bluuebunny/crossref_metadata_2025 huggingface dataset:
Alternations and Applications of the Structural and Functional Connectome in Gliomas: A Mini-Review
Authors: Chen Ziyan , Ye Ningrong , Teng Chubei , Li Xuejun
Published: April 2022

In the central nervous system, gliomas are the most common, but complex primary tumors. Genome-based molecular and clinical studies have revealed different classifications and subtypes of gliomas. Neuroradiological approaches have non-invasively provided a macroscopic view for surgical resection and therapeutic effects. The connectome is a structural map of a physical object, the brain, which raises issues of spatial scale and definition, and it is calculated through diffusion magnetic resonance imaging (MRI) and functional MRI. In this study, we reviewed the basic principles and attributes of the structural and functional connectome, followed by the alternations of connectomes and their influences on glioma. To extend the applications of connectome, we demonstrated that a series of multi-center projects still need to be conducted to systemically investigate the connectome and the structural–functional coupling of glioma. Additionally, the brain–computer interface based on accurate connectome could provide more precise structural and functional data, which are significant for surgery and postoperative recovery. Besides, integrating the data from different sources, including connectome and other omics information, and their processing with artificial intelligence, together with validated biological and clinical findings will be significant for the development of a personalized surgical strategy.
Prognostic Nutritional Index and Oxygen Therapy Requirement Associated With Longer Hospital Length of Stay in Patients With Moderate to Severe COVID-19: Multicenter Prospective Cohort Analyses
Authors: Fernandes Alan L. , Reis Bruna Z. , Murai Igor H. , Pereira Rosa M. R.
Published: April 2022

Purpose

To evaluate whether the prognostic nutritional index (PNI) is related to the oxygen therapy requirement at hospital admission and to ascertain the prognostic effect of the PNI and the oxygen therapy requirement as predictors of hospital length of stay in patients with moderate to severe coronavirus disease 2019 (COVID-19).

Methods

This is a post-hoc analysis in hospitalized patients with moderate to severe COVID-19. The participants were categorized: (1) non-oxygen therapy (moderate COVID-19 not requiring oxygen therapy); (2) nasal cannula therapy (severe COVID-19 requiring nasal cannula oxygen therapy); and (3) high-flow therapy (severe COVID-19 requiring high-flow oxygen therapy). PNI was calculated for each patient according to the following equation: serum albumin [g/dL] × 10 + total lymphocyte count [per mm3] × 0.005. The participants were categorized into malnutrition (PNI <40), mild malnutrition (PNI 40–45), and non-malnutrition (PNI > 45).

Results

According to PNI, malnutrition was more prevalent in the high-flow therapy group (94.9%; P < 0.001) with significantly lower PNI compared to both groups even after adjusting for the center and C-reactive protein. Patients in the high-flow therapy group [9 days (95% CI 7.2, 10.7), P < 0.001] and malnutrition status [7 days (95% CI 6.6, 7.4), P = 0.016] showed a significant longer hospital length of stay compared to their counterparts. The multivariable Cox proportional hazard models showed significant associations between both oxygen therapy requirement and PNI categories and hospital discharge.

Conclusion

In addition to oxygen therapy requirement, low PNI was associated with longer hospital length of stay. Our findings suggest that PNI could be useful in the assessment of nutritional status related to the prognosis of patients with moderate to severe COVID-19.
Hot Tea Consumption and Esophageal Cancer Risk: A Meta-Analysis of Observational Studies
Authors: Luo Hui , Ge Hong
Published: April 2022

Objective

Many laboratory studies have shown that tea consumption protected against the development of esophageal cancer (EC). However, in epidemiological studies, inconsistent or even contradictory results were frequently observed, especially when drinking tea at higher temperatures.

Methods

We conducted a meta-analysis based on published observational studies to explore whether hot tea consumption was a risk factor of EC. Relevant studies were searched in PubMed, Embase, and Web of science up to October 13, 2021, and we also manually retrieved the literature in the included studies and recent reviews.

Results

A total of 23 eligible reports were identified, including 5,050 cases and 10,609 controls, and a meta-analysis with Comprehensive Meta-Analysis (CMA) software (version 2.0) was conducted. A statistically significant increased EC risk was observed when drinking tea at higher temperature (odds ratios (ORs) = 1.79, 95% CI: 1.48–2.15, p = 0.00). Except for esophageal adenocarcinoma (EAC), this increased risk was also found in the majority of subgroups, which are the European and Australian populations.

Conclusions

This meta-analysis showed that people who drank hot tea had a significantly increased risk of Esophageal squamous cell carcinoma (ESCC), but no significant association for EAC.
Comparison of the Suitability Between NRS2002 and MUST as the First-Step Screening Tool for GLIM Criteria in Hospitalized Patients With GIST
Authors: Zhou Xin , Liu Junjin , Zhang Qijuan , Rao Siqi , Wu Xingye , Zhang Jun , Li Juan
Published: April 2022

Objective

The Global Leader Initiative on Malnutrition (GLIM) criteria have been recommended for malnutrition diagnosis recently, for which the first step is malnutrition risk screening with any validated tool. This study aims to investigate the incidence of malnutrition risk in gastrointestinal stromal tumor (GIST) inpatients and compare the suitability of Nutritional Risk Screening 2002 (NRS2002) and Malnutrition Universal Screening Tool (MUST) as the first-step screening tool for GLIM criteria.

Methods

We retrospectively analyzed the clinical data of GIST inpatients in our hospital from January 2015 to December 2019. NRS2002 and MUST were used to screen malnutrition risk at the time of admission. The diagnostic consistency of these two tools with GLIM criteria for malnutrition was analyzed, and the predictive performance of both tools for the length of hospital stay and the occurrence of complications was also evaluated in surgical and non-surgical inpatients.

Results

A total of 269 GIST inpatients were included in this study, of which 45.7 and 40.9% were at malnutrition risk determined by NRS2002 and MUST, respectively. In non-surgical inpatients, NRS2002 and MUST had similar diagnostic consistency with GLIM criteria in sensitivity (93.0 vs. 97.7%), specificity (81.1 vs. 81.1%), and Kappa value (K = 0.75 vs. 0.80), and high nutritional risk classified by NRS2002 and malnutrition identified by GLIM criteria were found to be associated with the length of hospital stay. In surgical inpatients, MUST had better diagnostic consistency with GLIM criteria in sensitivity (86.1 vs. 53.5%) and Kappa value (K = 0.61 vs. 0.30) than NRS2002, but no factors were found associated with the length of postoperative hospital stay or the occurrence of complications.

Conclusion

The malnutrition risk is common in GIST inpatients. NRS2002 is more suitable than MUST for the first-step risk screening of the GLIM scheme in non-surgical inpatients, considering its better performance in screening malnutrition risk and predicting clinical outcomes. MUST was found to have good diagnostic consistency with GLIM criteria for malnutrition in both non-surgical and surgical GIST inpatients, and further studies need to be conducted to investigate its predictive performance on clinical outcomes.
Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects
Authors: Okabe Keisuke , Yaku Keisuke , Uchida Yoshiaki , Fukamizu Yuichiro , Sato Toshiya , Sakurai Takanobu , Tobe Kazuyuki , Nakagawa Takashi
Published: April 2022

Nicotinamide mononucleotide (NNM) is an orally bioavailable NAD+ precursor that has demonstrated beneficial effects against aging and aging-associated diseases in animal models. NMN is ultimately converted to NAD+, a redox cofactor that mediates many metabolic enzymes. NAD+ also serves as the substrate for poly(ADP-ribose) polymerase (PARP) and sirtuins, and regulates various biological processes, such as metabolism, DNA repair, gene expression, and stress responses. Previous mouse models showed that NMN administration can increase NAD+ in various organs and ameliorate aging-related diseases, such as obesity, diabetes, heart failure, stroke, kidney failure, and Alzheimer’s disease through NAD+-mediated pathways. However, evidence of its effect on humans is still scarce. In this study, we conducted a placebo-controlled, randomized, double blind, parallel-group trial to investigate the safety of orally administered NMN and its efficacy to increase NAD+ levels in thirty healthy subjects. Healthy volunteers received 250 mg/day of NMN (n = 15) or placebo (n = 15) for 12 weeks, and physiological and laboratory tests were performed during this period. In addition, NAD+ and its related metabolites in whole blood were examined. Oral supplementation of NMN for 12 weeks caused no abnormalities in physiological and laboratory tests, and no obvious adverse effects were observed. NAD+ levels in whole blood were significantly increased after NMN administration. We also observed the significant rise in nicotinic acid mononucleotide (NAMN) levels, but not in NMN. We also found that the increased amount of NAD+ was strongly correlated with pulse rate before the administration of NMN. These results suggest that oral administration of NMN is a safe and practical strategy to boost NAD+ levels in humans.

Clinical Trial Registration: JRCT [https://jrct.niph.go.jp/], identifier: [jRCTs041200034].
A Novel Angiotensin I-Converting Enzyme Inhibitory Peptide Derived From Goat Milk Casein Hydrolysate Modulates Angiotensin II-Stimulated Effects on Vascular Smooth Muscle Cells
Authors: Qiao Zijiao , Wang Jiaqi , He Zeqi , Pan Lina , Feng Konglong , Peng Xiaoyu , Lin Qianru , Gao Yu , Song Mingyue , Cao Sufang , Chen Yunjiao , Cao Yong , Liu Guo
Published: April 2022

Hypertension is a major risk factor leading to cardiovascular disease, and is frequently treated with angiotensin I-converting enzyme (ACE) inhibitory peptides. The objective of this study was to separate and identify an ACE-inhibitory peptide from goat milk casein hydrolysates, and to evaluate its potential for improving angiotensin II (Ang II)-mediated adverse effects on vascular smooth muscle cells (VSMCs). A novel ACE-inhibitory peptide with the highest activity from the goat milk casein hydrolysates as determined by four steps of RP-HPLC was purified and identified as Phe-Pro-Gln-Tyr-Leu-Gln-Tyr-Pro-Tyr (FPQYLQYPY). The results of inhibitory kinetics studies indicated that the peptide was a non-competitive inhibitor against ACE. Gastrointestinal digest in vitro analysis showed that the hydrolysate of FPQYLQYPY was still active after digestion with gastrointestinal proteases. Moreover, we found that the peptide could significantly inhibit the proliferation and migration of Ang II-stimulated VSMCs. Further transcriptomic analysis revealed that differentially expressed genes (DEGs) were enriched in the cardiovascular disease-related pathways, and that the peptide may have the ability to regulate vascular remodeling. Our findings indicate the potential anti-hypertensive effects of FPQYLQYPY, as well-implicate its role in regulating vascular dysfunction.
Preoperative Prediction of Perineural Invasion Status of Rectal Cancer Based on Radiomics Nomogram of Multiparametric Magnetic Resonance Imaging
Authors: Zhang Yang , Peng Jiaxuan , Liu Jing , Ma Yanqing , Shu Zhenyu
Published: April 2022

Objectives

To compare the predictive performance of different radiomics signatures from multiparametric magnetic resonance imaging (mpMRI), including four sequences when used individually or combined, and to establish and validate an optimal nomogram for predicting perineural invasion (PNI) in rectal cancer (RC) patients.

Methods

Our retrospective study included 279 RC patients without preoperative antitumor therapy (194 in the training dataset and 85 in the test dataset) who underwent preoperative mpMRI scan between January 2017 and January 2021. Among them, 72 cases were PNI-positive. Then, clinical and radiological variables were collected, including carcinoembryonic antigen (CEA), radiological tumour stage (T1-4), lymph node stage (N0-2) and so on. Quantitative radiomics features were extracted and selected from oblique axial T2-weighted imaging (T2WI), T1-weighted imaging (T1WI), apparent diffusion coefficient (ADC), and enhanced T1WI (T1CE) sequences. The clinical model was constructed by integrating the final selected clinical and radiological variables. The radiomics signatures included four single-sequence signatures and one fusion signature were built using the respective remaining optimized features. And the nomogram was constructed based on the independent predictors by using multivariable logistic regression. The area under curve (AUC), DeLong test, calibration curve, and decision curve analysis (DCA) were used to evaluate the performance.

Results

Ultimately, 20 radiomics features were retained from the four sequences—T1WI (n = 4), T2WI (n = 5), ADC (n = 5), and T1CE (n = 6)—to construct four single-sequence radiomics signatures and one fusion radiomics signature. The fusion radiomics signature performed better than four single-sequence radiomics signatures and clinical model (AUCs of 0.835 and 0.773 vs. 0.680-0.737 and 0.666-0.709 in the training and test datasets, respectively). The nomogram constructed by incorporating CEA, tumour stage and rad-score performed best, with AUCs of 0.869 and 0.864 in the training and test datasets, respectively. Delong test showed that the nomogram was significantly different from the clinical model and four single-sequence radiomics signatures (P < 0.05). Moreover, calibration curves demonstrated good agreement, and DCA highlighted benefits of the nomogram.

Conclusions

The comprehensive nomogram can preoperatively and noninvasively predict PNI status, provide a convenient and practical tool for treatment strategy, and help optimize individualized clinical decision-making in RC patients.
An Efficient Nomogram for Discriminating Intrahepatic Cholangiocarcinoma From Hepatocellular Carcinoma: A Retrospective Study
Authors: Si Yuan-Quan , Wang Xiu-Qin , Pan Cui-Cui , Wang Yong , Lu Zhi-Ming
Published: April 2022

Objective

This study aims to establish a nomogram and provide an effective method to distinguish between intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC).

Methods

A total of 1,591 patients with HCC or ICC hospitalized at Shandong Provincial Hospital between January 2016 and August 2021 were included and randomly divided into development and validation groups in a ratio of 3:1. Univariate and multivariate analyses were performed to determine the independent differential factors between HCC and ICC patients in the development cohort. By combining these independent differential factors, the nomogram was established for discriminating ICC from HCC. The accuracy of the nomogram was estimated by using receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Furthermore, the predictive nomogram was assessed in the internal testing set.

Results

Through multivariate analysis, independent differential factors between HCC and ICC involved hepatitis B virus (HBV), logarithm of alpha-fetoprotein (Log AFP), logarithm of protein induced by vitamin K absence or antagonist-II (Log PIVKA-II), logarithm of carbohydrate antigen 199 (Log CA199), and logarithm of carbohydrate antigen 125 (Log CA125). A nomogram was finally established by incorporating these five independent differential factors. Comparing a model of conventional tumor biomarkers including AFP and CA199, the nomogram showed a better distinction between ICC and HCC. The area under the ROC curve (AUC) of ICC diagnosis was 0.951 (95% CI, 0.938–0.964) for the nomogram. The results were consistent in the validation cohort with an AUC of 0.958 (95% CI, 0.938–0.978). After integrating patient preferences into the analysis, the DCA showed that using this nomogram to distinguish ICC and HCC increased more benefit compared with the conventional model.

Conclusion

An efficient nomogram has been established for the differential diagnosis between ICC and HCC, which may facilitate the detection and diagnosis of ICC. Further use of the nomogram in multicenter investigations will confirm the practicality of the tool for future clinical application.
Review: Neurological Complications From Therapies for Pediatric Brain Tumors
Authors: Nguyen Thien , Mueller Sabine , Malbari Fatema
Published: April 2022

Surgery, chemotherapy and radiation have been the mainstay of pediatric brain tumor treatment over the past decades. Recently, new treatment modalities have emerged for the management of pediatric brain tumors. These therapies range from novel radiotherapy techniques and targeted immunotherapies to checkpoint inhibitors and T cell transfer therapies. These treatments are currently investigated with the goal of improving survival and decreasing morbidity. However, compared to traditional therapies, these novel modalities are not as well elucidated and similarly has the potential to cause significant short and long-term sequelae, impacting quality of life. Treatment complications are commonly mediated through direct drug toxicity or vascular, infectious, or autoimmune mechanisms, ranging from immune effector cell associated neurotoxicity syndrome with CART-cells to neuropathy with checkpoint inhibitors. Addressing treatment-induced complications is the focus of new trials, specifically improving neurocognitive outcomes. The aim of this review is to explore the pathophysiology underlying treatment related neurologic side effects, highlight associated complications, and describe the future direction of brain tumor protocols. Increasing awareness of these neurologic complications from novel therapies underscores the need for quality-of-life metrics and considerations in clinical trials to decrease associated treatment-induced morbidity.
Multiple Metastases of the Liver and Lung After Breast-Conserving Surgery for Ductal Carcinoma In Situ Without Microinvasion of the Breast: A Case Report and Literature Review
Authors: Wang Zhen , Zhang Xinyang , Ren Huiyang , Zhang Lei , Chen Bo
Published: April 2022

Background

Ductal carcinoma in situ (DCIS) is a non-invasive disease that rarely causes distant metastasis. It is extremely rare for patients diagnosed with DCIS without microinvasion to develop distant metastasis in the absence of ipsilateral or contralateral breast recurrence. This is the first case report of multiple liver and lung metastases from DCIS after breast-conserving surgery and radiotherapy.

Case Presentation

A 45-year-old woman who was diagnosed with DCIS and received breast-conserving surgery, radiotherapy, and sequential endocrine therapy developed multiple metastases in the liver and lung despite not having bilateral breast recurrence at the 62-month follow-up. Comprehensive advanced breast cancer therapy was administered but did not prevent the progression of metastatic foci in the liver.

Conclusions

This case shows the poor potential outcome in DCIS. Further research should be conducted on metastasis in DCIS; reexamination and monitoring are indispensable for patients diagnosed with DCIS.
Cyclin-Dependent Kinase 6 Identified as the Target Protein in the Antitumor Activity of Tetrastigma hemsleyanum
Authors: Wei Chaoguang , Zhao Yuxiang , Ji Tao , Sun Yong , Cai Xudong , Peng Xin
Published: April 2022

Background

Tetrastigma hemsleyanum (T. hemsleyanum) is widely used as an adjuvant drug for tumor therapy but its antitumor therapeutic targets and molecular mechanisms have remained unclear. The prediction and analysis of natural products has previously used only network pharmacology methods to identify potential target proteins from public databases. In this study, we use comprehensive bioinformatics analysis and experimental verification to determine the antitumor mechanism of T. hemsleyanum.

Methods

Network pharmacology analysis was used to predict the potential in vivo target proteins of T. hemsleyanum. The expression matrix and clinical data to perform an analysis of hub genes were collected from the TCGA and GTEx databases, specifically the analysis of expression, prognosis, tumor immune cell infiltration analysis, immune checkpoint genes, microsatellite instability, tumor mutational burden, tumor neoantigen, and immune microenvironment, which identify the roles and biological functions of the hub genes in pan-cancer. Finally, gene set enrichment analysis was used to verify the biological processes and signaling pathways involved in the pan-cancer expression profile.

Results

We found 124 potential in vivo target proteins of T. hemsleyanum through network pharmacological analysis, and five hub genes (AKR1C1, MET, PTK2, PIK3R1, and CDK6) were then screened by protein–protein interaction (PPI) network analysis and molecular complex detection analysis (MCODE). Experimental intervention with an aqueous extract of T. hemsleyanum verified that these hub genes are the target proteins involved in the regulation of T. hemsleyanum in cells. A pan-cancer analysis then confirmed that CDK6 and MET are potential targets upon which T. hemsleyanum may exert antitumor action, especially in ACC, CESC, LGG, and PAAD. The CDK6 protein targeted by T. hemsleyanum is also involved in the immune and mutation process of pan-cancer, especially in the regulation of immune cell infiltration, immune checkpoint gene expression, microsatellite instability, tumor mutation burdens, and tumor neoantigens. Together, these analyses show that T. hemsleyanum affects tumor immune regulation and genomic stability. Finally, a gene set enrichment analysis confirmed that T. hemsleyanum regulates the cell cycle checkpoint.

Conclusions

We found that T. hemsleyanum can behave as an antitumor agent by acting as a potential cell cycle checkpoint inhibitor in CDK6-driven tumors, such as ACC, CESC, LGG, and PAAD, and that it acts as a tyrosine kinase receptor inhibitor that inhibits the expression of the proto-oncogene MET. Combined with an analysis of immune and mutation correlations in pan-cancer, we determined that T. hemsleyanum may function biologically as an immune regulator and interfere with the stability of the tumor genome, which is worthy of further study.
Compassionate Use of Yuanjiang Decoction, a Traditional Chinese Medicinal Prescription, for Symptomatic Bradyarrhythmia
Authors: Wan-Tong Zhang , Bao-Chen Zhu , Zhao Liu , Xu-Jie Wang , Rui Gao , Ning Xiao , Wei Tang , Yu-Fei Wu , Miles Phoebe , Wei-Liang Weng , Hao-Xiang Lin , Qiu-Yan Li
Published: April 2022

Background: No effective medication is available for symptomatic bradyarrhythmia, particularly in low socioeconomic status (SES) population.

Objective: To explore the safety and efficacy of Yuanjiang decoction, a traditional Chinese medicinal prescription, for symptomatic bradyarrhythmia on a compassionate-use basis.

Methods: This compassionate-use study was conducted in Beijing, China between January 2019 and January 2020. Eligible participants were recruited and treated with Yuanjiang decoction (composed of 6 Chinese herbal medicines), 200 ml twice daily for 16 weeks. Analyses were done with the intention-to-treat (ITT) approach. The primary outcome measure was the proportion of participants who achieved a favorable treatment outcome at 16 weeks.

Results: As of January 2020, 184 patients were included. After 16-weeks treatment, 12 participants were lost to contact while 21 participants were terminated from this study, with a drop-out rate of 17.93%. The most common treatment-related adverse events were xerostomia (6.52%), constipation (6.45%) and sleepiness (3.26%). The proportion of participants with favorable treatment outcome was 65.22% at 4 weeks, 59.78% at 8 weeks (OR: 1.11, 95% CI: 0.71–1.73), 61.41% at 12 weeks (OR: 1.16, 95% CI: 0.92–1.45) and 60.87% at 16 weeks (OR: 1.15, 95% CI: 0.98–1.35). In the multifactor regression analysis, the favorable treatment outcome at 16 weeks was significantly associated with completing at least 8 weeks treatment (OR: 2.053, 95% CI: 1.064–3.560), while unfavorable treatment outcome was significantly associated with an atrioventricular block (OR: 0.255, 95% CI: 0.083–0.784), current smoking (OR: 0.343, 95% CI: 0.027–0.487), and syncope in the month before treatment (OR: 0.321, 95%CI: 0.114–0.904).

Conclusion: This compassionate-use study showed encouraging outcomes of treatment with Yuanjiang decoction, without serious adverse events. This study identified several key factors that may affect outcomes. These findings helped inform the design and assess the feasibility of a large-scale randomized clinical trial.
The Genus Alternanthera: Phytochemical and Ethnopharmacological Perspectives
Authors: Singla Rajeev K. , Dhir Vivek , Madaan Reecha , Kumar Deepak , Singh Bola Simranjit , Bansal Monika , Kumar Suresh , Dubey Ankit Kumar , Singla Shailja , Shen Bairong
Published: April 2022

Ethnopharmacological relevance:The genusAlternanthera(Amaranthaceae) comprises 139 species including 14 species used traditionally for the treatment of various ailments such as hypertension, pain, inflammation, diabetes, cancer, microbial and mental disorders.

Aim of the review:To search research gaps through critical assessment of pharmacological activities not performed to validate traditional claims of various species ofAlternanthera.This review will aid natural product researchers in identifyingAlternantheraspecies with therapeutic potential for future investigation.

Materials and methods:Scattered raw data on ethnopharmacological, morphological, phytochemical, pharmacological, toxicological, and clinical studies of various species of the genusAlternantherahave been compiled utilizing search engines like SciFinder, Google Scholar, PubMed, Science Direct, and Open J-Gate for 100 years up to April 2021.

Results:Few species ofAlternantheragenus have been exhaustively investigated phytochemically, and about 129 chemical constituents related to different classes such as flavonoids, steroids, saponins, alkaloids, triterpenoids, glycosides, and phenolic compounds have been isolated from 9 species. Anticancer, antioxidant, antibacterial, CNS depressive, antidiabetic, analgesic, anti-inflammatory, and immunomodulator effects have been explored in the twelve species of the genus. A toxicity study has been conducted on 3 species and a clinical study on 2 species.

Conclusions:The available literature on pharmacological studies ofAlternantheraspecies reveals that few species have been selected based on ethnobotanical surveys for scientific validation of their traditional claims. But most of these studies have been conducted on uncharacterized and non-standardized crude extracts. A roadmap of research needs to be developed for the isolation of new bioactive compounds fromAlternantheraspecies, which can emerge out as clinically potential medicines.
Evaluation of Wound Healing and Antibacterial Potential of Greyia radlkoferi Szyszyl. Ethanolic Leaf Extract
Authors: Loggenberg Samantha Rae , Twilley Danielle , De Canha Marco Nuno , Meyer Debra , Mabena Ephraim Cebisa , Lall Namrita
Published: April 2022

Angiogenesis is an essential mechanism in both physiological and pathological functions, such as wound healing and cancer metastasis. Several growth factors mediate angiogenesis, including vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). This study evaluated the potential wound healing activity of Greyia radlkoferi Szyszyl (GR) and its effect on growth factors regulating angiogenesis. The ethanolic leaf extract of GR was evaluated for antibacterial activity against wound associated bacteria; Staphylococcus aureus and Pseudomonas aeruginosa. It exhibited antibacterial activity against two strains of S. aureus (ATCC 25293 and ATCC 6538) displaying a minimum inhibitory concentration (MIC) at 250 and 500 μg/ml, respectively. The antioxidant activity of the extract was investigated for nitric oxide (NO) scavenging activity and showed a fifty percent inhibitory concentration (IC50) of 1266.5 ± 243.95 μg/ml. The extract was further investigated to determine its effect on the proliferation and modulation of growth factors secreted by human keratinocytes (HaCaT). Its effect on wound closure was evaluated using the scratch assay, where non-toxic concentrations were tested, as determined by the antiproliferative assay against HaCat cells (IC50 > 400 μg/ml). Results showed that the extract significantly inhibited wound closure, with a percentage closure of 60.15 ± 1.41% (p < 0.05) and 49.52 ± 1.43% (p < 0.01) at a concentration of 50 and 100 μg/ml, respectively, when compared to the 0.25% Dimethyl sulfoxide vehicle control (65.86 ± 1.12%). Quantification of secreted growth factors from cell-free supernatant, collected from the scratch assay, revealed that the extract significantly decreased the concentration of platelet-derived growth factor (PDGF-AA) at both 50 (p < 0.05) and 100 μg/ml (p < 0.001) (443.08 ± 77.36 and 178.98 ± 36.60 pg/ml) when compared to the 0.25% DMSO vehicle control (538.33 ± 12.64 pg/ml). Therefore, whilst the extract showed antibacterial activity against wound associated bacteria, it did not induce wound healing but rather showed a significant inhibition of wound closure, which was confirmed by the inhibition of PDGF-AA, a major growth factor involved in angiogenesis. Therefore, the GR extract, should be considered for further investigation of anti-angiogenic and anti-metastatic properties against cancer cells.
Efficacy, Safety, and Retention Rate of Extended-Release Divalproex Versus Conventional Delayed-Release Divalproex: A Meta-Analysis of Controlled Clinical Trials
Authors: Zhang Chen Qi , Li Hong Yan , Wan Yong , Bai Xue Yang , Gan Lu , Wang Juan , Sun Hong Bin
Published: April 2022

Purpose: A novel once-daily divalproex-extended release (ER) dose formulation has been developed; this formulation prolongs the therapeutic serum levels of the drug, compared with the twice-daily conventional divalproex-delayed release (DR) formulation. This study aimed to systematically examine and compare the efficacy, safety, and retention rates of the ER divalproex (VPA-ER) and conventional DR divalproex (VPA-DR) formulations.

Methods: Randomized control trials (RCTs) reporting the efficacy, adverse events (AEs), and medication compliance of ER and DR divalproex were searched in online databases, including PubMed, Embase, and Cochrane Library databases, by searching MeSH words and term words. Observational studies with potential biases were excluded. The meta-analysis was performed using Stata 16.0 software.

Findings: Thirteen RCTs, involving 1,028 participants, were included in this meta-analysis. Efficacy, AEs, and drug retention rates were the main study outcomes. According to our study, VPA-ER presented clinically significant benefits compared with the placebo in the population with bipolar disorder (BD) (39.5% versus 27.2%, p < 0.001). A similar efficacy of VPA-ER and VPA-DR in controlling seizures was observed in epilepsy patients (87.4% versus 86.5%, p = 0.769). A significantly lower incidence of AEs was reported in the VPA-ER group than in the placebo group (26.8% versus 34.8%, p = 0.003). By contrast, there was no evidence of difference in safety between VPA-ER and VPA-DR (29.4% versus 30.5%, p = 0.750). In addition, the drug retention rate was significantly lower in the VPA-ER group than in the placebo group (76.0% versus 82.7%, p = 0.020), especially in migraine patients (p = 0.022) and in patients who were treated for fewer than 4 weeks (p = 0.018).

Implications: The efficacy of VPA-ER was significantly superior to that of the placebo treatment, which provided efficacy similar to that of conventional VPA-DR. VPA-ER is well tolerated with a low rate of AEs compared to the placebo. In addition, the acceptable medicine compliance of VPA-ER was conducive to the long-term maintenance treatment of chronic diseases. Although we analyzed open labels and crossover design RCTs, large-scale multicenter studies on the efficacy and medicine compliance of new ER formulations with less AEs are required to validate our conclusion.
Icariin: A Potential Molecule for Treatment of Knee Osteoarthritis
Authors: Zhang Juntao , Fan Fangyang , Liu Aifeng , Zhang Chao , Li Qi , Zhang Chenglong , He Feng , Shang Man
Published: April 2022

Background: Knee osteoarthritis (KOA) is a degenerative disease that develops over time. Icariin (ICA) has a positive effect on KOA, although the mechanism is unknown. To investigate drug-disease connections and processes, network pharmacology is commonly used. The molecular mechanisms of ICA for the treatment of KOA were investigated using network pharmacology, molecular docking and literature research approaches in this study.

Methods: We gathered KOA-related genes using the DisGeNET database, the OMIM database, and GEO microarray data. TCMSP database, Pubchem database, TTD database, SwissTargetPrediction database, and Pharmmapper database were used to gather ICA-related data. Following that, a protein-protein interaction (PPI) network was created. Using the Metascape database, we performed GO and KEGG enrichment analyses. After that, we built a targets-pathways network. Furthermore, molecular docking confirms the prediction. Finally, we looked back over the last 5 years of literature on icariin for knee osteoarthritis to see if the findings of this study were accurate.

Results: core targets relevant to KOA treatment include TNF, IGF1, MMP9, PTGS2, ESR1, MMP2 and so on. The main biological process involved regulation of inflammatory response, collagen catabolic process, extracellular matrix disassembly and so on. The most likely pathways involved were the IL-17 signaling pathway, TNF signaling pathway, Estrogen signaling pathway.

Conclusion: ICA may alleviate KOA by inhibiting inflammation, cartilage breakdown and extracellular matrix degradation. Our study reveals the molecular mechanism of ICA for the treatment of KOA, demonstrating its potential value for further research and as a new drug.
Intestinal Haemorrhage and Colitis Induced by Treatment With Osimertinib for Non-Small-Cell Lung Carcinoma: A Case Report
Authors: Shujun Wang , Lili Lou , Lei Yang , Feng Wang , Hefeng Zhan
Published: April 2022

Background: Osimertinib is recommended either as the first-line therapy for sensitizing EGFR-mutations (FLAURA trial) or at progression to first-/second-generation EGFR inhibitors in the presence of resistance mutation T790M (AURA 3 study). It can effectively improve the prognosis of patients with NSCLC with manageable adverse reactions. Among adverse events, intestinal haemorrhage is rare and requires extensive study on its potential lethality.

Case presentation: A 59-year-old female, diagnosed with relapsed stage IV (cT4N2M1c) NSCLC with T790M mutation of the EGFR gene, received osimertinib treatment. Eight months after osimertinib treatment, she complained of lower abdominal pain and haematochezia without haemorrhoids. Potential causes of intestinal haemorrhage other than osimertinib toxicity were ruled out. Colonoscopy examination showed severe colitis with grade 3 CTCAE. Osimertinib was discontinued, and prednisone 0.5 mg/kg was administered. Follow-up endoscopy showed no pathological findings. A novel third-generation EGFR-TKI, aumolertinib, was administrated. Five months after aumolertinib initiation, CT evaluation showed stable disease (SD), and this patient was free of colitis recurrence.

Conclusion: To our knowledge, this is the first case report of severe colitis as an adverse event associated with osimertinib. Although osimertinib is the standard treatment for NSCLC in patients with T790M mutation and has fewer side effects, colitis may occur after months of treatment. Aumolertinib, a novel third-generation EGFR-TKI, might be an effective alternative for the treatment of patients with NSCLC experiencing colitis from osimertinib.
Salidroside Ameliorates Cardiomyocyte Hypertrophy by Upregulating Peroxisome Proliferator-Activated Receptor-α
Authors: Gao Hui , Tian Kunming , Meng Yichong , Liu Xueping , Peng Yingfu
Published: April 2022

Cardiac hypertrophy is an adaptive change in response to pressure overload, however the hypertrophy may evolve toward heart failure if cannot be corrected as soon as possible. The dysfunction of peroxisome proliferator-activated receptor-α (PPARα) plays a key role in cardiac hypertrophy. In the present study, salidroside inhibited the mRNA expressions of hypertrophic markers including atrial natriuretic factor and brain natriuretic peptide in a dosage-dependent manner. Furthermore, the protein expression and transcriptional activity of PPARα were increased by salidroside in H9C2 cells treated with angiotensin II, as well as the target genes of PPARα, while the situations were nearly reversed when PPARα was knocked down. Next, salidroside could elevate the expression of ATGL, a key upstream regulator of PPARα; the effects of salidroside including increasing PPARα function and inhibiting cardiomyocyte hypertrophy were impaired by ATGL knockdown. Our present studies suggested that salidroside elevated PPARα function to alleviate cardiomyocyte hypertrophy, which was involved in the increase of ATGL expression.
Roles and new Insights of Macrophages in the Tumor Microenvironment of Thyroid Cancer
Authors: Liu Qi , Sun Wei , Zhang Hao
Published: April 2022

Although most thyroid cancers have a good and predictable prognosis, the anaplastic, medullary, and refractory thyroid cancers still prone to recurrence and metastasis, resulting in poor prognosis. Although a number of newly developed targeted therapies have begun to be indicated for the above types of thyroid cancer in recent years, their ability to improve overall survival remain hindered by low efficacy. As the largest component of immune cells in tumor microenvironment, tumor-associated macrophages play a key role in the invasion and metastasis of thyroid cancer. There is much evidence that the immune system, tumor microenvironment and cancer stem cell interactions may revolutionize traditional therapeutic directions. Tumor-associated macrophages have been extensively studied in a variety of tumors, however, research on the relationship between thyroid cancer and macrophages is still insufficient. In this review, we summarize the functions of tumor-associated macrophages in different types of thyroid cancer, their cytokines or chemokines effect on thyroid cancer and the mechanisms that promote tumor proliferation and migration. In addition, we discuss the mechanisms by which tumor-associated macrophages maintain the stemness of thyroid cancer and potential strategies for targeting tumor-associated macrophages to treat thyroid cancer.
New Antenna for Detecting Polarization States of Terahertz
Authors: Shi Wei , Wang Zhiquan , Li Chaofan , Hou Lei , Pan Yue
Published: April 2022

The polarization measurement of terahertz (THz) waves is indispensable in THz time-domain spectroscopy (THz-TDS) applications to detect material properties. The rapid development of accurate THz wave polarization-sensitive detectors will greatly promote THz-TDS applications. A new type of photoconductive antenna array detector is proposed in this paper. The antenna is composed of two vertical 1*2 arrays, which respectively detect the orthogonal component of the terahertz pulse in any direction, while quickly and accurately detecting the polarized THz waves. Rotating the detector to measure the THz electric field at different angles shows the reliability of the detector for THz wave polarization measurement. Its polarization detection accuracy is 0.2°. At the same time, we use the response matrix to analyze the symmetry of the antenna array.
Dose of Bicarbonate to Maintain Plasma pH During Maximal Ergometer Rowing and Consequence for Plasma Volume
Authors: Nielsen Henning Bay , Volianitis Stefanos , Secher Niels H.
Published: April 2022

Rowing performance may be enhanced by attenuated metabolic acidosis following bicarbonate (BIC) supplementation. This study evaluated the dose of BIC needed to eliminate the decrease in plasma pH during maximal ergometer rowing and assessed the consequence for change in plasma volume. Six oarsmen performed “2,000-m” maximal ergometer rowing trials with BIC (1 M; 100–325 ml) and control (CON; the same volume of isotonic saline). During CON, pH decreased from 7.42 ± 0.01 to 7.17 ± 0.04 (mean and SD; p < 0.05), while during BIC, pH was maintained until the sixth minute where it dropped to 7.32 ± 0.08 and was thus higher than during CON (p < 0.05). The buffering effect of BIC on metabolic acidosis was dose dependent and 300–325 mmol required to maintain plasma pH. Compared to CON, BIC increased plasma sodium by 4 mmol/L, bicarbonate was maintained, and lactate increased to 25 ± 7 vs. 18 ± 3 mmol/L (p < 0.05). Plasma volume was estimated to decrease by 24 ± 4% in CON, while with BIC the estimate was by only 7 ± 6% (p < 0.05) and yet BIC had no significant effect on performance [median 6 min 27 s (range 6 min 09 s to 6 min 57 s) vs. 6 min 33 s (6 min 14 s to 6 min 55 s)]. Bicarbonate administration attenuates acidosis during maximal rowing in a dose-dependent manner and the reduction in plasma volume is attenuated with little consequence for performance.
Prognostic Value of Lung Ultrasound in Aortic Stenosis
Authors: Szabó István Adorján , Gargani Luna , Morvai-Illés Blanka , Polestyuk-Németh Nóra , Frigy Attila , Varga Albert , Ágoston Gergely
Published: April 2022

Background: Aortic stenosis (AS) is the most common primary valve lesion requiring intervention in Europe and North America. It has a prolonged subclinical period during which, as AS worsens, left ventricular adaptation becomes inadequate and impaired systolic and/or diastolic dysfunction may lead to overt heart failure (HF). The development of HF is an inflexion point in the natural history of AS. Pulmonary congestion is a cardinal feature in HF, and lung ultrasound (LUS) evaluation of B-lines has been proposed as a simple, noninvasive tool to assess pulmonary congestion.

Aim: To assess the presence and the prognostic value of sonographic pulmonary congestion in patients with moderate or severe AS.

Methods: 75 consecutive patients (39 women, mean age 73.85 ± 7.7 years) with moderate or severe AS were enrolled. All patients underwent comprehensive echocardiography and LUS with the 28 scanning-site assessment. Patients were followed-up for 13.4 ± 6 months to establish the prognostic value of LUS. A composite endpoint of death (of any cause), hospitalization for HF and intensification of loop diuretic therapy was considered.

Results: We found a severe degree of B-lines (≥30) in 29.33% of patients. The number of B-lines correlated with the estimated pulmonary artery systolic pressure (p < 0.001, r = 0.574) and increased along with NYHA class (p < 0.05, rho = 0.383). At multivariable analysis, B-lines ≥30, and mean gradient were the independent predictors of events [B-lines: 2.79 (CI 1.03–7.54), p = 0.04; mean gradient: 1.04 (CI 1.01–1.07), p = 0.004].

Conclusion: Evaluation of B-lines is a simple, highly feasible method to detect pulmonary congestion in AS. The number of B-lines correlates with the hemodynamic changes caused by AS and with the functional status of patients. A severe degree of sonographic pulmonary congestion is associated with an increased risk of adverse events.
Reproductive Toxicity and Recovery Associated With 4-Non-ylphenol Exposure in Juvenile African Catfish (Clarias garepinus)
Authors: Sayed Alaa El-Din H. , Eid Zainab , Mahmoud Usama M. , Lee Jae-Seong , Mekkawy Imam A. A.
Published: April 2022

Although, the effects of 4-non-ylphenol (4-NP) on fish’s reproductive hormones were assessed in several studies using adult models, however, the effect of this endocrine disruptor on immature fish’s reproductive hormones was not addressed commonly. We aimed to study the apoptosis induction, hematotoxicity, reproductive toxicity, and the recovery associated with 4-NP exposure in juvenile African catfish [Clarias garepinus) using some hormones [17β-estradiol (E2), testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)] and gonad histology as biomarkers. The toxic effects of 4-NP have been studied in many animal models, but there is still limited knowledge about the dose-dependent damage caused by 4-NP exposure in juvenile Clarias gariepinus. A healthy juvenile C. gariepinus was categorized into four groups (n = 3/group; three replicates in each group). The first group was the control, and the other three groups were subjected to 4-NP concentrations as 0.1, 0.2, and 0.3 mg/L for 15 days; they were left for a recovery period of another 15 days. The reproductive hormones of C. gariepinus exposed to 4-NP for 15 days exhibited significant variations between the treatment groups and the control (P < 0.05), which were evident in E2 and T-values, whereas FSH, LH, total protein, and lipid peroxidation values showed non-significant differences among all groups at P < 0.05. Such a situation referred to the fact that the 15-day recovery period was insufficient to remove the impacts of 4-NP doses in concern. The trend of dose-dependent increase/decrease was recorded for T, E2, FSH, and LH. The histopathological alterations of 4-NP treated in gonad tissues were recorded in juvenile C. gariepinus, reflecting their sensitivity to 4-NP estrogenic-like effects. Overall, our results investigate that recovery has improved the reproductive toxicity caused by 4-NP in juvenile C. garepinus. Significant variations between the treated groups and the control group (P < 0.05) were evident in hematological parameters except for hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). The parameters exhibiting significance decreased with such increased doses [red blood cells (RBCs), hematocrit (Hct), and white blood cells (WBCs)]. Similar patterns of significant variations toward the increase or decrease were recorded following the 15-day recovery period. Apoptotic frequency in erythrocytes and brain cells has increased significantly with increased 4-NP exposure, indicating that 4-NP caused cytotoxic effects, such as apoptosis in a dose-dependent manner. However, these cellular alterations greatly decreased after the 15-day recovery period.