bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Serotonergic Modulation of Principal Neurons and Interneurons in the Anterior Piriform Cortex
Authors: Piszár Ildikó , Lőrincz Magor L.
Published: February 2022

Originating from the brainstem raphe nuclei, serotonin is an important neuromodulator involved in a variety of physiological and pathological functions. Specific optogenetic stimulation of serotonergic neurons results in the divisive suppression of spontaneous, but not sensory evoked activity in the majority of neurons in the primary olfactory cortex and an increase in firing in a minority of neurons. To reveal the mechanisms involved in this dual serotonergic control of cortical activity we used a combination of in vitro electrophysiological recordings from identified neurons in the primary olfactory cortex, optogenetics and pharmacology and found that serotonin suppressed the activity of principal neurons, but excited local interneurons. The results have important implications in sensory information processing and other functions of the olfactory cortex and related brain areas.
Nanomaterials for Postharvest Management of Insect Pests: Current State and Future Perspectives
Authors: Jasrotia Poonam , Nagpal Mohini , Mishra Chandra Nath , Sharma Amit Kumar , Kumar Satish , Kamble Umesh , Bhardwaj Ajay Kumar , Kashyap Prem Lal , Kumar Sudheer , Singh Gyanendra Pratap
Published: February 2022

Globally, between one quarter and one-third of total grains produced each year are lost during storage mainly through infestation of insect pests. Among the available control options such as chemical and physical techniques, fumigation with aluminum phosphide (AlP) is so far considered the best control strategy against storage insect pests. However, these insect pests are now developing resistance against AIP due to its indiscriminate use due to non-availability of any effective alternative control option. Resistance to AIP among storage insect pests is increasing, and its inhalation has shown adverse effects on animals and human beings. Nanotechnology has opened up a wide range of opportunities in various fields such as agriculture (pesticides, fertilizers, etc.), pharmaceuticals, and electronics. One of the applications of nanotechnology is the usage of nanomaterial-based insecticide formulations for mitigating field and storage insect pests. Several formulations, namely, nanoemulsions, nanosuspensions, controlled release formulations, and solid-based nanopesticides, have been developed with different modes of action and application. The major advantage is their small size which helps in proper spreading on the pest surface, and thus, better action than conventional pesticides is achieved. Besides their minute size, these have no or reduced harmful effects on non-target species. Nanopesticides can therefore provide green and efficient alternatives for the management of insect pests of field and storage. However, an outcry against the utilization of nano-based pesticides is also revealed. It is considered by some that nano-insecticides may also have hazardous effects on humans as well as on the environment. Due to limited available data, nanopesticides have become a double-edged weapon. Therefore, nanomaterials need to be evaluated extensively for their large-scale adoption. In this article, we reviewed the nanoformulations that are developed and have proved effective against the insect pests under postharvest storage of grains.
Remote Ischemic Conditioning in the Prevention for Stroke-Associated Pneumonia: A Pilot Randomized Controlled Trial
Authors: Zhang Bowei , Zhao Wenbo , Ma Hongrui , Zhang Yunzhou , Che Ruiwen , Bian Tingting , Yan Heli , Xu Jiali , Wang Lin , Yu Wantong , Liu Jia , Song Haiqing , Duan Jiangang , Chang Hong , Ma Qingfeng , Zhang Qian , Ji Xunming
Published: February 2022

Background

Despite the continuing effort in investigating the preventive therapies for stroke-associated pneumonia (SAP), which is closely associated with unfavorable outcomes, conclusively effective therapy for the prevention of SAP is still lacking. Remote ischemic conditioning (RIC) has been proven to improve the survival in the sepsis model and inflammatory responses have been indicated as important mechanisms involved in the multi-organ protection effect of RIC. This study aimed to assess the safety and the preliminary efficacy of RIC in the prevention of SAP in patients with acute ischemic stroke.

Methods

We performed a proof-of-concept, pilot open-label randomized controlled trial. Eligible patients (age > 18 years) within 48 h after stroke onset between March 2019 and October 2019 with acute ischemic stroke were randomly allocated (1:1) to the RIC group and the control group. All participants received standard medical therapy. Patients in the RIC group underwent RIC twice daily for 6 consecutive days. The safety outcome included any adverse events associated with RIC procedures. The efficacy outcome included the incidence of SAP, changes of immunological profiles including mHLA-DR, TLR-2, and TLR-4 as well as other plasma parameters from routine blood tests.

Results

In total, 46 patients aged 63.1 ± 12.5 years, were recruited (23 in each group). Overall, 19 patients in the RIC group and 22 patients in the control group completed this study. No severe adverse event was attributed to RIC procedures. The incidence of SAP was lower in the remote ischemic conditioning group (2 patients [10.5%]) than that in the control group (6 patients [27.3%]), but no significant difference was detected in both univariate and multivariate analysis (p = 0.249 and adjusted p = 0.666). No significance has been found in this pilot trial in the level of immunological profiles HLA-DR, TLR4 and TLR2 expressed on monocytes as well as blood parameters tested through routine blood tests between the two groups (p > 0.05). The IL-6 and IL-1β levels at day 5 after admission in the RIC group were lower than those in the control group (p < 0.05).

Interpretation

This proof-of-concept pilot randomized controlled trial was to investigate RIC as a prevention method for SAP. Remote ischemic conditioning is safe in the prevention of SAP in patients with acute ischemic stroke. The preventive effect of RIC on SAP should be further validated in future studies.
Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development
Authors: Papapetropoulos Spyros , Pontius Angela , Finger Elizabeth , Karrenbauer Virginija , Lynch David S. , Brennan Matthew , Zappia Samantha , Koehler Wolfgang , Schoels Ludger , Hayer Stefanie N. , Konno Takuya , Ikeuchi Takeshi , Lund Troy , Orthmann-Murphy Jennifer , Eichler Florian , Wszolek Zbigniew K.
Published: February 2022

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.
Long-Term Sonographical Follow-Up of Arterial Stenosis Due to Spontaneous Cervical Artery Dissection
Authors: Strunk Daniel , Schwindt Wolfram , Wiendl Heinz , Dittrich Ralf , Minnerup Jens
Published: February 2022

Purpose

Little is known about the long-term course of arterial stenosis after spontaneous cervical artery dissection (sCAD). We analyzed changes over time and evaluated factors potentially associated with these changes and recurring sCAD.

Materials and Methods

Adult patients with sCAD, admitted to our neurological department between 2004 and 2018, were included. All patients underwent initial and follow-up repetitive neurovascular ultrasound for a mean duration of 15.3 ± 21 months. Clinical and imaging data were registered for each patient.

Results

A total of 259 sCADs were diagnosed in 224 patients. Either internal carotid arteries (n = 133, 59.4%), vertebral arteries (n = 58, 25.9%), or multiple arteries (n = 33, 14.7%) were affected. In 93 out of 183 patients (51%), and in 117 out of 210 arteries under investigation (55.7%), vascular stenosis decreased over time. Occluded arteries recanalized early in 34 (54%) and stayed occluded in 29 patients (46.0%). Of 145 initially hemodynamically relevant stenosis, 77 (53.1%) improved over time. Overall, 12 patients (5.4 %) had a recurring sCAD during follow-up. Pseudoaneurysms were found in 19 patients.

Conclusion

The sonographical course of sCAD is highly dynamic within the first year after disease onset and should be monitored carefully. Decreasing degrees of stenosis and recanalization of occluded arteries occurred in half of all patients. Recurrent sCAD was a rare event in our cohort.
Leukoaraiosis Mediates the Association of Total White Blood Cell Count With Post-Stroke Cognitive Impairment
Authors: Shan Wanying , Xu Liang , Xu Yuan , Qiu Zhuoyin , Feng Jie , Zhao Jie , Wang Jingwen
Published: February 2022

Background and Purpose

The inflammatory response could play a key role in cognitive impairment. However, there has been limited research into the association between total white blood cell (WBC) count and post-stroke cognitive impairment (PSCI), and the significance of leukoaraiosis (LA) in this relationship is unknown. We aimed to examine the total WBC count in relation to PSCI and whether this association was mediated by LA.

Methods

Consecutive patients with first-ever ischemic stroke were prospectively enrolled from October 2020 to June 2021. The total WBC count was measured after admission. Cognitive function evaluations were performed at the 3-month follow-up using Mini-mental State Examination (MMSE). We defined the PSCI as an MMSE score <27.

Results

A total of 276 patients (mean age, 66.5 years; 54.7% male) were included in this analysis. Among them, 137 (49.6%) patients experienced PSCI. After adjustment for potential confounders, higher total WBC count was significantly correlated with an increased risk of LA [per 1-SD increase, odds ratio (OR), 1.39; 95% CI 1.06–1.82; p = 0.017] and PSCI (per 1-SD increase, OR, 1.51; 95% CI 1.12–2.04; p = 0.006). Furthermore, mediation analysis demonstrated that the association between total WBC count and PSCI was partly mediated by LA (the regression coefficient was changed by 9.7% for PSCI, and 12.4% for PSCI severity, respectively).

Conclusion

Increased total WBC count is a risk factor for PSCI. The presence of LA was partially responsible for the PSCI in patients who had a higher total WBC count.
Is the Phenotype Designation by PSP-MDS Criteria Stable Throughout the Disease Course and Consistent With Tau Distribution?
Authors: Sánchez-Ruiz de Gordoa Javier , Zelaya Victoria , Tellechea-Aramburo Paula , Acha Blanca , Roldán Miren , López-Molina Carlos , Coca Valle , Galbete Arkaitz , Mendioroz Maite , Erro M. Elena
Published: February 2022

Introduction

The MDS-PSP criteria have shown high sensitivity for the PSP diagnosis, but do not discriminate the phenotype diversity. Our purpose was to search for anatomopathological differences among PSP phenotypes resulting from the application of the MDS-PSP criteria comparing with the previous ones.

Methods

Thirty-four PSP cases from a single brain bank were retrospectively classified according to the criteria used by Respondek et al. in 2014 and the PSP-MDS criteria at 3 years (MDS-3y), 6 years (MDS-6y) and at the last clinical evaluation before death (MDS-last). Semiquantitative measurement of total, cortical and subcortical tau load was compared. For comparative analysis, PSP-Richardson syndrome and PSP postural instability were grouped (PSP-RS/PI) as well as the PSP atypical cortical phenotypes (PSP-Cx).

Results

Applying the Respondek's criteria, PSP phenotypes were distributed as follow: 55.9% PSP-RS/PI, 26.5% PSP-Cx, 11.8% PSP-Parkinsonism (PSP-P), and 5.9% PSP-Cerebellum. PSP-RS/PI and PSP-Cx had a higher total tau load than PSP-P; PSP-Cx showed a higher cortical tau load than PSP-RS/PI and PSP-P; and PSP-RS/PI had a higher subcortical tau load than PSP-P. Applying the MDS-3y, MDS-6y and MDS-last criteria; the PSP-RS/PI group increased (67.6, 70.6 and 70.6% respectively) whereas the PSP-Cx group decreased (8.8, and 8.8 and 11.8%). Then, only differences in total and subcortical tau burden between PSP-RS/PI and PSP-P were observed.

Interpretation

After the retrospective application of the new MDS-PSP criteria, total and subcortical tau load is higher in PSP-RS/PI than in PSP-P whereas no other differences in tau load between phenotypes were found, as a consequence of the loss of phenotypic diversity.
Review—Emerging Portable Technologies for Gait Analysis in Neurological Disorders
Authors: Salchow-Hömmen Christina , Skrobot Matej , Jochner Magdalena C. E. , Schauer Thomas , Kühn Andrea A. , Wenger Nikolaus
Published: February 2022

The understanding of locomotion in neurological disorders requires technologies for quantitative gait analysis. Numerous modalities are available today to objectively capture spatiotemporal gait and postural control features. Nevertheless, many obstacles prevent the application of these technologies to their full potential in neurological research and especially clinical practice. These include the required expert knowledge, time for data collection, and missing standards for data analysis and reporting. Here, we provide a technological review of wearable and vision-based portable motion analysis tools that emerged in the last decade with recent applications in neurological disorders such as Parkinson's disease and Multiple Sclerosis. The goal is to enable the reader to understand the available technologies with their individual strengths and limitations in order to make an informed decision for own investigations and clinical applications. We foresee that ongoing developments toward user-friendly automated devices will allow for closed-loop applications, long-term monitoring, and telemedical consulting in real-life environments.
Argan Oil: Chemical Composition, Extraction Process, and Quality Control
Authors: Gharby Said , Charrouf Zoubida
Published: February 2022

Argan oil is considered a relatively international product exported from Morocco, although different companies in Europe and North America distribute argan oil around the globe. Argan oil is non-refined vegetable oil, of the more well-known “virgin oil” type, is produced from the argan tree [Argania spinosa (L.) Skeels]. The argan tree is deemed to be an important forest species from both social and economic standpoints. Argan oil has rapidly emerged as an important product able to bring more income to the local population. In addition, it also has important environmental implications, owing to its ability to stand against desert progression. Currently, argan oil is mainly produced by women's cooperatives in Morocco using a semi-industrial mechanical extraction process. This allows the production of high-quality argan oil. Depending on the method used to prepare argan kernels, two types of argan oil can be obtained: food or cosmetic grade. Cosmetic argan oil is prepared from unroasted kernels, whereas food argan oil is achieved by cold pressing kernels roasted for a few minutes. Previously, the same food argan oil was prepared exclusively by women according to a laborious ancestral process. Extraction technology has been evolved to obtain high-quality argan oil at a large scale. The extraction process and several accompanying parameters can influence the quality, stability, and purity of argan oil. In view of this, the present review discusses different aspects related to argan oil chemical composition along with its nutritional and cosmetic values. Similarly, it details different processes used to prepare argan oil, as well as its quality control, oxidative stability, and authenticity assessment.
Mutation Landscape of Homologous Recombination Repair Genes in Epithelial Ovarian Cancer in China and Its Relationship With Clinicopathlological Characteristics
Authors: Yao Qianlan , Liu Yanhui , Zhang Lihua , Dong Lin , Bao Longlong , Bai Qianming , Cui Qian , Xu Jie , Li Min , Liu Jing , Chuai Shannon , Ying Jianming , Zhang Zhihong , Zhou Xiaoyan
Published: February 2022

Objective

The status of homologous recombination repair (HRR) gene mutations and their impact on the survival of patients with Chinese epithelial ovarian cancer (EOC) are still unclear. In this study, we retrospectively analyzed the mutations of HRR genes in tumor tissues and evaluated their values for predicting the survival of Chinese EOC patients.

Methods

A total of 273 primary EOC patients from five different hospitals between 2015 and 2016 were recruited. All patients received staging surgeries or debulking surgeries combined with systemic platinum-based chemotherapy. DNA was extracted from formalin-fixed, paraffin-embedded sections and analyzed for mutations using a 21-gene panel (including 13 well-known HRR genes) by next-generation sequencing.

Results

High-grade serous carcinoma (HGSOC) accounted for 76.2% of the cohort. A total of 34.1% (93/273) cases had 99 deleterious mutations in 9 HRR genes, namely, BRCA1 (56/273, 20.5%), BRCA2 (20/273, 7.3%), ATM (5/273, 1.8%), RAD51C (5/273, 1.8%), RAD51D (5/273, 1.8%), BRIP1 (2/273, 1.8%), CHEK2 (2/273, 0.7%), FANCI (2/273, 0.7%), and RAD54L (1/273, 0.4%). There is a strong mutual exclusion between HRR genes. The mutation landscape revealed several unappreciated deleterious variants in BRCA1/2 and other HRR genes reported previously. Estimated according to the mutation allele frequency, about 4.8% of the patients had potential somatic HRR gene mutations, which might be underestimated. Moreover, HRR mutations mainly exist in HGSOC (83/208, 39.9%), clear cell (2/30, 6.7%), and endometroid subtypes (8/20, 40%), but not seen in other rare subtypes. BRCA1 mutations tend to be present in younger patients with family history or multiple primary foci. Patients with BRCA1/2 mutations tend to have a longer progression-free survival and overall survival, while other HRR mutation carriers tend to have a shorter progression-free survival, but no significant difference in overall survival.

Conclusion

This study revealed the distribution of HRR gene mutations in Chinese EOC tissues. BRCA1/2 account for the majority of HRR gene mutations and predict long prognosis in HGSOC. Non-BRCA HRR mutations also account for a very important proportion and might be associated with poor prognosis in HGSOC. It is suggested that HRR gene mutations need to be detected in EOC tissues and germline status be further clarified in clinical algorithm for potential targeted therapy, genetic screening, and prognosis prediction.
Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis
Authors: Ma Jiao , Li Lanying , Liao Taiping , Gong Weidong , Zhang Chunyin
Published: February 2022

Objective

To conduct a meta-analysis of the efficacy and safety of 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer based on existing clinical evidence.

Methods

Search for retrospective studies about 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer from establishment to July 2021 in PubMed and EMBASE. The primary endpoint was 225Ac-PSMA-617 biochemical response evaluation criteria after treatment [any prostate specific antigen (PSA) decrease and PSA decrease >50% from baseline] to evaluate the treatment effect. Secondary endpoints included assessment of overall survival (OS), progression-free survival (PFS), molecular response, and toxicity for all studies. Two researchers conducted literature screening, data extraction and quality evaluation according to the inclusion and exclusion criteria. Use stata16.0 software for analysis, fixed-effects model for data merging and forest plots for display.

Results

A total of 6 retrospective studies, namely, 201 patients, were included in the final analysis. The pooled proportions of patients with decreased PSA and PSA decreased by more than 50% were 87.0% (95% confidence interval, 0.820 to 0.920) and 66.1% (95% confidence interval, 0.596 to 0.726), respectively. The pooled proportions of OS and PFS were 12.5 months (95%CI: 6.2–18.8 months) and 9.1 months (95%CI: 2.6–15.7 months). The patients showing molecular responses were 54% (95% confidence interval: 25–84%). In all studies, the most common side effect of 225Ac-PSMA-617 TAT was xerostomia, with any degree of xerostomia occurring in 77.1% (155 out of 201), and grade III only accounted for 3.0%. The second was 30.3% (61 out of 201) anemia of any degree, and grade III accounts for 7.5% (15 out of 201). Grade III leukopenia and thrombocytopenia were 4.5% (9 out of 201) and 5.5% (11 out of 201), respectively. Only 6 (3.0%) of 201 patients had Grade III nephrotoxicity.

Conclusion

225Ac-PSMA-617 is an effective and safe treatment option for mCRPC patients, and the toxicity caused by it is relatively low. However, future randomized controlled trials and prospective trials are required in the future to judge the therapeutic effects and survival benefits compared with existing clinical treatments.

Systematic Review Registration

PROSPERO: CRD42021281967.
Characterization of Cell Cycle-Related Competing Endogenous RNAs Using Robust Rank Aggregation as Prognostic Biomarker in Lung Adenocarcinoma
Authors: Yang Yifei , Zhang Shiqi , Guo Li
Published: February 2022

Lung adenocarcinoma (LUAD), one of the most common pathological subtypes in lung cancer, has been of concern because it is the leading cause of cancer-related deaths. Due to its poor prognosis, to identify a prognostic biomarker, this study performed an integrative analysis to screen curial RNAs and discuss their cross-talks. The messenger RNA (mRNA) profiles were primarily screened using robust rank aggregation (RRA) through several datasets, and these deregulated genes showed important roles in multiple biological pathways, especially for cell cycle and oocyte meiosis. Then, 31 candidate genes were obtained via integrating 12 algorithms, and 16 hub genes (containing homologous genes) were further screened according to the potential prognostic values. These hub genes were used to search their regulators and biological-related microRNAs (miRNAs). In this way, 10 miRNAs were identified as candidate small RNAs associated with LUAD, and then miRNA-related long non-coding RNAs (lncRNAs) were further obtained. In-depth analysis showed that 4 hub mRNAs, 2 miRNAs, and 2 lncRNAs were potential crucial RNAs in the occurrence and development of cancer, and a competing endogenous RNA (ceRNA) network was then constructed. Finally, we identified CCNA2/MKI67/KIF11:miR-30a-5p:VPS9D1-AS1 axis-related cell cycle as a prognostic biomarker, which provided RNA cross-talks among mRNAs and non-coding RNAs (ncRNAs), especially at the multiple isomiR levels that further complicated the coding–non-coding RNA regulatory network. Our findings provide insight into complex cross-talks among diverse RNAs particularly involved in isomiRs, which will enrich our understanding of mRNA–ncRNA interactions in coding–non-coding RNA regulatory networks and their roles in tumorigenesis.
SPOCK1 Promotes the Development of Hepatocellular Carcinoma
Authors: Váncza Lóránd , Karászi Katalin , Péterfia Bálint , Turiák Lilla , Dezső Katalin , Sebestyén Anna , Reszegi Andrea , Petővári Gábor , Kiss András , Schaff Zsuzsanna , Baghy Kornélia , Kovalszky Ilona
Published: February 2022

The extracellular matrix proteoglycan SPOCK1 is increasingly recognized as a contributor to the development and progression of cancers. Here, we study how SPOCK1, which is present in non-tumorous hepatocytes at low concentrations, promotes the development and progression of malignant hepatocellular tumors. Although SPOCK1 is an extracellular matrix proteoglycan, its concentration increases in the cytoplasm of hepatocytes starting with very low expression in the normal cells and then appearing in much higher quantities in cells of cirrhotic human liver and hepatocellular carcinoma. This observation is similar to that observed after diethylnitrosamine induction of mouse hepatocarcinogenesis. Furthermore, syndecan-1, the major proteoglycan of the liver, and SPOCK1 are in inverse correlation in the course of these events. In hepatoma cell lines, the cytoplasmic SPOCK1 colocalized with mitochondrial markers, such as MitoTracker and TOMM20, a characteristic protein of the outer membrane of the mitochondrion and could be detected in the cell nucleus. SPOCK1 downregulation of hepatoma cell lines by siRNA inhibited cell proliferation, upregulated p21 and p27, and interfered with pAkt and CDK4 expression. A tyrosine kinase array revealed that inhibition of SPOCK1 in the liver cancer cells altered MAPK signaling and downregulated several members of the Sarc family, all related to the aggressivity of the hepatoma cell lines. These studies support the idea that SPOCK1 enhancement in the liver is an active contributor to human and rodent hepatocarcinogenesis and cancer progression. However, its mitochondrial localization raises the possibility that it has a currently unidentified physiological function in normal hepatocytes.
Potential Biomarkers for Liver Cancer Diagnosis Based on Multi-Omics Strategy
Authors: Chen Fanghua , Wang Junming , Wu Yingcheng , Gao Qiang , Zhang Shu
Published: February 2022

Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients are eligible for curative therapy mainly due to the lack of early-detection strategies, highlighting the significance of reliable and accurate biomarkers. The integration of multi-omics became an important tool for biomarker screening and unique alterations in tumor-associated genes, transcripts, proteins, post-translational modifications and metabolites have been observed. We here summarized the novel biomarkers for HCC diagnosis based on multi-omics technology as well as the clinical significance of these potential biomarkers in the early detection of HCC.
Local Anesthetic Ropivacaine Exhibits Therapeutic Effects in Cancers
Authors: Xu Peng , Zhang Shaobo , Tan Lili , Wang Lei , Yang Zhongwei , Li Jinbao
Published: February 2022

Despite the significant progress in cancer treatment, new anticancer therapeutics drugs with new structures and/or mechanisms are still in urgent need to tackle many key challenges. Drug repurposing is a feasible strategy in discovering new drugs among the approved drugs by defining new indications. Recently, ropivacaine, a local anesthetic that has been applied in clinical practice for several decades, has been found to possess inhibitory activity and sensitizing effects when combined with conventional chemotherapeutics toward cancer cells. While its full applications and the exact targets remain to be revealed, it has been indicated that its anticancer potency was mediated by multiple mechanisms, such as modulating sodium channel, inducing mitochondria-associated apoptosis, cell cycle arrest, inhibiting autophagy, and/or regulating other key players in cancer cells, which can be termed as multi-targets/functions that require more in-depth studies. In this review, we attempted to summarize the research past decade of using ropivacaine in suppressing cancer growth and sensitizing anticancer drugs both in-vitro and in-vivo, and tried to interpret the underlying action modes. The information gained in these findings may inspire multidisciplinary efforts to develop/discover more novel anticancer agents via drug repurposing.
Henoch-Schönlein Purpura /IgA Vasculitis Complicated by Coronary Artery Aneurysm: A Case Report and Literature Review
Authors: Kang Zhijuan , Wu Wentao , Xun Mai , Ding Yunfeng , Li Zhihui
Published: February 2022

Henoch-Schönlein purpura (HSP)/ IgA vasculitis (IgAV) is the most common form of systemic vasculitis in children and often involves the skin, gastrointestinal tract, joints, and kidneys, though cardiac involvement rarely occurs. We report on a 6-year-old male child with HSP/IgAV who had renal and cardiac involvement at the initial stage of the disease and in whom we found an extremely rare coronary artery aneurysm. After administration of glucocorticoid combined with mycophenolate mofetil, the renal involvement improved, but the coronary artery aneurysm remained. Pursuant to this case, we retrieved information on other cases of HSP/IgAV complicated with cardiac involvement from the PubMed database, and excluded cases of cardiac involvement accompanied by Kawasaki disease, polyarteritis nodosa, rheumatic fever, Takayasu arteritis, systemic lupus erythematosus, poststreptococcal glomerulonephritis, or sepsis. We then analyzed gender, age, cardiac involvement, renal involvement, treatment, and prognoses. To date, 24 cases of HSP/IgAV complicated with cardiac involvement have been reported. Among them, there were 22 male and 2 female patients, with the onset age ranging from 3 to 71 years old. A total of 10 children (including the child we examined) and 14 adults were identified, and 17 patients (70.8%) had HSP/IgAV complicated with renal involvement. The majority of patients were treated with glucocorticoid and/or immunosuppressants or biological agents, 4 patients died (16.7%), 8 patients were completely relieved (33.3%), and 3 patients had unknown prognoses. This article suggests that HSP/IgAV complicated with cardiac involvement may result in a poor prognosis and early treatment may therefore be essential. Our case revealed that glucocorticoid does not prevent the occurrence of renal and cardiac involvement in HSP/IgAV patients. If HSP/IgAV is complicated with coronary artery dilation, the therapeutic effect of glucocorticoid combined with immunosuppressants is not satisfactory, and early administration of biological agents or IVIG may be an effective therapeutic regimen.
Congenitally Corrected Transposition of the Great Arteries: Mid-term Outcomes of Different Surgical Strategies
Authors: He Xiaomin , Shi Bozhong , Song Zhiying , Pan Yanjun , Luo Kai , Sun Qi , Zhu Zhongqun , Xu Zhiwei , Zheng Jinghao , Zhang Zhifang
Published: February 2022

Background

Optimal management for congenitally corrected transposition of the great arteries (ccTGA) is controversial. We applied different surgical strategies based on individual variations in our single-centered practice over 10 years, aming to describe the mid-term results.

Methods

From January 2008 to June 2021, 90 patients with ccTGA were reviewed and grouped by three different surgical strategies: 41 cases with biventricular correction as biventricular group, 11 cases with 1.5 ventricular correction as 1.5 ventricular group, and 38 cases with Fontan palliation as univentricular group. The mean age at primary surgery was 41.4 ± 22.7 months. Patients were followed for mortality, complications, reoperation, cardiac function, and valve status.

Results

The median follow-up period was 5.1 years (range, 1.5–12.5 years). The overall 10-year survival and freedom from reoperation rate was 86.7 and 82.4%, respectively. There were 3 early deaths and 3 mid-term deaths in the biventricular group, while 2 early deaths and 1 mid-term deaths were reported in the univentricular group. Although 1.5 ventricular group presented no death and the fewest complications, we still found similar mortality (p = 0.340) and morbidity (p = 0.670) among the three groups. The bypass time, aortic-clamp time, and ICU stay length were the longest in the biventricular group, followed by the 1.5 ventricular group (p < 0.001). However, in mid-term follow-up, biventricular and 1.5 ventricular groups both showed excellent cardiac function and obvious improvement of tricuspid regurgitation (p = 0.008 and p = 0.051, respectively). Fontan palliation provided acceptable mid-term outcomes as well, despite a lower ejection fraction.

Conclusion

Satisfactory mid-term outcomes could be achieved for highly selected ccTGA patients using the whole spectrum of surgical techniques. Moreover, 1.5 ventricular correction, as a new emerging technique in recent years, might hold great promise in future practice.
Different Reaction Patterns of Caregivers of Children With Imperforate Anus: A Latent Profile Analysis
Authors: Wang Dan , Xu Hongzhen , Liu Kexian , Tou Jinfa , Jia Yushuang , Gao Wei , Chen Xiaofei , Luo Feixiang
Published: February 2022

Aim

This study aimed to explore how different dimensions of caregivers' reaction shape their caring experience, and the factors associated with different reaction patterns.

Design

A second analysis of a multisite cross-sectional study were conducted. Caregivers of children with imperforate anus (IA) were enrolled in three tertiary children's hospitals in Eastern China between November 2018 and February 2019.

Methods

The caregiver's experience, stigma feeling, social support level and perception of uncertainty were assessed by Caregiver Reaction Assessment, Parent Stigma Scale, Social Support Scale and Parent's Perception of Uncertainty Scale accordingly. The demographic information of caregivers as well as the children's clinical data were collected. Latent profile analysis was conducted to determine different patterns of caregiver's reaction, and logistics analysis was used to explore the associated factors of the reaction pattern.

Findings

A total number of 229 caregivers (median age = 30, quartiles: 28, 36) were included. Three distinguishable caregiving reaction types were identified (Class 1: low burden and high benefit, 4.8%; Class 2: moderate burden and benefit, 48.9%; Class 3: high burden and low benefit, 46.3%). In logistics analysis, the Class 1 and Class 2 were combined as one group due to the low population in Class 1. The marital status of caregiver (OR = 0.067, 95% CI: 0.006, 0.700, P = 0.024), IA type (OR = 1.745, 95% CI: 1.198, 2.541, P = 0.004), children aged > 2 years (OR = 3.219, 95% CI: 1.364, 7.597, P = 0.008), social support (OR = 0.907, 95% CI: 0.865, 0.951, P < 0.001) and perception of uncertainty (OR = 1.054, 95% CI: 1.026, 1.083, P < 0.001) were associated with different caregiver reaction patterns.

Conclusion

Nearly half of the caregivers of children with IA experience reaction of high burden and low benefit, but considerable proportion of caregivers could benefit from the caregiving rather than burden from. Married caregivers may have more negative reaction, especially when children > 2 years and diagnosed with intermediate or high type of IA. However, increasing caregiver's social support and reducing perception of uncertainty may have the potential to modify their reaction pattern.
Berberine Facilitates Extinction and Prevents the Return of Fear
Authors: Huang Shihao , Zhou Yu , Wu Feilong , Shi Cuijie , Yan He , Chen Liangpei , Yang Chang , Luo Yixiao
Published: February 2022

Exposure to a catastrophic event or intense stimulation can trigger fear memories, and the threatening memories persist even over a lifetime. Exposure therapy is based on extinction learning and is widely used to treat fear-related disorders, but its effect on remote fear memory is modest. Berberine, an isoquinoline alkaloid derived from Coptis chinensis or Berberis spp., has been recently reported to exert a diversity of pharmacological effects on the central nervous system, such as facilitating extinction of drug memory. Here, we explored the effect of berberine on extinction of fear memory using a classical contextual fear conditioning (CFC) paradigm, which is Pavlovian conditioning, can rapidly create fear memories related to contexts. Twenty-four hours or 30 days after CFC training, mice were subjected to context extinction (10 days) to extinguish their behaviors and treated with 12.5 or 25 mg/kg berberine intragastrically 1 or 6 h after each extinction session, followed by reinstatement and spontaneous recovery tests. The results showed that intragastric administration of 25 mg/kg berberine 1 h after extinction significantly promoted the extinction of recent and remote fear memories and prevented reinstatement and spontaneous recovery of extinguished fear in mice. These findings indicate that berberine combined with extinction training could serve as a promising novel avenue for the treatment of fear-related disorders.
Suppressing NK Cells by Astragaloside IV Protects Against Acute Ischemic Stroke in Mice Via Inhibiting STAT3
Authors: Li Shichun , Dou Baokai , Shu Shi , Wei Luyao , Zhu Shiguo , Ke Zunji , Wang Zhifei
Published: February 2022

Natural killer (NK) cells, a key member of innate lymphocytes, are a promising immunotherapeutic target for ischemic stroke. Astragaloside IV (ASIV) is isolated fromAstragalus mongholicus Bunge(Fabaceae), a herbal medicine possessing immunomodulatory ability. This study investigated the effect of ASIV on NK cells during the acute stage of brain ischemic injury in a mouse model of middle cerebral artery occlusion (MCAO). MCAO mice treated with ASIV had better functional outcomes, smaller brain infarction and less NK cell brain infiltration. NK cell depletion echoed the protective effect of ASIV. Notably, ASIV did not enhance the protective effect of NK cell depletion against brain ischemic injury. ASIV inhibited glial cell-derived CCL2-mediated chemotaxis to prevent post-ischemic NK cell brain recruitment. Meanwhile, ASIV also abrogated NK cell-mediated cytolytic killing of neurons subjected to oxygen-glucose deprivation and suppressed NK cell-derived IFN-γ and NKG2D expression in the ischemic brain. The inhibitory effect of ASIV on NK cell brain infiltration and activation was mimicked by cryptotanshinone, a STAT3 inhibitor. There was no additive effect when ASIV and cryptotanshinone were used together. In conclusion, ASIV inhibits post-ischemic brain infiltration and activation of NK cells through STAT3 suppression, and this inhibitory effect of ASIV on NK cells plays a key role in its protection against acute ischemic brain injury. Our findings suggest that ASIV is a promising therapeutic candidate in NK cell-based immunotherapy for the treatment of acute ischemic stroke and pave the way for potential clinical trials.
Effects of the Full Coverage Policy of Essential Medicines on Inequality in Medication Adherence: A Longitudinal Study in Taizhou, China
Authors: Guo Zhigang , Zheng Liguang , Fu Mengyuan , Li Huangqianyu , Bai Lin , Guan Xiaodong , Shi Luwen
Published: February 2022

The full coverage policy for essential medicines (FCPEMs) was proposed and implemented in Taizhou city of Zhejiang Province, China, to promote equal access and adherence to medicines. This study aimed to examine the effects of FCPEMs on the income-related inequality in medication adherence among local patients with hypertension or diabetes. We collected electronic health records of patients with hypertension or diabetes of three districts of Taizhou from 2011 to 2016. As the implementation schedule of the FCPEMs varied across districts, we applied a retrospective longitudinal study design and assigned records from 1 year before to 3 years following the implementation of FCPEMs as baseline and follow-up data. We thus generated a dataset with 4-year longitudinal data. The concentration index (CI) and its decomposition method were employed to measure factors contributing to inequality in medication adherence and the role played by FCPEMs. The sample size rose from 264,836 at the baseline to 315,677, 340,512, and 355,676 by each follow-up year, and the proportion of patients taking free medicines rose from 17.6 to 25.0 and 29.8% after FCPEMs implementation. The proportion of patients with high adherence increased from 39.9% at baseline to 51.6, 57.2, and 60.5%, while CI decreased from 0.073 to −0.011, −0.029, and −0.035. The contribution of FCPEMs ranked at 2nd/13, 7th/13, and 2nd/13 after the implementation of FCPEMs. Changes in CI of medication adherence for every 2 years were −0.084, −0.018, and −0.006, and the contribution of FCPEMs was −0.006, 0.006, and 0.007, ranking at 2nd/13, 2nd/13, and 1st/13, respectively. Most changes in CI of medication adherence can be attributed to FCPEMs. The medication adherence of patients with hypertension or diabetes improved after the implementation FCPEMs in Taizhou, although inequality did not improve consistently. In general, FCPEMs could be a protective factor against income-related inequalities in access and adherence to medicines. Future research is needed to investigate the change mechanism and the optimal design of similar interventions.
A Novel Compound, Tanshinol Borneol Ester, Ameliorates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Oxidative Stress via the mTOR/β-TrCP/NRF2 Pathway
Authors: Han Dongjian , Wang Fuhang , Wang Bo , Qiao Zhentao , Cui Xinyue , Zhang Yi , Jiang Qingjiao , Liu Miaomiao , Shangguan Jiahong , Zheng Xiaohui , Bai Yajun , Du Chunyan , Shen Deliang
Published: February 2022

Tanshinol borneol ester (DBZ) exerts anti-atherosclerotic and anti-inflammatory effects. However, its effects on cardiac hypertrophy are not well understood. In this work, we investigated the treatment effects and potential mechanisms of DBZ on the hypertrophic heart under oxidative stress and endoplasmic reticulum (ER) stress. A hypertrophic model was established in rats using transverse-aortic constriction (TAC) surgery and in neonatal rat cardiomyocytes (NRCMs) using angiotensin II (Ang II). Our results revealed that DBZ remarkably inhibited oxidative stress and ER stress, blocked autophagy flow, and decreased apoptosisin vivoandin vitrothrough nuclear NRF2 accumulation, and enhanced NRF2 stabilityviaregulating the mTOR/β-TrcP/NRF2 signal pathway. Thus, DBZ may serve as a promising therapeutic for stress-induced cardiac hypertrophy.
Pharmacodynamics and Pharmacokinetics of HSK3486, a Novel 2,6-Disubstituted Phenol Derivative as a General Anesthetic
Authors: Liao Juan , Li Meiting , Huang Chaoli , Yu Yan , Chen Yashu , Gan Jiaqi , Xiao Jie , Xiang Guilin , Ding Xizhi , Jiang Rong , Li Peng , Yang Mengchang
Published: February 2022

Background: The purpose of this study was to characterize the novel sedative/hypnotic agent HSK3486, a 2,6-disubstituted alkylphenol analogue.

Methods: The mechanism of action of HSK3486 was studied in competitive binding assays and whole-cell patch clamp assays. HSK3486 was administered by bolus intravenous injection to dogs and rats, and the loss of righting reflex as well as effects on the cardiovascular and respiratory systems were assessed. The in vitro metabolism of HSK3486 was analyzed by CYP450 genotyping and enzyme inhibition.

Results: HSK3486 competed with t-butylbicycloorthobenzoate (TBOB) and t-butylbicyclophosphorothionate (TBPS) for binding to the gamma-aminobutyric acid type A (GABAA) receptor. HSK3486 potentiated GABA-evoked chloride currents at lower concentrations while activating GABAA receptor at higher concentrations. HSK3486 induced hypnosis in rats and dogs, and had a higher therapeutic index than propofol in rats. The hypnotic potency of HSK3486 was approximately 4-5 fold higher than that of propofol. HSK3486 exerted minimal effects on the cardiovascular system.

Conclusions: HSK3486 is a positive allosteric regulator and direct agonist of GABAA receptor. It has a promising sedative/hypnotic effect and good in vivo pharmacokinetic properties, which justify further studies towards its clinical application.
The Protective Effect of Trichilia catigua A. Juss. on DEHP-Induced Reproductive System Damage in Male Mice
Authors: Chang Xinyue , Dong Mingran , Mi Xiao , Hu Meigeng , Lu Juan , Chen Xi
Published: February 2022

The present study aimed to explore the protective effect and molecular mechanisms ofTrichilia catiguaA. Juss. extract (TCE) against di (2-ethylhexyl) phthalate (DEHP)-induced damage to the reproductive system of mice. Acute toxicity tests revealed that the maximum tolerated dose (MTD) in mice was up to 2.7 g kg−1. After induction with DEHP, TCE (L-TCE, M-TCE, H-TCE) was orally administered to mice for 28 days. Differences in indicators among groups showed that TCE significantly improved the anogenital distance and the organ indexes of the epididymides and testes. It also significantly reduced varicocele and interstitial cell lesions compared to the model group. H-TCE reduced the sperm abnormality rate, increased the levels of sex hormones, Na+K+and Mg2+, Ca2+-ATPase enzyme activity, antioxidant enzyme vitality, coupled with a significant decrease in LH and MDA contents. The levels of testicular marker enzymes ACP and LDH were significantly augmented by both M-TCE and H-TCE. Further studies claimed that DEHP induction reduced the mRNA expression levels ofNrf2, SOD2, SOD3, CDC25C CDK1,CYP11A1, 3β-HSD, 5ɑ-R, AR, SF1,andCYP17A1,increased the level ofKeap1, while TCE reversed the expression levels of these genes. Meanwhile, IHC results demonstrated a significant change in the expression activity of the relevant proteins compared to the control group. The results suggest that M-TCE and H-TCE enabled the recovery of DEHP-induced reproductive system damage in male mice by improving testicular histopathology, repairing testicular function, and reducing oxidative stress damage. The oxidation-related Keap1-Nrf2 pathway, SODs enzyme, the cell cycle control-related CDC25C-CDK1 pathway, and the steroidogenic-related pathway may contribute to this protective effects of TCE.
Optimal Classification of Atrial Fibrillation and Congestive Heart Failure Using Machine Learning
Authors: Fuadah Yunendah Nur , Lim Ki Moo
Published: February 2022

Cardiovascular disorders, including atrial fibrillation (AF) and congestive heart failure (CHF), are the significant causes of mortality worldwide. The diagnosis of cardiovascular disorders is heavily reliant on ECG signals. Therefore, extracting significant features from ECG signals is the most challenging aspect of representing each condition of ECG signal. Earlier studies have claimed that the Hjorth descriptor is assigned as a simple feature extraction algorithm capable of class separation among AF, CHF, and normal sinus rhythm (NSR) conditions. However, due to noise interference, certain features do not represent the characteristics of the ECG signals. This study addressed this critical gap by applying the discrete wavelet transform (DWT) to decompose the ECG signals into sub-bands and extracting Hjorth descriptor features and entropy-based features in the DWT domain. Therefore, the calculation of Hjorth descriptor and entropy-based features performed on each sub-band will produce more detailed information of ECG signals. The optimization of various classifier algorithms, including k-nearest neighbor (k-NN), support vector machine (SVM), random forest (RF), artificial neural network (ANN), and radial basis function network (RBFN), was investigated to provide the best system performance. This study obtained an accuracy of 100% for the k-NN, SVM, RF, and ANN classifiers, respectively, and 97% for the RBFN classifier. The results demonstrated that the optimization of the classifier algorithm could improve the classification accuracy of AF, CHF, and NSR conditions, compared to earlier studies.