bluuebunny/crossref_metadata_2025 huggingface dataset:
Disparity of Gut Microbiota Composition Among Elite Athletes and Young Adults With Different Physical Activity Independent of Dietary Status: A Matching Study
Authors: Xu Yongjin , Zhong Fei , Zheng Xiaoqian , Lai Hsin-Yi , Wu Chunchun , Huang Cong
Published: March 2022

Objective

This study aimed to investigate the disparity of gut microbiota among elite athletes and young adults with different physical activity independent of dietary status.

Methods

In Hangzhou, China, an age and sex matching study was conducted between April and May 2021. A total of 66 Chinese young adults were recruited in this study and divided into an elite athlete group, physically active group, and physically inactive group. Fecal samples were collected to assess gut microbiota composition. Dietary status was measured using a food-frequency questionnaire. Comparisons in gut microbiota and blood biomarkers among three groups were analyzed by using the analysis of covariance.

Results

The findings depicted a tendency to form clusters for beta diversity among three groups, while no significant difference was observed in both alpha and beta diversity. In the multiple analysis model, by adjusting dietary status, a significantly higher abundance of Clostridiaceae (p = 0.029) and Megamonas_rupellensis (p = 0.087) was observed in elite athletes compared to that in general young adults. Furthermore, inflammation-related bacteria such as Bilophila (p = 0.011) and Faecalicoccus (p = 0.050) were enriched in physically inactive young adults compared to two other groups. Pearson's correlation analysis showed a positive association between Bilophila and circulating white body cell count (r = 0.332, p = 0.006) and its subtypes including neutrophils (r = 0.273, p = 0.027), and lymphocytes (r = 0.327, p = 0.007). Megamonas_rupellensis has been shown associated positively with serum lymphocytes levels (r = 0.268, p = 0.03). Although no significant differences were observed, the elite athletes tended to have lower levels of blood biomarkers of immunity within a normal range, which may reflect a better immune function.

Conclusion

This matching study indicated that physically inactive young adults are more likely to have a lower immune function and a higher abundance of pro-inflammatory gut bacteria than elite athletes and physically active young adults. Dietary status should be considered as an important factor that may affect the association of physical activity with immune function and gut microbiota.
Risk Factors on the Incidence and Prognostic Effects of Colorectal Cancer With Brain Metastasis: A SEER-Based Study
Authors: Chen Quan , He Le , Li Yuhong , Zuo Chenghai , Li Mengxia , Wu Xiaofeng , Pu Chengxiu , Xu Xiang , Tang Rongrui , Xiong Yanli , Li Juan
Published: March 2022

Background

Colorectal cancer (CRC) with brain metastases (BM) is uncommon and often diagnosed at a late stage. The aims of this study were to identify the clinical factors that can influence the incidence of CRC patients with BM (CRCBM) and to investigate the impact of clinical factors and therapies on the outcomes of CRCBM.

Methods

Between 2010 and 2018, patients with CRCBM were enrolled under the Surveillance, Epidemiology, and End Results (SEER) program. Multivariable logistic and Cox regression models were used to identify risk factors and prognostic factors of BM. Kaplan–Meier curve and log-rank test were used to evaluate overall survival (OS) and tumor-specific survival (CSS) of CRCBM patients.

Results

A total of 195 (0.34%) CRC patients initially diagnosed with BM were included for analysis. The positive level of CEA, pN2a-b, and additional organ metastases were positively associated with developing BM from the CRC cohort (p < 0.05). The median OS and CSS of the BM patients were both 4.0 months, while the corresponding survival time in CRC patients without BM was 14.0 and 16.0 months, respectively (HR = 2.621, 95% CI = 2.061–3.333 for CSS; HR = 2.556, 95% CI = 2.026–3.225 for OS; log rank p < 0.001, each). Only systematic treatment was independently associated with better survival (p < 0.05, each).

Conclusions

Although the overall prognosis of CRCBM patients was extremely poor, the positive level of CEA, pN2a-b, and distant metastases could be bad risk factors for the incidence of CRCBM. In addition, only systematic treatment was found to be a negative prognostic factor for CRCBM patients. These related factors can provide more valuable reference for clinical individualized treatments.
The Role of m5C-Related lncRNAs in Predicting Overall Prognosis and Regulating the Lower Grade Glioma Microenvironment
Authors: Zhou Hongshu , Meng Ming , Wang Zeyu , Zhang Hao , Yang Liting , Li Chuntao , Zhang Liyang
Published: March 2022

Glioma is the most lethal primary brain tumor with a poor prognosis and high recurrence rate. Enormous efforts have been made to find therapeutic targets for gliomas. In the current study, we identified m5C-related lncRNAs through Pearson correlation analysis by the criteria |R|>0.5 and p<0.001 in TCGA LGG and CGGA325 datasets. We then established an eight-lncRNA m5C-related prognostic signature (m5C LPS) through lasso cox regression analysis and multivariate analysis. The performance of the signature was confirmed in the CGGA325 dataset and evaluated in differential subgroups divided by relevant clinicopathological characteristics. Patients were then divided into high and low risk groups using risk scores calculated with the signature. Next, we performed GO, KEGG and gene set enrichment analysis (GSEA) and identified the m5C LPS to be related with glioma microenvironment, immune response, EMT, cell cycle, and hypoxia. Correlation of the risk groups with immune cell infiltration, somatic mutation, and CNVs was then explored. Responses to immuno- and chemotherapies in different risk groups were evaluated using submap and pRRophetic R packages respectively. The high-risk group was more sensitive to anti-CTLA4 therapy and to compounds including Temozolomide, Bleomycin, Cisplatin, Cyclopamine, A.443654 (Akt inhibitor), AZD6482 (PI3K inhibitor), GDC0941(PI3K inhibitor), and metformin. We present for the first time a m5C-related lncRNA signature for lower grade glioma patient prognosis and therapy response prediction with validated performance, providing a promising target for future research.
Association of Polymorphisms in Inflammation Genes With the Prognosis of Advanced Non-Small Cell Lung Cancer Patients Receiving Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Authors: Zhang Xuelin , Ye Tengfei , Li Mingdong , Yan Hongwang , Lin Hui , Lu Hongsheng , Qi Zecheng , Sheng Haihui , He Chunya
Published: March 2022

Background

Inflammation is not only involved in the development and progression of cancer but also affects the response to therapy. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) in inflammation genes with the prognosis of advanced non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).

Methods

Forty-seven SNPs were genotyped in 318 advanced NSCLC patients receiving EGFR-TKIs. Of 318 patients, 182 (57.2%) patients died during follow-up period. We assessed the association of SNPs with the progression-free survival (PFS) and overall survival (OS) as well as calculated the weighted genetic risk score (GRS). We also explored the expression levels and prognostic values of inflammation genes in lung adenocarcinoma (LUAD) in Gene Expression Profiling Interactive Analysis (GEPIA) and using UCSC Xena, respectively. The relationship between the expression levels of IL15, IL17RA, AGER, MIF, and TNFRSF1A and EGFR mutation status was analyzed using UCSC Xena.

Results

In single variant analyses, 3 SNPs (rs10519613, rs4819554, and rs4149570) were significantly associated with worse PFS. Five SNPs (rs10519613, rs4819554, rs2070600, rs755622, and rs4149570) were significantly with worse OS. In addition, high and intermediate GRSs (based on rs10519613, rs4819554, and rs4149570) were associated with worse PFS than those with low GRS. For OS, patients with high GRSs (based on rs10519613, rs4819554, rs2070600, rs755622, and rs4149570) had shorter survival time than those with low GRS. Furthermore, IL15, IL17RA, AGER, MIF, and TNFRSF1A were dysregulated in LUAD. There was difference in the expression level of TNFRSF1A between EGFR wildtype and EGFR-mutant LUAD. Both low AGER expression and high TNFRSF1A expression were significantly associated with worse PFS in LUAD. In addition, low IL17RA and AGER expression, high MIF and TNFRSF1A expression were significantly associated with worse OS in LUAD.

Conclusion

SNPs in inflammation genes could serve as prognostic biomarkers for NSCLC patients treated with EGFR-TKIs.
Durable Response of Dabrafenib, Trametinib, and Capmatinib in an NSCLC Patient With Co-Existing BRAF-KIAA1549 Fusion and MET Amplification: A Case Report
Authors: Chou Yun-Tse , Lin Chien-Chung , Lee Chung-Ta , Pavlick Dean C. , Su Po-Lan
Published: March 2022

BRAF fusions are rare driver oncogenes in non-small cell lung cancer (NSCLC). Similar with BRAF V600E mutation, it could also activate the MAPK signaling pathway. There are a few case reports which had indicated the potential response to BRAF inhibitors and its important role as de novo driver mutation. In addition, the co-occurring MET amplification has been defined as a poor prognostic factor in patients with epidermal growth factor receptor (EGFR) mutant NSCLC. Currently, there are ongoing clinical trials which investigate the MET amplification as a therapeutic target in patients with EGFR mutant NSCLC and acquired resistance to osimertinib, which imply that the MET amplification also had a therapeutic significance. However, the co-occurring MET amplification had not been studied in patients with BRAF fusion before. A 67-year-old man was diagnosed with metastatic poorly-differentiated adenocarcinoma. He received first-line therapy with the combination of pembrolizumab and chemotherapy because the genomic test revealed wild-type EGFR, and negativity of ALK and ROS1 by immunohistochemical stain. Upon disease progression, the next-generation sequencing revealed co-occurring KIAA1549-BRAF fusion and MET amplification. Subsequent dabrafenib, trametinib, and capmatinib combination therapy showed a remarkable treatment effect. The combination therapy targeting the co-occurring driver mutations is a potential effective treatment for NSCLC patients. Further prospective study is still warranted to investigate the role of co-occurring driver mutations and the relevant treatment strategy.
Prognosticators and Prognostic Nomograms for Leiomyosarcoma Patients With Metastasis
Authors: Zou YuChi , Yang QianKun , Wu YuTong , Ai HongBo , Yao ZhongXiang , Zhang ChengMin , Luo Fei
Published: March 2022

Individual survival prediction and risk stratification are of vital importance to optimize the individualized treatment of metastatic leiomyosarcoma (LMS) patients. This study aimed to identify the prognostic factors for metastatic LMS patients and establish prognostic models for overall survival (OS) and cancer-specific survival (CSS). The data of LMS patients with metastasis between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The entire cohort was randomly divided into a training cohort and a validation cohort. The influences of primary tumor site, localized and distant metastases, and sites and number of metastases on the prognosis of metastatic LMS patients were firstly explored by Kaplan–Meier curves and log-rank tests. Furthermore, the effective therapeutic regimens and prognosticators for metastatic LMS patients were also analyzed by Cox analysis. In addition, two prognostic nomograms for OS and CSS were established, and their predictive performances were evaluated by the methods of receiver operating characteristic (ROC) curves, time-dependent ROC curves, calibration curves, and decision curve analysis (DCA). A total of 498 patients were finally collected from the SEER database and were randomly assigned to the training set (N = 332) and validation set (N = 166). No significant differences in OS were observed in patients with distant organ metastasis and localized metastasis. For patients who have already developed distant organ metastasis, the sites and number of metastases seemed to be not closely associated with survival. Patients who received chemotherapy got significantly longer survival than that of their counterparts. In univariate and multivariate Cox analyses, variables of surgery, chemotherapy, age, and tumor size were identified as independent predictors for OS and CSS, and distant metastasis was also independently associated with CSS. The areas under the curve (AUCs) of ROC curves of the nomogram for predicting 1-, 3-, and 5-year OS were 0.770, 0.800, and 0.843, respectively, and those for CSS were 0.777, 0.758, and 0.761, respectively. The AUCs of time-dependent AUCs were all over 0.750. The calibration curves and DCA curves also showed excellent performance of the prognostic nomograms. Metastasis is associated with reduced survival, while the sites and the number of metastases are not significantly associated with survival. The established nomogram is a useful tool that can help to perform survival stratification and to optimize prognosis-based decision-making in clinical practice.
Identifying the Effect of Celastrol Against Ovarian Cancer With Network Pharmacology and In Vitro Experiments
Authors: Wang Xuan , Liu Qiong , Wu Sisi , Xu Nana , Li Hua , Feng Aihua
Published: March 2022

Aim: We aimed to reveal the function of celastrol in the treatment of ovarian cancer using network pharmacology and molecular docking.

Background: Ovarian cancer is a growth of cells that forms in the ovaries. Celastrol is a useful bioactive compound derived from the root of the thunder god vine.

Method: Celastrol and ovarian cancer targets were determined by analyzing datasets. Protein–protein interaction (PPI) networks were obtained with network pharmacology. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Molecular docking using SWISS-MODEL, CB-Dock and Discovery Studio was conducted. A methylthiazolyltetrazolium bromide (MTT) assay was performed to evaluate cell proliferation. Cell apoptosis and cell cycle were measured with a fluorescence assay. Reverse transcription PCR (RT-PCR) and Western blot were performed to measure the expression of core targets.

Result: Celastrol possessed 29 potential targets, while ovarian cancer possessed 471 potential targets. The core PPI network contained 163 nodes and 4,483 edges. The biological processes identified in the GO analysis indicated that the targets were related with the cellular response to DNA damage stimulus, DNA recombination, and cell proliferation, among other processes. The KEGG analysis indicated that the pathways were related with the cell cycle, viral carcinogenesis, and MAPK signaling pathway, among others. The three core targets shared between the core PPI network and celastrol targets were MYC, CDC37, and FN1. Celastrol directly combined with the targets according to the results from CB-Dock and Discovery Studio. Celastrol inhibited ovarian cancer cell proliferation and promoted ovarian cancer cell apoptosis in a dose-dependent manner. RT-PCR and Western blot analyses showed that celastrol inhibited core target expression. In addition, celastrol also influenced the related inflammatory signaling pathways in ovarian cancer cells.

Conclusion: Celastrol exerts effective antitumor activity toward ovarian cancer. Celastrol regulated cell proliferation, DNA repair and replication, apoptotic processes, and inflammatory responses in ovarian cancer cells.
Chemerin Regulates the Proliferation and Migration of Pulmonary Arterial Smooth Muscle Cells via the ERK1/2 Signaling Pathway
Authors: Peng Linqian , Chen Yunwei , Li Yan , Feng Panpan , Zheng Yan , Dong Yongjie , Yang Yunjing , Wang Ruiyu , Li Ailing , Yan Jianghong , Shang Feifei , Tang Ping , Chen Dewei , Gao Yuqi , Huang Wei
Published: March 2022

Pulmonary arterial hypertension (PAH) is an incurable disease with high mortality. Chemerin has been found to be associated with pulmonary hypertension (PH). However, the specific role of chemerin in mediating PH development remains unclear. This study aimed to elucidate the regulatory effects and the underlying mechanism of chemerin on PH and to investigate the expression levels of chemerin protein in plasma in PAH patients. In vivo, two animal models of PH were established in rats by monocrotaline (MCT) injection and hypoxia. We found that the expression levels of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), were significantly upregulated in the lungs of PH rats. Primary cultured pulmonary arterial smooth muscle cells [(PASMCs) (isolated from pulmonary arteries of normal healthy rats)] were exposed to hypoxia or treated with recombinant human chemerin, we found that CMKLR1 expression was upregulated in PASMCs in response to hypoxia or chemerin stimulation, whereas the exogenous chemerin significantly promoted the migration and proliferation of PASMCs. Notably, the regulatory effects of chemerin on PASMCs were blunted by PD98059 (a selective ERK1/2 inhibitor). Using enzyme linked immunosorbent assay (ELISA), we found that the protein level of chemerin was also markedly increased in plasma from idiopathic pulmonary arterial hypertension (IPAH) patients compared to that from healthy controls. Moreover, the diagnostic value of chemerin expression in IPAH patients was determined through receiver operating characteristic (ROC) curve analysis and the result revealed that area under ROC curve (AUC) for plasma chemerin was 0.949. Taken together, these results suggest that chemerin exacerbates PH progression by promoting the proliferation and migration of PASMCs via the ERK1/2 signaling pathway, and chemerin is associated with pulmonary hypertension.
A Combined Pharmacometrics Analysis of Biomarker Distribution Under Treatment With Standard- or Low-Dose Rivaroxaban in Real-World Chinese Patients With Nonvalvular Atrial Fibrillation
Authors: Zhao Nan , Liu Zhiyan , Xie Qiufen , Wang Zhe , Sun Zhongyi , Xiang Qian , Cui Yimin
Published: March 2022

Background: The rivaroxaban dose regimen for patients with nonvalvular atrial fibrillation (NVAF) is complex in Asia. Given the high interindividual variability and the risk of bleeding caused by rivaroxaban in Asians, the influencing factors and the relationship between outlier biomarkers and bleeding events need exploration.

Methods: The integrated pharmacokinetics (PK)/pharmacodynamics (PD) models were characterized based on rich PK/PD data from 304 healthy volunteers and sparse PD [anti-factor Xa activity (anti-Xa) and prothrombin (PT)] data from 223 patients with NVAF. The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. The final integrated PK/PD model was used to evaluate the influence of dosage and individual covariates on PD parameters.

Results: A two-compartment, linear model with sequential zero-order and first-order absorption was adopted. The dose-specific relative bioavailability (F1), diet status, creatinine clearance, and body mass index (BMI) improved the model fit. The apparent systemic clearance was 7.39 L/h, and the central and peripheral volumes were 10.9 and 50.9 L, respectively. The linear direct-effects model with shape factor plus the additive (and/or proportional) error model described the correlation between anti-Xa/PT and plasma concentration. Bodyweight, total cholesterol (TCHO), and diet status were selected as the covariates of the anti-Xa/PT model. Anti-Xa was more sensitive to the increase in rivaroxaban exposure compared with PT. An elevated bleeding tendency was seen with higher peak anti-Xa and PT. For a typical Chinese patient, the peak anti-Xa value (median (5%–95% PI)) of 20 and 15 mg were 309 ng/ml (139–597 ng/ml) and 296 ng/ml (138–604 ng/ml), both median values were within the expected range. For patients with CrCL 30–49 ml/min, the median peak anti-Xa with recommended 10 mg other than 15 mg were within the expected range.

Conclusion: Fixed doses of rivaroxaban could be prescribed for patients with NVAF without adjustment for bodyweight, BMI, and TCHO. Randomized studies should be performed to evaluate the efficacy and safety of low-dose rivaroxaban in Chinese patients with NVAF.
Esketamine as an Adjuvant to Ciprofol or Propofol Sedation for Same-Day Bidirectional Endoscopy: Protocol for a Randomized, Double-Blind, Controlled Trial With Factorial Design
Authors: Long Yu-qin , Feng Chang-dong , Ding Yun-ying , Feng Xiao-mei , Liu Hong , Ji Fu-hai , Peng Ke
Published: March 2022

Background: Same-day esophagogastroduodenoscopy and colonoscopy procedures under sedation have been increasingly performed. This study aims to assess the effects of esketamine combined with ciprofol (a novel anesthetic/sedative agent) or propofol on respiratory and hemodynamic adverse events in patients undergoing same-day bidirectional endoscopy.

Methods: This is a prospective, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial. A total of 180 adult patients scheduled for same-day bidirectional endoscopy under sedation will be randomized, in a 1:1:1:1 ratio, to receive 1 of 4 sedation regimens: 1) ciprofol and esketamine, 2) propofol and esketamine, 3) ciprofol and normal saline placebo, or 4) propofol and normal saline placebo. The primary outcome is a composite of desaturation [peripheral oxygen saturation (SpO2) < 95%] and hypotension [mean blood pressure (MBP) < 65 mmHg or decrease in MBP ≥20% of baseline] during the sedation and in the recovery room. Secondary outcomes include episodes of desaturation, severe desaturation (SpO2 < 90%), hypotension, severe hypotension (decrease in MBP ≥30% of baseline), bradycardia, postoperative nausea and vomiting, dizziness or headache, hallucination or nightmare, injection pain, pain scores and fatigue scores, endoscopist satisfaction, and patient satisfaction. Data will be analyzed on the modified intention-to-treat basis.

Discussion: We hypothesize that esketamine as an adjuvant to ciprofol or propofol sedation would improve cardiorespiratory stability. In addition, the potential interactions between interventions will be explored using the factorial design. The results of this trial will provide evidence for daily practice of sedation regimens for same-day bidirectional endoscopy.

Clinical Trial Registration: Chinese Clinical Trials Registry, Identifier ChiCTR2100052523.
The Efficacy and Safety of Ginkgo Terpene Lactone Preparations in the Treatment of Ischemic Stroke: A Systematic Review and Meta-Analysis of Randomized Clinical Trials
Authors: Zhao Huan , Guo Qiang , Li Baoli , Shi Min
Published: March 2022

Background: This meta-analysis aimed to assess the efficacy and safety of ginkgo terpene lactone preparations including ginkgo diterpene lactone meglumine injection, ginkgolide injection, and ginkgolide B injection for ischemic stroke (IS).

Methods: We searched the randomized controlled trials (RCTs) with publication date earlier than 31 August 2021 in PubMed, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals Database (VIP), Chinese Biomedical Literature Database (CBM), Wanfang Database, Embase, and the Cochrane Library. RevMan 5.3 software was applied to analyze the data and generate the forest plot and funnel plot. Meanwhile, publication bias was also assessed by Egger’s test with STATA 12 software.

Results: A total of 28 RCTs were eligible for inclusion. Among them, 23 RCTs were used to evaluate the efficacy of ginkgo terpene lactone preparations as the main treatment intervention for IS. To be specific, ginkgo diterpene lactone meglumine injection was superior to control drug in improving clinical efficacy [RR = 1.18, 95% CI (1.12, 1.24), Z = 6.36, p < 0.001] and neurological function [MD = −1.42, 95% CI (−1.91, −0.93), Z = 5.66, p < 0.001]. However, the effectiveness of the ginkgolide B injection group was equivalent to that of the control group. Additionally, ginkgolide injection achieved better clinical efficacy [RR = 1.10, 95% CI (1.02, 1.18), Z = 2.36, p = 0.02], but the changes of neurological function deficit was not obviously different between two groups [MD = −0.43, 95% CI (−4.32, 3.46), Z = 0.22, p = 0.83]. Furthermore, meta-analysis of five trials on ginkgo diterpene lactone meglumine injection combined with recombinant tissue plasminogen activator (rt-PA) thrombolytic therapy for acute IS showed that combination therapy was better in improving clinical efficacy [OR = 1.91, 95% CI (1.13, 3.22), Z = 2.41, p = 0.02] and neurological function [MD = −3.31, 95% Cl (−3.64,−2.98), Z = 19.63, p < 0.001]. Importantly, no serious adverse drug reactions/adverse drug events (ADRs/ADEs) were reported.

Conclusion: Ginkgo terpene lactone preparations have good therapeutic effects on patients with IS. For acute IS, ginkgo diterpene lactone meglumine injection can be used as a complementary therapy to improve the clinical efficacy of rt-PA.
The Impact of Clinical Pharmacist Implemented Protocol on Albumin Utilization and Cost in an Intensive Care Unit in Egypt
Authors: Ibrahim Dina Mohamed , Shawki May Ahmed , Solayman Mohamed Hassan , Sabri Nagwa Ali
Published: March 2022

Introduction: Albumin is an expensive non-blood plasma substitutes with limited availability that has been reported to be inappropriately used in healthcare settings. Hence, interventions are recommended to control its misuse.

Objective: To evaluate the impact of clinical pharmacist implemented dispensing protocol on optimization of albumin use in an intensive care unit (ICU).

Design: A retrospective prospective 3-phase interventional study was conducted in an ICU in a tertiary Egyptian hospital over a period of 2 years.

Methods: The study included three phases; a preparation phase where a local albumin dispensing protocol and a restriction dispensing form were prepared by clinical pharmacists and was approved by the local Drugs and Therapeutics Committee, a retrospective pre-implementation phase in which the medical records of all ICU patients receiving albumin were evaluated for appropriateness of albumin use according to the developed protocol, and a prospective implementation phase where the dispensing protocol and restriction dispensing form were applied. The pattern of albumin consumption and cost were recorded and compared between the retrospective and prospective phases.

Results: In the retrospective phase, 190 ICU patients received albumin of whom 83.6% was considered inappropriate indications for albumin compared to only 44 patients in the prospective phase of whom 16% was considered inappropriate (p-value <0.001). Clinical pharmacists’ interventions significantly decreased the inappropriate albumin consumption from 4.7 vials/patient in the retrospective phase to 2.7 vials/patient in the prospective phase (p-value <0.001) with a total cost savings of 313,900 Egyptian Pounds (19,930 US Dollars).

Conclusion: The current study showed that clinical pharmacists’ interventions led to a significant control on albumin use and consequently reduced the cost associated with its consumption.
Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man
Authors: Berry Angela V. , Kuti Joseph L.
Published: March 2022

Beta-lactams remain a critical member of our antibiotic armamentarium and are among the most commonly prescribed antibiotic classes in the inpatient setting. For these agents, the percentage of time that the free concentration remains above the minimum inhibitory concentration (%fT > MIC) of the pathogen has been shown to be the best predictor of antibacterial killing effects. However, debate remains about the quantity of fT > MIC exposure needed for successful clinical response. While pre-clinical animal based studies, such as the neutropenic thigh infection model, have been widely used to support dosing regimen selection for clinical development and susceptibility breakpoint evaluation, pharmacodynamic based studies in human patients are used validate exposures needed in the clinic and for guidance during therapeutic drug monitoring (TDM). For the majority of studied beta-lactams, pre-clinical animal studies routinely demonstrated the fT > MIC should exceed approximately 40–70% fT > MIC to achieve 1 log reductions in colony forming units. In contrast, clinical studies tend to suggest higher exposures may be needed, but tremendous variability exists study to study. Herein, we will review and critique pre-clinical versus human-based pharmacodynamic studies aimed at determining beta-lactam exposure thresholds, so as to determine which targets may be best suited for optimal dosage selection, TDM, and for susceptibility breakpoint determination. Based on our review of murine and clinical literature on beta-lactam pharmacodynamic thresholds, murine based targets specific to each antibiotic are most useful during dosage regimen development and susceptibility breakpoint assessment, while a range of exposures between 50 and 100% fT > MIC are reasonable to define the beta-lactam TDM therapeutic window for most infections.
Saikosaponin D Inhibited IL-1β Induced ATDC 5 Chondrocytes Apoptosis In Vitro and Delayed Articular Cartilage Degeneration in OA Model Mice In Vivo
Authors: Wu Xinhui , Zhao Kangxian , Fang Xiaoxin , Lu Feng , Cheng Pu , Song Xiaoting , Zhang Weikang , Yao Can , Zhu Jiling , Chen Haixiao
Published: March 2022

Osteoarthritis (OA) is the most common joint disease in the elderly, characterized by cartilage degradation and proliferation of subchondral bone. The pathogenesis of OA involves a variety of inflammatory mediators, including nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. From the molecular mechanism, the nuclear factor-erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway and the expression of ROS regulated the production of the above inflammatory mediators. Saikosaponin D (SSD), which is an active ingredient isolated from Bupleurum, has various biological functions. In this study, IL-1β was used as a pro-inflammatory factor to create an in vitro OA model. According to the results of high-density culture, qPCR, ROS measurement, Western blot, and immunofluorescence, SSD activated the Nrf2/HO-1/ROS axis, inhibited the production of inflammatory mediators, and protected against ECM destruction. The DMM mouse model was used as a model of OA in mice. From the results of safranin O/fast green staining, hematoxylin–eosin staining, tartrate-resistant acid phosphatase (TRAP) staining, and OARSI scores, SSD protected against the mice knee articular cartilage degeneration and reduced the number of osteoclasts in the subchondral bone. Experimental results found that SSD suppressed IL-1β–induced differentiated ATDC 5 chondrocytes apoptosis via the Nrf2/HO-1/ROS axis in vitro. SSD delayed the progression of OA in DMMs model mice in vivo. Therefore, SSD has the potential to become a drug for clinical treatment of OA.
Comparison of the Effectiveness and Safety of d-Penicillamine and Zinc Salt Treatment for Symptomatic Wilson Disease: A Systematic Review and Meta‐Analysis
Authors: Tang Shan , Bai Li , Hou Wei , Hu Zhongjie , Chen Xinyue , Zhao Jing , Liang Chen , Zhang Wei , Duan Zhongping , Zheng Sujun
Published: March 2022

Background: Pharmacological therapy is currently the main treatment method for patients with Wilson disease (WD). We aimed to evaluate the efficacy and safety of the common treatment regimens in these patients.

Methods: We conducted a systemic review and meta-analysis by searching multiple databases for studies from inception to October 2021. Outcomes of interest were the improved rate and safety of d-penicillamine and zinc salts treatment in WD patients. Two independent reviewers performed the study selection and data extraction.

Results: Sixteen studies were included in this meta-analysis. The pooled improved rate for all included symptomatic WD patients was 78.0% (95% CI: 70.8%–85.2%). In symptomatic hepatic WD patients, there is no difference in the treatment efficiency of d-penicillamine and zinc salts (RR: 0.98, 95% CI: 0.86%–1.12%; p = 0.765). In neurological WD patients, the pooled improved rate of those who received d-penicillamine and zinc salts was 56.3% (95% CI: 37.5%–75.1%) and 80.2% (95% CI: 67.2%–93.2%), respectively. The incidence of adverse effects (RR: 2.42, 95% CI: 1.20%–4.88%; p = 0.014) and neurological deterioration (RR: 1.96, 95% CI: 1.31%–2.93%; p = 0.001) in all symptomatic WD patients treated with d-penicillamine was both higher than that of patients treated with zinc salts.

Conclusion: Our analysis suggests that symptomatic WD patients treated with d-penicillamine have higher incidence of adverse effects and neurological deterioration than that of zinc salts. The therapeutic effectiveness of these two regimens does not seem to be significantly different, and these results must be interpreted with caution.

Systematic Review Registration: PROSPERO registration, identifier CRD 42021287126.
CX3CL1 Worsens Cardiorenal Dysfunction and Serves as a Therapeutic Target of Canagliflozin for Cardiorenal Syndrome
Authors: Zheng Cankun , Xuan Wanling , Chen Zhenhuan , Zhang Rui , Huang Xiaoxia , Zhu Yingqi , Ma Siyuan , Chen Kaitong , Chen Lu , He Mingyuan , Lin Hairuo , Liao Wangjun , Bin Jianping , Liao Yulin
Published: March 2022

The prognosis of cardiorenal dysfunction induced by diabetes mellitus (DM), which belongs to cardiorenal syndrome type 5, is poor and its pathogenesis remains elusive. We have reported that CX3CL1 exacerbated heart failure and direct inhibition of CX3CL1 improved cardiac function. Emerging evidence supports that CX3CL1 is involved in renal impairment. Here we attempt to clarify whether CX3CL1 might be a therapeutic target for cardiorenal dysfunction in diabetes. We found that cardiac and renal CX3CL1 protein levels were significantly increased in both streptozotocin-induced diabetic mice and in non-obese diabetic mice, and that hyperglycemia led to persistent CX3CL1 expression in the heart and kidneys even after it was controlled by insulin. In cultured cardiac and renal cells, soluble CX3CL1 accelerated mitochondrial-dependent apoptosis via activation of the RhoA/ROCK1-Bax signaling pathway and promoted fibrosis through cellular phenotypic trans-differentiation mediated by the TGF-β/Smad pathway. In the two diabetic mouse models, knockout of CX3CL1 receptor CX3CR1 or treatment with an CX3CL1 neutralizing antibody significantly improved cardiorenal dysfunction by inhibiting apoptosis, mitochondrial dysfunction, and fibrosis. Moreover, sodium glucose cotransporter 2 inhibitor canagliflozin significantly downregulated cardiac and renal CX3CL1 expression and improved cardiorenal dysfunction. These findings indicate that CX3CL1 could be a new therapeutic target for diabetes-induced cardiorenal dysfunction.
Cleavage Stimulation Factor Subunit 2: Function Across Cancers and Potential Target for Chemotherapeutic Drugs
Authors: Feng Linfei , Jing Fengyang , Qin Xiaofeng , Zhou Liming , Ning Yujie , Hou Jun , Kong Weihao , Zhu Youming
Published: March 2022

The cleavage stimulation factor subunit complex is involved in the cleavage and polyadenylation of 3′-end pre-mRNAs that regulate mRNA formation and processing. However, cleavage stimulation factor subunit 2 (CSTF2) was found to play a more critical regulatory role across cancers. General cancer data sets from The Cancer Genome Atlas and Genotype-Tissue Expression project were thus downloaded for differential analysis, and the possible functions and mechanisms of CSTF2 in general cancer were analyzed using the Compartments database, cBioPortal database, Tumor Immune Single-cell Hub database, and Comparative Toxigenomics database using gene set enrichment analysis and R software. The results showed that CSTF2 could affect DNA repair and methylation in tumor cells. In addition, CSTF2 was associated with multiple tumor immune infiltrates in a wide range of cancers, and its high expression was associated with multiple immune checkpoints; therefore, it could serve as a potential target for many drug molecules. We also proved that CSTF2 promotes oral cell proliferation and migration. The high diagnostic efficacy of CSTF2 suggested that this gene may act as a new biomarker and personalized therapeutic target for a variety of tumors.
Major Constituents From Brucea javanica and Their Pharmacological Actions
Authors: Zhang Juan , Xu Hong-Xi , Dou Yao-Xing , Huang Qiong-Hui , Xian Yan-Fang , Lin Zhi-Xiu
Published: March 2022

Brucea javanica (Ya-dan-zi in Chinese) is a well-known Chinese herbal medicine, which is traditionally used in Chinese medicine for the treatment of intestinal inflammation, diarrhea, malaria, and cancer. The formulation of the oil (Brucea javanica oil) has been widely used to treat various types of cancer. It has also been found that B. javanica is rich in chemical constituents, including quassinoids, triterpenes, alkaloids and flavonoids. Pharmacological studies have revealed that chemical compounds derived from B. javanica exhibit multiple bioactivities, such as anti-cancer, anti-bacterial, anti-diabetic, and others. This review provides a comprehensive summary on the pharmacological properties of the main chemical constituents presented in B. javanica and their underlying molecular mechanisms. Moreover, the review will also provide scientific references for further research and development of B. javanica and its chemical constituents into novel pharmaceutical products for disease management.
PD-1/PD-L1 Inhibitors in Patients With Preexisting Autoimmune Diseases
Authors: Zhang Ke , Kong Xiangyi , Li Yuan , Wang Zhongzhao , Zhang Lin , Xuan Lixue
Published: March 2022

Autoimmune diseases and malignant tumors are the two hotspots and difficulties that are currently being studied and concerned by the medical field. The use of PD-1/PD-L1 inhibitors improves the prognosis of advanced tumors, but excessive immune responses can also induce immune-related adverse events (irAEs). Due to this concern, many clinical trials exclude cancer patients with preexisting autoimmune disease (AID). This review outlines the possible mechanisms of irAE, discusses the safety and efficacy of PD-1/PD-L1 inhibitors in cancer patients with preexisting AID, and emphasizes the importance of early recognition, continuous monitoring, and multidisciplinary cooperation in the prevention and management of cancer patients with preexisting AID.
KRIBB11: A Promising Drug that Promotes Microglial Process Elongation and Suppresses Neuroinflammation
Authors: Su Jianbin , Dou Zhihua , Hong Hongxiang , Xu Feng , Lu Xu , Lu Qun , Ye Ting , Huang Chao
Published: March 2022

Microglia are key components of the central innate immune system. The over-activation of microglia, which occurs in nervous system disorders, is usually accompanied with retractions of their ramified processes. Reversing of microglial process retraction is a potential strategy for the prevention of neuroinflammation. Our previous studies have reported some endogenous molecules and drugs that can promote microglial process elongation at conditions in vitro and in vivo, such as butyrate and β-hydroxybutyrate, sulforaphane, and diallyl disulfide. Here, reported another compound that can promote microglial process elongation. We found that KRIBB11, a compound which has been reported to suppress nitric oxide production in microglia, induced significant elongations of the processes in microglia in cultured and in vivo conditions in a reversible manner. KRIBB11 pretreatment also prevented lipopolysaccharide (LPS)-induced shortenings of microglial process in cultured conditions and in vivo conditions, inflammatory responses in primary cultured microglia and the prefrontal cortex, and depression-like behaviors in mice. Mechanistic studies revealed that KRIBB11 incubation up-regulated phospho-Akt in cultured microglia and Akt inhibition blocked the pro-elongation effect of KRIBB11 on microglial process in cultured conditions and in vivo conditions, suggesting that the regulatory effect of KRIBB11 is Akt-dependent. Akt inhibition was also found to abrogate the preventive effect of KRIBB11 on LPS-induced inflammatory responses in primary cultured microglia and prefrontal cortexes as well as LPS-induced depression-like behaviors in mice. Collectively, our findings demonstrated that KRIBB11 is a novel compound that can prevent microglial activation and neuroinflammation-associated behavioral deficits possibly through inducing the Akt-mediated elongation of microglial process.
Influenza A Virus-Driven Airway Inflammation may be Dissociated From Limb Muscle Atrophy in Cigarette Smoke-Exposed Mice
Authors: Mou Kevin , Chan Stanley M. H. , Brassington Kurt , Dobric Aleksandar , De Luca Simone N. , Seow Huei Jiunn , Selemidis Stavros , Bozinovski Steven , Vlahos Ross
Published: March 2022

Limb muscle dysfunction is a hallmark of Chronic Obstructive Pulmonary Disease (COPD) which is further worsened following a viral-induced acute exacerbation of COPD (AECOPD). An amplified airway inflammation underlies the aggravated respiratory symptoms seen during AECOPD, however, its contributory role to limb muscle dysfunction is unclear. The present study examined the impact of influenza A virus (IAV)-induced exacerbation on hind limb muscle parameters. Airway inflammation was established in male BALB/c mice by exposure to cigarette smoke (CS) for 8 weeks. Exacerbation was then induced via inoculation with IAV, and various lung and muscle parameters were assessed on day 3 (peak of airway inflammation) and day 10 (resolution phase) post-infection. IAV infection exacerbated CS-induced airway inflammation as evidenced by further increases in immune cell counts within bronchoalveolar lavage fluid. Despite no significant impact on muscle mass, IAV exacerbation worsened the force-generating capacity of the tibialis anterior (TA) muscle. Protein oxidation and myogenic disruption was observed in the TA following CS exposure, however, IAV exacerbation did not augment these detrimental processes. To further explore the contributory role of airway inflammation on myogenic signaling, cultured myotubes were exposed to conditioned medium (CM) derived from bronchial epithelial cells stimulated with polyinosinic:polycytidylic acid and cigarette smoke extract (CSE). Despite an amplified inflammatory response in the lung epithelial cells, the CM derived from these cells did not potentiate myogenic disruption in the C2C12 myotubes. In conclusion, our data suggest that certain parameters of limb muscle dysfunction seen during viral-induced AECOPD may be independent of airway inflammation.
Polydatin Glycosides Improve Monocrotaline-Induced Pulmonary Hypertension Injury by Inhibiting Endothelial-To-Mesenchymal Transition
Authors: Chen Xing , He Yao , Yu Zhijie , Zuo Jianli , Huang Yan , Ruan Yi , Zheng Xiaoyuan , Ma Yu
Published: March 2022

Objective: To study the effect of polydatin on the injury of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT).

Methods: SD rats were induced to develop PAH injury by a single subcutaneous injection of MCT (60 mg/kg). From the second day, rats in the administration group were orally given sildenafil (20 mg/kg) and polydatin (30 or 60 mg/kg) for 3 weeks. At the end of the experiment, right ventricular hypertrophy (RVH) index of SD rats was calculated, pathological damage was assessed by HE staining, transcription levels of target genes were detected by RT-PCR and Elisa, and expression levels of Endothelial-to-mesenchymal transition (EndMT) related proteins were detected by immunohistochemistry (IHC) and immunofluorescence (IF). Finally, molecular docking analysis was used to verify the interaction of polydatin on the main targets.

Results: Polydatin could significantly restore the body function, reduce MCT-induced PAH injury, reduce serum biochemical indices; polydatin could effectively inhibit EndMT process by decreasing the expression of N-cadherin, β-catenin and vimentin; polydatin could down-regulate TAGLN expression and increase PECAM1 expression to reduce pulmonary vascular remodeling. The interaction between polydatin and EndMT target was confirmed by molecular docking operation.

Conclusion: Pharmacological experiments combined with Combining molecular docking was first used to clarify that polydatin can reduce the pulmonary endothelial dysfunction and pulmonary vascular remodeling induced by MCT by inhibiting EndMT. The results of the study provide new ideas for the further treatment of PAH injury.
Amiodarone Provides Long-Lasting Local Anesthesia and Analgesia in Open-State Mouse Nociceptors
Authors: Kotoda Masakazu , Matsuoka Toru , Wada Keiichi , Jayakar Selwyn , Ino Hirofumi , Kawago Koji , Kumakura Yasutomo
Published: March 2022

Local anesthetics with long-lasting effects and selectivity for nociceptors have been sought over the past decades. In this study, we investigated whether amiodarone, a multiple channel blocker, provides long-lasting local anesthesia and whether adding a TRPV1 channel activator selectively prolongs sensory anesthetic effects without prolonging motor blockade. Additionally, we examined whether amiodarone provides long-lasting analgesic effects against inflammatory pain without TRPV1 channel activator co-administration. In the sciatic nerve block model, 32 adult C57BL/6J mice received either bupivacaine, amiodarone with or without capsaicin (a TRPV1 agonist), or vehicle via peri-sciatic nerve injection. Sensory and motor blockade were assessed either by pinprick and toe spread tests, respectively. In another set of 16 mice, inflammatory pain was induced in the hind paw by zymosan injection, followed by administration of either amiodarone or vehicle. Mechanical and thermal sensitivity and paw thickness were assessed using the von Frey and Hargreaves tests, respectively. The possible cardiovascular and neurological side effects of local amiodarone injection were assessed in another set of 12 mice. In the sciatic nerve block model, amiodarone produced robust anesthesia, and the co-administration of TRPV1 agonist capsaicin prolonged the duration of sensory blockade, but not that of motor blockade [complete sensory block duration: 195.0 ± 9.8 min vs. 28.8 ± 1.3 min, F (2, 21) = 317.6, p < 0.01, complete motor block duration: 27.5 ± 1.6 min vs. 21.3 ± 2.3 min, F (2, 22) = 11.1, p = 0.0695]. In the zymosan-induced inflammatory pain model, low-dose amiodarone was effective in reversing the mechanical and thermal hypersensitivity not requiring capsaicin co-administration [50% withdrawal threshold at 8 h (g): 0.85 ± 0.09 vs. 0.25 ± 0.08, p < 0.01, withdrawal latency at 4 h (s) 8.5 ± 0.5 vs. 5.7 ± 1.4, p < 0.05]. Low-dose amiodarone did not affect zymosan-induced paw inflammation. Local amiodarone did not cause cardiovascular or central nervous system side effects. Amiodarone may have the potential to be a long-acting and nociceptor-selective local anesthetic and analgesic method acting over open-state large-pore channels.