict prognosis and guide clinical therapy.
Radiation-induced eosinophil increase ratio predicts patient outcomes in non-small celllung cancer
Authors: Wang Nuo-Han , Zhang Xin , Sui Jiang-Dong , Wang Ying , Wu Yong-Zhong , Lei Qian-Qian , Tu Hong-Lei , Yang Li-Na , Liu Yun-Chang , Yang Meng-Qi , Yang Hao-Nan , Li Dan , Lei Zheng
Published: October 2022

Background and purpose

Radiotherapy (RT) is a double-edged sword in regulating immune responses. This study aimed to investigate the impact of thoracic RT on circulating eosinophils and its association with patient outcomes in non-small cell lung cancer (NSCLC).

Materials and methods

This retrospective study included 240 patients with advanced NSCLC treated with definitive thoracic RT from January 2012 to January 2020. Statistics included Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS), multivariate Cox analyses to identify significant variables, and Spearman’s correlation to qualify the relationship between dose-volume histogram (DVH) parameters and EIR.

Results

Absolute eosinophil counts (AECs) showed an increasing trend during RT and an obvious peak in the 1st month after RT. Thresholds of eosinophil increase ratio (EIR) at the 1st month after RT for both OS and PFS were 1.43. Patients with high EIR above 1.43 experienced particularly favorable clinical outcomes (five-year OS: 21% versus 10%, P<0.0001; five-year PFS: 10% versus 8%, P=0.014), but may not derive PFS benefit from the addition of chemotherapy to RT. The higher a patient’s EIR, the larger the potential benefit in the absence of chemotherapy. DVH parameters including heart mean dose and heart V10 were negatively associated with EIR. None of these DVH parameters was correlated with the clinical outcomes.

Conclusion

EIR may serve as a potential biomarker to predict OS and PFS in NSCLC patients treated with RT. These findings require prospective studies to evaluate the role of such prognostic marker to identify patients at risk to tailor interventions.
Rivaroxaban in heart failure patients with left ventricular thrombus: A retrospective study
Authors: Zhang Qian , Zhang Zhongfan , Zheng Haikuo , Qu Ming , Li Shouping , Yang Ping , Si Daoyuan , Zhang Wenqi
Published: October 2022

Background: The role of rivaroxaban in patients with heart failure (HF) combined with left ventricular (LV) thrombus remains unknown in current guideline-directed anticoagulant therapy. The aim of this study was to investigate the impact on clinical outcomes of rivaroxaban compared to vitamin K antagonists (VKAs) in patients with HF combined with LV thrombus.

Methods: We retrospectively extracted clinical, echocardiographic and follow-up data of HF patients (all classifications) admitted at China-Japan Union Hospital of Jilin University from January 2017 to June 2021. A total of 198 patients with HF were identified with LV thrombus by echocardiography, 78 of them were managed with VKAs, 109 with rivaroxaban.

Results: The median follow-up was 17.0 months (interquartile range: 6.0–24.0 months). High rates of major cardiovascular adverse events (MACEs) were observed in both the rivaroxaban and VKAs groups (49.5% vs. 57.7%). However, rivaroxaban versus VKAs observed a decrease in MACEs (adjusted HR:0.636; 95%CI:0.418–0.970; p = 0.035) and systemic embolism (4.6% vs. 12.8%; adjusted HR:0.318; 95%CI:0.108–0.933; p = 0.037; Gray’s test p = 0.041) but was not found to have a benefit with regard to LV thrombus resolution (59.6% vs. 70.6%; adjusted HR: 1.303; 95% CI:0.898–1.890; p = 0.163; Gray’s test p = 0.073). Additionally, there was no significant between-group difference in the rate of International Society on Thrombosis and Hemostasis (ISTH) bleeding events.

Conclusion: Our data found that in populations with HF combined with LV thrombus, the overall prognosis in both the rivaroxaban and VKAs groups was catastrophic. Although rivaroxaban improved the prognosis to some extent, a considerable need remains for new treatments to improve their clinical course.
A study on green synthesis, characterization of chromium oxide nanoparticles and their enzyme inhibitory potential
Authors: Zainab  , Ahmad Shujaat , Khan Idrees , Saeed Khalid , Ahmad Hanif , Alam Aftab , Almehmadi Mazen , Alsaiari Ahad Amer , Haitao Yu , Ahmad Manzoor
Published: October 2022

The conventional chemical methods of nanoparticles synthesis have been effectively replaced by nanoparticle synthesis mediated by plants. The current study describes the environmental friendly synthesis of chromium oxide nanoparticles (Cr2O3 NPs) using Erythrophleum guineense plant extract. The synthesis of Cr2O3 NPs was validated by UV/VIS spectroscopy, Energy Dispersive X-Ray (EDX), Scanning Electron Microscopy (SEM), and X-ray diffraction (XRD) studies. The appearance of the Sharpe peak at 460 nm in the UV/Vis spectrum and the colour change caused by surface plasma resonance confirmed the formation of Cr2O3 NPs. The EDX spectrum of Cr2O3 nanoparticles revealed the presence of carbon, oxygen, and chromium, while SEM analysis revealed an irregular round morphology (with a size below 400 nm). In addition, XRD studies suggested their crystalline nature by the characteristic peaks at 34° and 36° and 42° (2Ɵ), respectively. The green synthesized Cr2O3 NPs showed promise as in-vitro cholinesterase inhibitor at tested concentrations (62.5–1,000 μg/ml), with IC50 values of 120 and 100 μg/ml against Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), respectively. The results suggested that the green synthesized Cr2O3 NPs could be used in the future to stop enzyme from working and for other biological activities.
Improvement of gut-vascular barrier by terlipressin reduces bacterial translocation and remote organ injuries in gut-derived sepsis
Authors: Chang Zenan , Zhang Yinan , Lin Ming , Wen Shihong , Lai Hanjin , Zhan Yaqing , Zhu Xiufen , Huang Zhikun , Zhang Xuyu , Liu Zimeng
Published: October 2022

Gut-vascular barrier (GVB) serves as the last barrier to limit the migration of intestinal toxins into the blood circulation. The efficacy of terlipressin (a vasopressin V1 receptor agonist) in reducing GVB and multiple organ damage in gut-derived sepsis is unknown. In this study, we hypothesized that, besides other intestinal barriers, GVB play a key role in gut-derived sepsis and terlipressin improve GVB damage and then reduce bacterial translocation and organ injuries. In vivo, a cecal ligation and puncture mouse model was established. The mice were subjected to examine the damage of GVB determined by intestinal plasmalemma vesicle-associated protein-1(PV-1) and vascular endothelial-cadherin. And the intestinal permeability was assessed by translocation of intestinal bacteria and macromolecules. In vitro, transendothelial electrical resistance (TER) during interleukin (IL)-1β stimulation was measured on endothelial cells with or without small interfering RNA targeting β-catenin (si β-catenin). Terlipressin significantly improved GVB damage and reduced translocation of intestinal macromolecules and bacteria by activating PI3K signaling. Of note, intestinal PV-1 expression was significantly correlated with translocation of macromolecules, and dramatic increase of macromolecules was observed in intestinal tissues whereas fewer macromolecules and bacteria were observed in blood, liver and lung following terlipressin treatment. In vitro, terlipressin restored TER during IL-1β stimulation and si β-catenin transfection blocked the changes delivered by terlipressin. Collectively, terlipressin alleviated GVB damage and subsequent bacterial translocation via blood vessels after sepsis challenge, resulting in reduced distant organ injuries and the responsible mechanisms may involve the activation of PI3K/β-catenin pathway.
The effect of a low dose hydrogen-oxygen mixture inhalation in midlife/older adults with hypertension: A randomized, placebo-controlled trial
Authors: Liu Boyan , Jiang Xue , Xie Yunbo , Jia Xiubin , Zhang Jiashuo , Xue Yazhuo , Qin Shucun
Published: October 2022

Objective: To explore the effect of a low-dose hydrogen–oxygen (H2-O2) mixture inhalation in midlife/older adults with hypertension.

Methods: This randomized, placebo-controlled trial included 60 participants with hypertension aged 50–70 years who were randomly divided into Air group (inhaled placebo air) or H2-O2 group [inhaled H2-O2 mixture (66% H2/33% O2)]. Participants in both groups were treated 4 h per day for 2 weeks. Four-limb blood pressure and 24-h ambulatory blood pressure were monitored before and after the intervention, and levels of plasma hormones related to hypertension were determined.

Results: A total of 56 patients completed the study (27 in the Air group and 29 in the H2-O2 group). The right and left arm systolic blood pressure (SBP) were significantly decreased in H2-O2 group compared with the baseline levels (151.9 ± 12.7 mmHg to 147.1 ± 12.0 mmHg, and 150.7 ± 13.3 mmHg to 145.7 ± 13.0 mmHg, respectively; all p < 0.05). Meanwhile, the H2-O2 intervention significantly decreased diastolic nighttime ambulatory blood pressure by 2.7 ± 6.5 mmHg (p < 0.05). All blood pressures were unaffected in placebo group (all p > 0.05). When stratified by age (aged 50–59 years versus aged 60–70 years), participants in the older H2-O2 group showed a larger reduction in right arm SBP compared with that in the younger group (p < 0.05). In addition, the angiotensin II, aldosterone, and cortisol levels as well as the aldosterone-to-renin ratio in plasma were significantly lower in H2-O2 group compared with baseline (p < 0.05). No significant differences were observed in the Air group before and after the intervention.

Conclusion: Inhalation of a low-dose H2-O2 mixture exerts a favorable effect on blood pressure, and reduces the plasma levels of hormones associated with hypertension on renin-angiotensin-aldosterone system and stress in midlife/older adults with hypertension.
Effects of metformin on Sonic hedgehog subgroup medulloblastoma progression: In vitro and in vivo studies
Authors: Fang Huangyi , Wang Lingfei , Yu Lisheng , Shen Fang , Yang Zelin , Yang Yue , Li Shize , Dai Haipeng , Tan Feng , Lin Jian , Sheng Hansong
Published: October 2022

Metformin is a first-line drug for type 2 diabetes, and its anticancer effects have also been widely studied in recent years. The Sonic hedgehog (Shh) signaling pathway is involved in the initiation and progression of medulloblastoma. In order to develop a new treatment strategy for medulloblastoma (MB), this study investigated the inhibitory effect of metformin on MB and the underlying mechanism of metformin on the Shh signaling pathway. The effect of metformin on proliferation was evaluated by the cell counting kit-8 (CCK-8) test and colony formation experiment. The effect of metformin on metastasis was assessed by the scratch-wound assay and transwell invasion assay. Cell cycle and apoptosis were evaluated by flow cytometry, and the associated proteins were examined by western blotting. The mRNA and protein expression levels related to the Shh pathway were measured by quantitative PCR, western blotting, and immunofluorescence staining. The xenograft murine model was carried out to evaluate the anticancer effect of metformin on medulloblastoma in vivo. Metformin inhibited proliferation and metastasis of the Shh subgroup MB cell line, and the inhibitory effect on proliferation was related to apoptosis and the block of the cell cycle at the G0/G1 phase. Animal experiments showed that metformin inhibits medulloblastoma growth in vivo. Moreover, metformin decreased mRNA and protein expression levels of the Shh pathway, and this effect was reversed by the AMP-activated protein kinase (AMPK) siRNA. Furthermore, the pro-apoptotic and cell cycle arrest effects of metformin on Daoy cells could be reversed by the Shh pathway activators. Our findings demonstrated that metformin could inhibit medulloblastoma progression in vitro and in vivo, and this effect was associated with AMPK-mediated inhibition of the Shh signaling pathway in vitro studies.
Analyzing the metabolic fate of oral administration drugs: A review and state-of-the-art roadmap
Authors: Liu Liu , Liu Yiming , Zhou Xiaojie , Xu Zhiwei , Zhang Yehui , Ji Liting , Hong Chunlan , Li Changyu
Published: October 2022

The key orally delivered drug metabolism processes are reviewed to aid the assessment of the current in vivo/vitro experimental systems applicability for evaluating drug metabolism and the interaction potential. Orally administration is the most commonly used state-of-the-art road for drug delivery due to its ease of administration, high patient compliance and cost-effectiveness. Roles of gut metabolic enzymes and microbiota in drug metabolism and absorption suggest that the gut is an important site for drug metabolism, while the liver has long been recognized as the principal organ responsible for drugs or other substances metabolism. In this contribution, we explore various experimental models from their development to the application for studying oral drugs metabolism of and summarized advantages and disadvantages. Undoubtedly, understanding the possible metabolic mechanism of drugs in vivo and evaluating the procedure with relevant models is of great significance for screening potential clinical drugs. With the increasing popularity and prevalence of orally delivered drugs, sophisticated experimental models with higher predictive capacity for the metabolism of oral drugs used in current preclinical studies will be needed. Collectively, the review seeks to provide a comprehensive roadmap for researchers in related fields.
Calycosin attenuates renal ischemia/reperfusion injury by suppressing NF-κB mediated inflammation via PPARγ/EGR1 pathway
Authors: Zhang Ningxin , Guan Chen , Liu Zengying , Li Chenyu , Yang Chengyu , Xu Lingyu , Niu Meng , Zhao Long , Zhou Bin , Che Lin , Wang Yanfei , Xu Yan
Published: October 2022

Renal ischemia reperfusion injury (IRI) is a leading and common cause of acute kidney injury (AKI), and inflammation is a critical factor in ischemic AKI progression. Calycosin (CAL), a major active component of Radix astragali, has been reported to have anti-inflammatory effect in multiple organs. However, whether CAL can alleviate renal IRI and its mechanism remain uncertain. In the present study, a renal IRI model is established by bilateral renal pedicles occlusion for 35 min in male C57BL/6 mice, and the effect of CAL on renal IRI is measured by serum creatinine and pathohistological assay. Hypoxia/reoxygenation (H/R) stimulated human renal tubular epithelial cells HK-2 were applied to explore the regulatory mechanisms of CAL. Luciferase reporter assay and molecular docking were applied to identify the CAL’s target protein and pathway. In the mice with renal IRI, CAL dose dependently alleviated the renal injury and decreased nuclear factor kappa B (NF-κB) mediated inflammatory response. Bioinformatics analysis and experiments showed that early growth response 1 (EGR1) increased in mice with renal IRI and promoted NF-κB mediated inflammatory processes, and CAL dose-dependably reduced EGR1. Through JASPAR database and luciferase reporter assay, peroxisome proliferator-activated receptor γ (PPARγ) was predicted to be a transcription factor of EGR1 and repressed the expression of EGR1 in renal tubular epithelial cells. CAL could increase PPARγ in a dose dependent manner in mice with renal IRI and molecular docking predicted CAL could bind stably to PPARγ. In HK-2 cells after H/R, CAL increased PPARγ, decreased EGR1, and inhibited NF-κB mediated inflammatory response. However, PPARγ knockdown by siRNA transfection abrogated the anti-inflammation therapeutic effect of CAL. CAL produced a protective effect on renal IRI by attenuating NF-κB mediated inflammatory response via PPARγ/EGR1 pathway.
A retrospective study of Pupingqinghua prescription versus Lianhuaqingwen in Chinese participants infected with SARS-CoV-2 Omicron variants
Authors: Dong Yidan , Zhai Wei , Fang Bangjiang , Liu Chenyang , Yuan Suyun , Wang Youhua , Song Qixiang , Li Hai , Chen Bin , Cui Dan , Wang Jun , Wu Qiong , Zhou Chang , Zhou Maolin , Li Shuchun , Zhuang Xu , Xu Qingrong , Zheng Yu , Wu Yingen , Zheng Junhua , Cao Min
Published: October 2022

Background:Coronavirus disease (COVID-19) seriously endangers global public health. Pupingqinghua prescription (PPQH) is an herbal formula from traditional Chinese medicine used for treatment of SARS-CoV-2 infection. This study aims to evaluate the clinical efficacy and safety of PPQH in Chinese participants infected with the SARS-CoV-2 Omicron variant.

Methods:A total of 873 SARS-CoV-2 (Omicron)-infected patients were included. Among them, the patients were divided into the PPQH group (653 cases) and LHQW group (220 cases) according to different medications. The effectiveness indicators (hematological indicators, Ct values of novel Coronavirus nucleic acid tests, and viral load-shedding time) and safety indicators (liver and kidney function and adverse events) were analyzed.

Results:There was no significant difference in baseline characteristics between the PPQH group and the LHQW group, except the gender; After the treatment, the levels of IL-5, IL-6, IL-10, NK cells, and INF-α of the patients in the PPQH group showed a downward trend (p< 0.05); The viral load shedding time was 5.0 (5.0, 7.0) in the PPQH group and 5.0 (4.0, 7.0) in the LHQW group; both PPQH and LHQW can shorten the duration of symptoms of fever, cough, and sore throat. The re-positive rate of COVID-19 test was 1.5 % in the PPQH group and 2.3 % in the LHQW group. In terms of safety, the levels of γ-GTT decreased significantly (p< 0.01); gastrointestinal reaction was the primary adverse reaction, and the reaction rate was 4.7 % in the PPQH group and 9.5 % in the LHQW group.

Conclusion:PPQH can shorten the length of hospital stay and improve clinical symptoms of patients with SARS-COV-2 (Omicron), and it also has a good safety profile.
The treatment of depression — searching for new ideas
Authors: Stachowicz Katarzyna , Sowa-Kućma Magdalena
Published: October 2022

Depression is a severe mental health problem that affects people regardless of social status or education, is associated with changes in mood and behavior, and can result in a suicide attempt. Therapy of depressive disorders is based mainly on drugs discovered in the 1960s and early 1970s. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are frontline pharmacological strategies for the medical treatment of depression. In addition, approved by FDA in 2019, esketamine [as nasal spray; N-methyl-D-aspartate (NMDA) receptors antagonist with additional effects on α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, L-type voltage-dependent calcium channel (L-VDCC), opioid receptors, and monoaminergic receptors] is an essential compound in suicide and drug-resistant depression. However, the treatment of depression is burdened with severe side effects, and in many cases, it is ineffective. An equally important issue is the choice of antidepressant therapy in people with comorbid somatic diseases, for example, due to possible interactions with the patient's other drugs. Therefore, there is a great need for new antidepressants with different mechanisms of action and the need to refine the search for new substances. The purpose of this review was to discuss new research directions and new trends that dominate laboratories worldwide. We have reviewed the literature to present new points on the pharmacological target of substances with antidepressant activity. In addition, we propose a new perspective on depressive therapies.
Comorbid epilepsy and depression—pharmacokinetic and pharmacodynamic drug interactions
Authors: Miziak Barbara , Czuczwar Stanisław J. , Pluta Ryszard
Published: October 2022

Background: Major depressive disorder may be encountered in 17% of patients with epilepsy and in patients with drug-resistant epilepsy its prevalence may reach 30%. This indicates that patients with epilepsy may require antidepressant treatment.

Purpose: Both pharmacodynamic and pharmacokinetic interactions between antiepileptic (antiseizure) and antidepressant drugs have been reviewed. Also, data on the adverse effects of co-administration of antiepileptic with antidepressant drugs have been added. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology.

Methods: The review of relevant literature was confined to English-language publications in PUBMED databases. Table data show effects of antidepressants on the seizure susceptibility in experimental animals, results of pharmacodynamic interactions between antiepileptic and antidepressant drugs mainly derived from electroconvulsions in mice, as well as results concerning pharmacokinetic interactions between these drugs in clinical conditions.

Conclusion: Antidepressant drugs may exert differentiated effects upon the convulsive threshold which may differ in their acute and chronic administration. Animal data indicate that chronic administration of antidepressants could reduce (mianserin, trazodone) or potentiate the anticonvulsant activity of some antiepileptics (fluoxetine, reboxetine, venlafaxine). There are also examples of neutral interactions (milnacipran).
Screening of anti-heart failure active compounds from fangjihuangqi decoction in verapamil-induced zebrafish model by anti-heart failure index approach
Authors: Li Jun , Zhu Yue , Zhao Xiaoping , Zhao Lu , Wang Yi , Yang Zhenzhong
Published: October 2022

Heart failure is the end stage of various cardiovascular diseases. Fangjihuangqi Decoction (FJHQD) is a famous traditional Chinese medicine (TCM) formula, which is clinically effective in the treatment of chronic heart failure. However, the anti-heart failure ingredients of FJHQD have not been clarified, and the related mechanisms of action are rarely studied. In the present study, through quantification analysis of heart rate and ventricular area changes, a heart failure model and cardiac function evaluation system in cardiomyocytes-labelled Tg (cmlc2: eGFP) transgenic zebrafish larvae were constructed, and the anti-heart failure index (AHFI) that can comprehensively evaluate the cardiac function of zebrafish was proposed. Based on this model, FJHQD, its mainly botanical drugs, components and ingredients were evaluated for the anti-heart failure effects. The results showed that FJHQD and its botanical drugs exhibited potent anti-heart failure activity. Furthermore, total alkaloids from Stephania tetrandra S. Moore, total flavonoids from Astragalus mongholicus Bunge and total flavonoids from Glycyrrhiza uralensis Fisch. ex DC. were identified to be the main components exerting the anti-heart failure activity of FJHQD. Then, we screened the main ingredients of these components, and glycyrrhizic acid, licochalcone A and calycosin were found to exhibit excellent cardioprotective effects. Finally, we found that FJHQD, glycyrrhizic acid, licochalcone A and calycosin may improve cardiac function in zebrafish by regulating oxidative stress, inflammatory response and apoptosis-related pathways. Taken together, our findings offer biological evidences toward the anti-heart failure effect of FJHQD, and provide guidance for the clinical application of FJHQD.
Magnetic resonance T1ρ quantification of human brain at 5.0 T: A pilot study
Authors: Liu Yuanyuan , Wang Wenxin , Zheng Yijia , Wang Haifeng , Zheng Hairong , Liang Dong , Zhu Yanjie
Published: October 2022

MR quantitative T1ρ mapping has gained increasing attention due to its capability to study low-frequency motional processes and chemical exchange in biological tissues. At ultra-high fields, the chemical exchange and proton diffusion in biological tissues should be more prominent. In this study, for the first time, we aim to test the feasibility of brain T1ρ mapping at 5.0 T MR scanner and compare the T1ρ values estimated using 3.0 T and 5.0 T scanners. Preliminary experimental results show that 5.0 T achieves T1ρ-weighted images with a higher signal-to-noise ratio than those acquired at 3.0T. The SNR benefit at 5.0 T is more obvious in high-resolution imaging. The T1ρ quantifications at 5.0 T are: Corpus callosum (67.4 ± 1.9 ms), Corona radiate (71.5 ± 1.8 ms), Superior frontal gyrus (67.6 ± 2.5 ms), Putamen (58.9 ± 1.2 ms), Centrum semiovale (84.0 ± 6.3 ms). Statistical analysis results indicate that the T1ρ values at 5.0 T show no significant difference with those obtained at 3.0 T (all p > 0.05). The interfield agreements in terms of T1ρ values between 3.0 T and 5.0 T were substantial (all ICCs >0.7). The coefficients of variation for T1ρ measurements from 3.0 T to 5.0 T were all less than 6.50% (2.28%–6.32%).
Effect of crystal-photodetector interface extraction efficiency on Cerenkov photons’ detection time
Authors: Trigila Carlotta , Roncali Emilie
Published: October 2022

Using Cerenkov photons to improve detector timing resolution in time-of-flight positron emission tomography scanners is promising since they constitute most of the signal rising edge. The main challenge in using Cerenkov light is its low yield per photoelectric interaction, which requires optimizing their complex optical transport in the detector. Monte Carlo simulations unlock information unavailable through benchtop measurements and help better understand the Cerenkov photon behavior. Although the first Cerenkov photons are emitted forward, part of the early triggering signal is lost due to poor light extraction at the crystal-photodetector interface. In addition, the electron path in the crystal, that determines the Cerenkov photon direction, is tortuous due to multiple scattering, causing the Cerenkov photons emitted after a few scatters to no longer be forward-directed. In this context, the transit time spread in the crystal, highly dependent on the detector geometry, plays a crucial role in the photon detection time. In this work, we performed optical simulations in bismuth germanium oxide using 511 keV gamma with GATE to investigate the optical photons extraction when modifying the index of refraction at the crystal-photodetector interface and the crystal aspect ratio. The mean detection time of the first, second, and third detected optical and Cerenkov photon separately was studied as a function of the total number of Cerenkov detected per event. For each configuration, we calculated the expected mean detection time using the probability of detection. Thinner crystals led to lower expected detection times due to the reduced transit time in the crystal. Reducing the refractive index discontinuity at the crystal-photodetector interface decreased all configurations expected mean detection time values. We showed that it not only improves the optical photons (scintillation and Cerenkov) detection efficiency at the photodetector face but directly ameliorates the probability of detecting the fastest one, reducing the effect of thicker materials and of losing the first detected photon information, both crucial to reduce the detector timing resolution. Thanks to their prompt emission and directionality at emission, Cerenkov photons represent the first detected optical photon in most configurations but increasing their detection efficiency is crucial to detect the fastest one.
Chest CT scan for the screening of air anomalies at risk of pulmonary barotrauma for the initial medical assessment of fitness to dive in a military population
Authors: Bonnemaison Brieuc , Castagna Olivier , de Maistre Sébastien , Blatteau Jean-Éric
Published: October 2022

Introduction: The presence of intra-pulmonary air lesions such as cysts, blebs and emphysema bullae, predisposes to pulmonary barotrauma during pressure variations, especially during underwater diving activities. These rare accidents can have dramatic consequences. Chest radiography has long been the baseline examination for the detection of respiratory pathologies in occupational medicine. It has been replaced since 2018 by the thoracic CT scan for military diving fitness in France. The objective of this work was to evaluate the prevalence of the pulmonary abnormalities of the thoracic CT scan, and to relate them to the characteristics of this population and the results of the spirometry.

Methods: 330 records of military diving candidates who underwent an initial assessment between October 2018 and March 2021 were analyzed, in a single-center retrospective analysis. The following data were collected: sex, age, BMI, history of respiratory pathologies and smoking, treatments, allergies, diving practice, results of spirometry, reports of thoracic CT scans, as well as fitness decision.

Results: The study included 307 candidates, mostly male, with a median age of 25 years. 19% of the subjects had abnormal spirometry. We identified 25% of divers with CT scan abnormalities. 76% of the abnormal scans were benign nodules, 26% of which measured 6 mm or more. Abnormalities with an aerial component accounted for 13% of the abnormal scans with six emphysema bullae, three bronchial dilatations and one cystic lesion. No association was found between the presence of nodules and the general characteristics of the population, whereas in six subjects emphysema bullae were found statistically associated with active smoking or abnormal spirometry results.

Conclusion: The systematic performance of thoracic CT scan in a young population free of pulmonary pathology revealed a majority of benign nodules. Abnormalities with an aerial component are much less frequent, but their presence generally leads to a decision of unfitness. These results argue in favor of a systematic screening of aeric pleuro-pulmonary lesions during the initial assessment for professional divers.
Eight weeks of dry dynamic breath-hold training results in larger spleen volume but does not increase haemoglobin concentration
Authors: Yang Kun , Wang Wen-Bin , Yu Ze-Hua , Cui Xiao-Lan , Yu Zhang-Biao , Jiang Yi , Gou Jin-Fei , Du Meng-Meng
Published: October 2022

Purpose: It has previously been reported that repeated exposure to hypoxia increases spleen size and haemoglobin (HGB) level and recent reports on the effect apnoea has on spleen size and haematological parameters are contradictory. Therefore, this study aims to evaluate the effect apnoea training has on spleen size and haematological parameters.

Methods: The breath-holding (BH) group was comprised of 12 local student-athletes with no BH exercise experience who performed BH jogging and BH jumping rope dynamic apnoea protocols, five times weekly for 8 weeks. The BH event duration was progressively increased as the apnoea tolerance of the athletes improved (20 to 35 s). The same training task was performed by the control group (n = 10) without BH. Spleen sizes were measured with an ultrasound system and a complete blood cell analysis was performed on the median cubital venous blood.

Results: Spleen volume in the BH group increased from 109 ± 13 ml to 136 ± 13 ml (p < 0.001), and bulky platelets decreased from 70.50 ± 5.83 to 65.17 ± 5.87 (p = 0.034), but no changes were recorded for erythrocytes (p = 0.914), HGB (p = 0.637), PLTs (p = 0.346) and WBC (p = 0.532). No changes were recorded for the control group regarding spleen size or haematological parameters.

Conclusion: Eight weeks of dry dynamic apnoea training increased spleen size and decreased the number of circulating bulky platelets in the athletes who were assessed in this study. However, the baseline RBC counts and HGB levels of the athletes were not altered by the training programme.