bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitigating Effect of Estrogen in Alzheimer’s Disease-Mimicking Cerebral Organoid
Authors: Kim Jennifer Yejean , Mo Hyunkyung , Kim Juryun , Kim Jang Woon , Nam Yoojun , Rim Yeri Alice , Ju Ji Hyeon
Published: March 2022

Alzheimer’s disease (AD) is the most common condition in patients with dementia and affects a large population worldwide. The incidence of AD is expected to increase in future owing to the rapid expansion of the aged population globally. Researchers have shown that women are twice more likely to be affected by AD than men. This phenomenon has been attributed to the postmenopausal state, during which the level of estrogen declines significantly. Estrogen is known to alleviate neurotoxicity in the brain and protect neurons. While the effects of estrogen have been investigated in AD models, to our knowledge, they have not been investigated in a stem cell-based three-dimensional in vitro system. Here, we designed a new model for AD using induced pluripotent stem cells (iPSCs) in a three-dimensional, in vitro culture system. We used 5xFAD mice to confirm the potential of estrogen in alleviating the effects of AD pathogenesis. Next, we confirmed a similar trend in an AD model developed using iPSC-derived cerebral organoids, in which the key characteristics of AD were recapitulated. The findings emphasized the potential of estrogen as a treatment agent for AD and also showed the suitability of AD-recapitulating cerebral organoids as a reliable platform for disease modeling and drug screening.
Neurotrophins as Therapeutic Agents for Parkinson’s Disease; New Chances From Focused Ultrasound?
Authors: Stefani Alessandro , Pierantozzi Mariangela , Cardarelli Silvia , Stefani Lucrezia , Cerroni Rocco , Conti Matteo , Garasto Elena , Mercuri Nicola B. , Marini Carmine , Sucapane Patrizia
Published: March 2022

Magnetic Resonance–guided Focused Ultrasound (MRgFUS) represents an effective micro-lesioning approach to target pharmaco-resistant tremor, mostly in patients afflicted by essential tremor (ET) and/or Parkinson’s disease (PD). So far, experimental protocols are verifying the clinical extension to other facets of the movement disorder galaxy (i.e., internal pallidus for disabling dyskinesias). Aside from those neurosurgical options, one of the most intriguing opportunities of this technique relies on its capability to remedy the impermeability of blood–brain barrier (BBB). Temporary BBB opening through low-intensity focused ultrasound turned out to be safe and feasible in patients with PD, Alzheimer’s disease, and amyotrophic lateral sclerosis. As a mere consequence of the procedures, some groups described even reversible but significant mild cognitive amelioration, up to hippocampal neurogenesis partially associated to the increased of endogenous brain-derived neurotrophic factor (BDNF). A further development elevates MRgFUS to the status of therapeutic tool for drug delivery of putative neurorestorative therapies. Since 2012, FUS-assisted intravenous administration of BDNF or neurturin allowed hippocampal or striatal delivery. Experimental studies emphasized synergistic modalities. In a rodent model for Huntington’s disease, engineered liposomes can carry glial cell line–derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex through pulsed FUS exposures with microbubbles; in a subacute MPTP-PD model, the combination of intravenous administration of neurotrophic factors (either through protein or gene delivery) plus FUS did curb nigrostriatal degeneration. Here, we explore these arguments, focusing on the current, translational application of neurotrophins in neurodegenerative diseases.
Prenatal Drugs and Their Effects on the Developing Brain: Insights From Three-Dimensional Human Organoids
Authors: Stankovic Isidora N. , Colak Dilek
Published: March 2022

Decades of research have unequivocally demonstrated that fetal exposure to both recreational and prescription drugs in utero negatively impacts the developing brain. More recently, the application of cutting-edge techniques in neurodevelopmental research has attempted to identify how the fetal brain responds to specific environmental stimuli. Meanwhile, human fetal brain studies still encounter ethical considerations and technical limitations in tissue collection. Human-induced pluripotent stem cell (iPSC)-derived brain organoid technology has emerged as a powerful alternative to examine fetal neurobiology. In fact, human 3D organoid tissues recapitulate cerebral development during the first trimester of pregnancy. In this review, we aim to provide a comprehensive summary of fetal brain metabolic studies related to drug abuse in animal and human models. Additionally, we will discuss the current challenges and prospects of using brain organoids for large-scale metabolomics. Incorporating cutting-edge techniques in human brain organoids may lead to uncovering novel molecular and cellular mechanisms of neurodevelopment, direct novel therapeutic approaches, and raise new exciting questions.
Micro-RNA let-7a-5p Derived From Mesenchymal Stem Cell-Derived Extracellular Vesicles Promotes the Regrowth of Neurons in Spinal-Cord-Injured Rats by Targeting the HMGA2/SMAD2 Axis
Authors: Wang Ying , Han Tianyu , Guo Ruocheng , Song Peiwen , Liu Yunlei , Wu Zuomeng , Ai Jichao , Shen Cailiang
Published: March 2022

Spinal cord injury (SCI) often causes neuronal and axonal damage, resulting in permanent neurological impairments. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising treatments for SCI. However, the underlying mechanisms remain unclear. Herein, we demonstrated that EVs from bone marrow-derived MSCs promoted the differentiation of neural stem cells (NSCs) into the neurons and outgrowth of neurites that are extending into astrocytic scars in SCI rats. Further study found that let-7a-5p exerted a similar biological effect as MSC-EVs in regulating the differentiation of NSCs and leading to neurological improvement in SCI rats. Moreover, these MSC-EV-induced effects were attenuated by let-7a-5p inhibitors/antagomirs. When investigating the mechanism, bioinformatics predictions combined with western blot and RT-PCR analyses showed that both MSC-EVs and let-7a-5p were able to downregulate the expression of SMAD2 by inhibiting HMGA2. In conclusion, MSC-EV-secreted let-7a-5p promoted the regrowth of neurons and improved neurological recovery in SCI rats by targeting the HMGA2/SMAD2 axis.
Regeneration of Hair Cells in the Human Vestibular System
Authors: Huang Yikang , Mao Huanyu , Chen Yan
Published: March 2022

The vestibular system is a critical part of the human balance system, malfunction of this system will lead to balance disorders, such as vertigo. Mammalian vestibular hair cells, the mechanical receptors for vestibular function, are sensitive to ototoxic drugs and virus infection, and have a limited restorative capacity after damage. Considering that no artificial device can be used to replace vestibular hair cells, promoting vestibular hair cell regeneration is an ideal way for vestibular function recovery. In this manuscript, the development of human vestibular hair cells during the whole embryonic stage and the latest research on human vestibular hair cell regeneration is summarized. The limitations of current studies are emphasized and future directions are discussed.
A Nomogram Predicting the Progression-Free Survival of Nonmetastatic Renal Cell Carcinoma Patients With Venous Thrombus After Surgery
Authors: Zhang Yu , Tian XiaoJun , Bi Hai , Yan Ye , Liu Zhuo , Liu Cheng , Zhang ShuDong , Ma LuLin
Published: March 2022

Objectives

To demonstrate the progression-free survival (PFS) of nonmetastatic renal cell carcinoma (RCC) patients with venous thrombus after radical nephrectomy and venous thrombectomy (RN-VT) and to develop and validate a nomogram to predict the PFS of patients after RN-VT.

Materials and Methods

We reported our prospective follow-up data of RCC patients with venous thrombus from January 2014 to September 2020 (n = 199). We used the Kaplan–Meier method to assess the PFS. The Cox proportional hazards regression model was used to determine the predictors. Nomograms predicting the PFS was established, and external validation was performed. Calibration curves and decision curves were generated to assess the predictive efficacy and clinical benefit.

Results

After a median follow-up of 32 months, 79 patients (39.7%) had disease progression and the median PFS was 41.0 months (95% CI 34.8–53.2 months). The 1-year, 3-year, and 5-year PFS rates were 78.4%, 45.4%, and 30.0%, respectively. Multivariate analysis showed that Fuhrman grade [grade 4: hazard ratio (HR) 1.92, 95% CI 1.10–3.34, P = 0.02], pathological type (papillary RCC: HR 3.02, 95% CI 1.79–5.10, P < 0.001), perinephric fat invasion (HR 1.54, 95% CI 1.12–2.10, P = 0.007), sarcomatoid differentiation (HR 2.97, 95% CI 1.24–7.13, P = 0.02) were associated with a worse PFS, and adjuvant therapy (HR 0.32, 95% CI 0.18–0.59, P < 0.001) could lead to a better PFS. A nomogram based on the predictors was externally validated to have good discrimination and calibration, and it could improve PFS prediction to obtain a clinical benefit.

Conclusions

We constructed and validated a nomogram to predict the 1-year, 3-year, and 5-year PFS of M0 RCC patients with venous thrombus after surgery. The model can help identify patients who can benefit the most from surgery and develop the criteria for clinical trial enrollment.
Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer
Authors: Moes-Sosnowska Joanna , Chorostowska-Wynimko Joanna
Published: March 2022

Fibroblast growth factor receptor (FGFR) inhibitors (FGFRis) are a potential therapeutic option for squamous non-small cell lung cancer (Sq-NSCLC). Because appropriate patient selection is needed for targeted therapy, molecular profiling is key to discovering candidate biomarker(s). Multiple FGFR aberrations are present in Sq-NSCLC tumors—alterations (mutations and fusions), amplification and mRNA/protein overexpression—but their predictive potential is unclear. Although FGFR1 amplification reliability was unsatisfactory, FGFR mRNA overexpression, mutations, and fusions are promising. However, currently their discriminatory power is insufficient, and the available clinical data are from small groups of Sq-NSCLC patients. Here, we focus on FGFR aberrations as predictive biomarkers for FGFR-targeting agents in Sq-NSCLC. Known and suggested molecular determinants of FGFRi resistance are also discussed.
A Comprehensive Analysis of the Glutathione Peroxidase 8 (GPX8) in Human Cancer
Authors: Ren Zhijing , He Yu , Yang Qinqin , Guo Jiajia , Huang Haifeng , Li Bo , Wang Dong , Yang Zhen , Tian Xiaobin
Published: March 2022

Objective

Nowadays, cancer is still a leading public health problem all over the world. Several studies have reported the GPX8 could be correlated with the poor prognostic of Gastric Cancer and Breast Cancer. However, the prognostic potential of GPX8 in pan-cancer remains unclear. In this work, we aimed to explore the prognostic and immunological role of GPX8 in human cancer and confirm the oncogenic value in GBM.

Methods

The data of TCGA, CPTAC and GEO databases were adopted for the survival analysis. Based on the RNAseq and Methylation450 data of TCGA, the R language and package “ggplot2” were used to analyze the DNA methylation at the region of the promoter of GPX8 in tumors. The genetic alteration of GPX8 from TCGA cancers was investigated in cBioPortal. The R package “GSVA” and “ssGSEA” were employed to evaluate the correlation of GPX8 expression with the immune infiltration. The KEGG website was used for pathway analysis. The STRING website and GEPIA were performed to predict GPX8-binding proteins. The R package “ggplot2” and “clusterprofile” were used to analyze and visualize the GO and KEGG analysis. A normal human astrocyte cell line and three GBM cell lines were cultured under suitable conditions. The shRNA was transferred to cells by Lipofectamine 3000. The qRT-PCR and WB were adopted to detect the expression of GPX8. The wound-healing assay and transwell assay were taken to analyze the invasive and metastatic abilities. The tumor tissues and paracancerous ones were collected from patients with GBM. WB assay was employed to analyze the expression of GPX8 protein.

Results

GPX8 was a valuable diagnostic biomarker in multiple cancers, including GBM/LGG (glioblastoma multiforme/Brain lower grade glioma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma) and STAD (stomach adenocarcinoma). Moreover, we observed a correlation between the expression of GPX8 and the reduced DNA methylation at the promoter region in several tumors, such as GBM/LGG. Our results indicated a positive correlation between the GPX8 expression and immune infiltration. In addition, the enrichment analysis demonstrated that antioxidant activity was mainly involved in the functional mechanism of GPX8. In particular, we first confirmed the up-regulated of GPX8 in GBM cells and observed the suppression of migrative and invasive phenotypes by knockdown of GPX8. Furthermore, we confirmed the expression of GPX8 was higher in GBM tumor tissues than paracancerous ones.

Conclusion

Our study showed a correlation of GPX8 expression with clinical prognosis, DNA methylation and immune infiltrates. Furthermore, we first confirmed GPX8 was highly expressed in GBM cells and contributed to migration and invasion. These results provided a predictive biomarker and an inclusive understanding of the GPX8 expression in multiple tumors types, especially in GBM.
Sentinel Lymph Node Biopsy Mapped With Carbon Nanoparticle Suspensions in Patients With Breast Cancer: A Systematic Review and Meta-Analysis
Authors: Jiang Yan , Li Jiayang , Chen Baolin , Bao Yuxiang , Luo Chengmin , Luo Yi , Li Taolang , Lv Junyuan , Cheng Xiaoming
Published: March 2022

Background

The mapping method represents a crucial factor affecting the rate of sentinel lymph node detection in breast cancer. We carried out this meta-analysis to assess the clinical utility of carbon nanoparticle suspensions (CNSs) in guiding sentinel lymph node biopsy (SLNB) for breast cancer patients.

Methods

Electronic databases, which comprised the China National Knowledge Infrastructure, the Wanfang electronic database, the Cochrane Library, EMBASE, and PubMed, were explored to identify relevant studies from database inception to July 2021 that studied the detection rate of CNSs-guided SLNB. A meta-analysis was performed to generate pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), a summary receiver operator characteristic curve (SROC), and a diagnostic odds ratio (DOR).

Results

A total of 33 publications that enrolled 2,171 patients were analyzed. The pooled sensitivity, specificity, PLR, and NLR were 0.93 (95% CI: 0.91–0.95, I2 = 0.0%), 0.99 (95% CI: 0.98–0.99, I2 = 56.5%), 42.85 (95% CI: 29.73–61.77, I2 = 47.0%), and 0.09 (95% CI: 0.07–0.11, I2 = 0.0%), respectively. The area under the curve (AUC) of the SROC curve was 0.98. There were no significant differences when analyzed based on the dose and site of CNS injection. There was significant publication bias among the included publications based on Deeks’ funnel plot [Slope (Bias) = −7.35, P = 0.00]. Nonetheless, the sensitivity analysis identified the results to be reliable and stable.

Conclusion

This meta-analysis highlights the accuracy and feasibility of using CNSs for SLNB in patients with breast cancer. Clinically, the identification and predictive values of CNSs as an optimal tracer for SLNB remains undisputed.
Re-Expression of ERα and AR in Receptor Negative Endocrine Cancers via GSK3 Inhibition
Authors: Sharma Vikas , Joshi Jayadev , Yeh I-Ju , Doughman YongQiu , Blankenberg Daniel , Wald David , Montano Monica M.
Published: March 2022

DNA methylation, catalyzed by DNA methyltransferase (DNMT), is a well-characterized epigenetic modification in cancer cells. In particular, promoter hypermethylation of AR and ESR1 results in loss of expression on Androgen Receptor (AR) and Estrogen Receptor (ER), respectively, and is associated with a hormone refractory state. We now report that Glycogen Synthase Kinase 3 (GSK3) phosphorylates DNMT1 at S714, which is localized to a 62 amino acid region referred to as auto-inhibitory linker, which functions to occlude the DNA from the active site of DNMT1 to prevent the methylation of unmethylated DNA. Molecular Dynamics simulation indicates that phosphorylation at S714 resulted in conformational rearrangement of the autoinhibitory domain that inactivated its ability to block the methylation of unmethylated DNA and resulted in enhanced DNA binding. Treatment with a novel and more selective inhibitor of GSK3 resulted in decreased methylation of the promoter region of genes encoding the Androgen Receptor (AR) and Estrogen Receptor alpha (ERa) and re-expression of the AR and ERa in AR negative prostate cancer and ER negative breast cancer cells, respectively. As a result, concurrent treatment with the GSK3 inhibitor resulted in responsiveness of AR negative prostate cancer and ER negative breast cancer cells to inhibitors of the AR or ER, respectively, in in vitro and in vivo experimental models.
Proteomic-Based Machine Learning Analysis Reveals PYGB as a Novel Immunohistochemical Biomarker to Distinguish Inverted Urothelial Papilloma From Low-Grade Papillary Urothelial Carcinoma With Inverted Growth
Authors: Jung Minsun , Lee Cheol , Han Dohyun , Kim Kwangsoo , Yang Sunah , Nikas Ilias P. , Moon Kyung Chul , Kim Hyeyoon , Song Min Ji , Kim Bohyun , Lee Hyebin , Ryu Han Suk
Published: March 2022

Background

The molecular biology of inverted urothelial papilloma (IUP) as a precursor disease of urothelial carcinoma is poorly understood. Furthermore, the overlapping histology between IUP and papillary urothelial carcinoma (PUC) with inverted growth is a diagnostic pitfall leading to frequent misdiagnoses.

Methods

To identify the oncologic significance of IUP and discover a novel biomarker for its diagnosis, we employed mass spectrometry-based proteomic analysis of IUP, PUC, and normal urothelium (NU). Machine learning analysis shortlisted candidate proteins, while subsequent immunohistochemical validation was performed in an independent sample cohort.

Results

From the overall proteomic landscape, we found divergent ‘NU-like’ (low-risk) and ‘PUC-like’ (high-risk) signatures in IUP. The latter were characterized by altered metabolism, biosynthesis, and cell–cell interaction functions, indicating oncologic significance. Further machine learning-based analysis revealed SERPINH1, PKP2, and PYGB as potential diagnostic biomarkers discriminating IUP from PUC. The immunohistochemical validation confirmed PYGB as a specific biomarker to distinguish between IUP and PUC with inverted growth.

Conclusion

In conclusion, we suggest PYGB as a promising immunohistochemical marker for IUP diagnosis in routine practice.
Oncological Patients With Endocrine Complications After Immunotherapy With Checkpoint Inhibitors Present Longer Progression-Free and Overall Survival
Authors: Paschou Stavroula A. , Liontos Michael , Eleftherakis-Papaiakovou Evangelos , Stefanaki Katerina , Markellos Christos , Koutsoukos Konstantinos , Zagouri Flora , Psaltopoulou Theodora , Dimopoulos Meletios-Athanasios
Published: March 2022

Aim

The aim of this study was to investigate the association of endocrine complications after ICI immunotherapy with progression-free survival (PFS) and overall survival (OS) in a large single-center oncological cohort.

Patients and Methods

In total, 351 patients were included in the analysis, 248 men (70.7%) and 103 women (29.3%). The median age was 66 years. Patients had a variety of cancer types, namely, bladder cancer (131, 37.3%), renal cancer (89, 25.4%), lung cancer (74, 21.1%), ovarian cancer (22, 6.3%), and other types of cancer (35, 10%). The majority (314, 89.4%) were classified as stage IV, while 10.6% (37) were classified as stage III. Most of the patients received immunotherapy with anti-PD1 agents (262, 74.6%) and the rest with anti-PD-L1 agents (89, 25.4%). Kaplan–Meier estimates were used to describe and visualize the effect of categorical variables on OS and PFS. Survival analysis was performed by Kaplan–Meier curves, and survival differences between groups were estimated using the log-rank test. The estimation of the prognostic value of several variables with patients’ survival was made by Cox regression models.

Results

In total, 68 (19.4%) of patients presented an endocrine complication after immunotherapy with ICIs. Specifically, 66 (18.8%) had thyroid dysfunction, 1 patient presented hypophysitis (0.3%), and 1 patient had a combination of thyroid dysfunction and hypophysitis (0.3%). Patients with an endocrine complication had mPFS of 15 months (95% CI 11.0–18.9 months), while in those without endocrine complication mPFS was 7 months (95% CI 6.1–7.9 months, p < 0.001). Similarly, median OS (mOS) was statistically significant lower in the patients’ group without endocrine complication. In fact, mOS was 51 months (95% CI 39.3–62.7 months) for these patients. The presence of endocrine complications after immunotherapy with ICIs retained its significance in terms of longer PFS (HR 0.57, 95% CI 0.39–0.81) and OS (HR 0.53, 95% CI 0.32–0.90) after multivariate analysis.

Conclusions

ICI endocrinopathies may be a positive predictor of immunotherapy response.
Treatment of Complicated Hepatic Alveolar Echinococcosis Disease With Suspicious Lymph Node Remote Metastasis Near the Inferior Vena Cava-Abdominal Aorta: A Case Report and Literature Review
Authors: Xu Xiaolei , Gao Cancan , Qian Xinye , Liu Hong'en , Wang Zhan , Zhou Hu , Zhou Ying , Wang Haijiu , Hou Lizhao , He Shaoshuai , Feng Xiaobin , Fan Haining
Published: March 2022

Echinococcosis is a human-animal parasitic disease caused by Echinococcosis tapeworm larvae in humans. From a global perspective, it is mainly prevalent in the mid-high latitudes of the Northern Hemisphere, and it is a widespread infectious disease. Its form, host and release areas are slightly different. In clinical practice, Echinococcus granulosus (hepatic cystic echinococcosis) is the most common. Its growth mode is swelling growth and its metastasis is more common in implanted metastasis; However, hepatic alveolar echinococcosis (HAE) is rare. It has been reported that HAE can metastasize through the blood or lymph nodes, and its invasive growth pattern is known as “carcinoma”. At this time, it may be accompanied by invasion of the portal vein and inferior vena cava(IVC)or metastasis to distant organs outside the liver (such as lung, brain, lymph nodes). Most patients are in the middle or late stages, making treatment complicated. World Health Organization guidelines recommend radical resection of HAE; However, there is no consensus on lymph node dissection. To date, there have been no reports of cases of HAE accompanied by inferior vena cava-para-abdominal aortic suspected lymph node metastasis and infection. This article reports a clinical case of a complex HAE treated by the surgical method of “middle liver resection + abdominal enlarged lymph node resection + inferior vena cava repair”, and histological examination was performed to illustrate the differences in microscopic pathology of alveolar echinococcosis invading the liver and lymph nodes at different magnifications. This article reviews the relevant literature on HAE and derives the latest treatment methods for HAE to provide a reference for future clinical cases of similar alveolar echinococcosis and maximize the benefits of patients.
Ground Glass Opacity and Adjuvant Chemotherapy in Pathological Stage IB–IIA Lung Adenocarcinoma
Authors: Zhai Wenyu , Gong Li , Zheng Yuzhen , Yan Qihang , Lai Renchun , Liang Dachuan , Wong Wingshing , Dai Shuqin , Wang Junye
Published: March 2022

Background

The prognostic value of ground glass opacity (GGO) in stage IA non-small cell lung cancer (NSCLC) has been widely recognized. However, studies investigating its value in the related stage IB–IIA lung adenocarcinoma (LUAD) remains lacking. The impact of adjuvant chemotherapy (ACT) on pathological stage IB–IIA LUAD is also controversial.

Materials and Methods

We retrospectively reviewed the clinical records of 501 patients with pathological stage IB–IIA LUAD at the Sun Yat-sen University Cancer Center from January 2008 to June 2018. We calculated and compared survival curves using the Kaplan–Meier test and log-rank test. Cox regression models were performed to determine independent prognostic factors of disease-free survival (DFS) and overall survival (OS). We established nomograms to predict the OS and DFS of LUAD patients. Calibration and receiver operator characteristic curves were conducted to assess the predictive performance of two nomograms. Based on the nomogram, we identified candidate patients that may most benefit from ACT after surgery.

Results

The number of patients with pure solid, part GGO, and pure GGO nodules was 240, 242, and 19, respectively, and 125 patients who received ACT. Patients with consolidation-to-tumor ratio (CTR) <0.75 had longer OS (P = 0.026) and DFS (P = 0.003). Pathological tumor size and at least 10 lymph nodes (LNs) resection were independent prognostic factors of both OS and DFS. CTR <0.75 was positively associated with DFS. The C-index of nomograms predicting individual OS and DFS was 0.660 and 0.634, respectively. Based on the nomogram for OS, ACT was found to be a positive prognostic indicator of OS (P = 0.031, HR = 0.5141, 95% CI 0.281–0.942) in patients with nomogram total points ≥5.

Conclusion

CTR <0.75 is associated with a better DFS in patients with stage IB–IIA LUAD. Nomograms developed by integrating pathological tumor size, at least 10 LNs resection, and CTR ≥0.75 for predicting individual OS and DFS displayed a good predictive capacity and clinical value, which were also proved to be a useful tool for selecting patients most benefiting from ACT.
Isodon rubescens (Hemls.) Hara.: A Comprehensive Review on Traditional Uses, Phytochemistry, and Pharmacological Activities
Authors: Chen Xufei , Dai Xufen , Liu Yinghai , He Xirui , Gong Gu
Published: March 2022

Isodon rubescens is a medicinal and food plant, often eaten as a wild vegetable in ancient China, and has been widely used for decades to treat sore throats, tonsillitis, colds and headaches, bronchitis, chronic hepatitis, joint rheumatism, snake and insect bites, and various cancers. This comprehensive and systematic review of the ethnomedicinal uses, phytochemical composition, pharmacological activity, quality control and toxicology of I. rubescens provides updated information for the further development and application in the fields of functional foods and new drugs research. To date, a total of 324 substances have been isolated and identified from the plant, including terpenoids, flavonoids, polyphenols, alkaloids, amino acids, and volatile oils. Among these substances, diterpenoids are the most important and abundant bioactive components. In the past decades pharmacological studies have shown that I. rubescens has significant biological activities, especially in the modulation of antitumor and multidrug resistance. However, most of these studies have been conducted in vitro. In-depth in vivo studies on the quality control of its crude extracts and active ingredients, as well as on metabolite identification are still very limited. Therefore, more well-designed preclinical and clinical studies are needed to confirm the reported therapeutic potential of I. rubescens.
The Effect of a Local Injection of Flurbiprofen Ester Microspheres on Systemic Inflammatory Model Rats With a Closed Femoral Shaft Fracture
Authors: Peng Hui-Ming , Xiao Ke , Zhu Wei , Wang Ying-Jie , Bian Yan-Yan , Wang Wei , Qian Wen-Wei , Weng Xi-Sheng
Published: March 2022

Background: Periarticular injections with a combination of local anesthetics, non-steroidal anti-inflammatory analgesics (NSAIDs), and epinephrine are becoming increasingly popular in the perioperative analgesia of artificial joint replacement. However, data on the efficacy and safety of local injection NSAIDs are still scarce. The purpose of this study was to investigate the efficacy and safety of a local injection of Flurbiprofen Ester Lipid microspheres into the inflammatory model of femoral shaft closed fractures in rats.

Methods: A systemic inflammatory model was induced in SD rats (60) by closed femoral shaft fracture; 12 non-fractured rats were used as the blank control group (group A). The systemic inflammation model of 60 rats was divided into 5 groups (12 in each group); Group B: intramuscular injectionof the same amount of normal saline at different time points as a negative control; Group C: intravenous injection of Flurbiprofen Ester microspheres (4.5 mg/kg) at different time points; Group D: intramuscular injection of Flurbiprofen Ester microspheres (2.25 mg/kg) at different time points; Group E: intramuscular injection of Flurbiprofen Ester microspheres (4.5 mg/kg) at different time points; Group F: intramuscular injection of Flurbiprofen Ester microspheres (9 mg/kg) at different time points. The behavioral test observed the behavior of the rats. Then, the inflammation factors of CRP, IL-6, COX-1, COX-2 and TNF-αby ELISA were recorded.

Results: Through the behavioral test it could be found that the effect of the intramuscular and intravenous injections of Flurbiprofen Ester microspheres was similar. Fracture rats with a local injection of Flurbiprofen Ester microspheres showed lower inflammation levels measured by COX-1, CRP, and TNF-α compared with the control group. Pathological sections at 24, 48, and 96 h after surgery did not display any local muscle necrosis at the local injection site. These findings suggested that a Flurbiprofen Ester microsphere muscular injection exhibited a similar effect to an intravenous injection.

Conclusion: The local injection of Flurbiprofen Ester microspheres significantly reduced the inflammatory response in fracture rats and did not increase the risk of muscle necrosis, suggesting its feasibility in local injection analgesia.
Sequential Therapy of Nadroparin and Rivaroxaban in the Initial Treatment of Patients With Acute Pulmonary Embolism
Authors: Xiong Wei , Zhao Yunfeng , Liu Song , Du He , Wang Yanmin , Li Wenjie , Guo Xuejun
Published: March 2022

Background: Sequential low molecular weight heparin (LMWH) plus warfarin, LMWH plus edoxaban, and LMWH plus dabigatran regimens have already shown efficacy and safety in the treatment of acute pulmonary embolism (PE). The efficacy and safety of sequential LMWH plus rivaroxaban regimen in the treatment of acute PE have been understudied.

Methods: A retrospective study was performed to explore the efficacy and safety of sequential therapy regimens of subcutaneous LMWH (nadroparin 86 IU/kg every 12 h for a week) followed by oral rivaroxaban (20 mg once daily for 3 months) for the management of patients with established acute PE without hemodynamic instability, compared with those of nadroparin plus dabigatran and nadroparin plus warfarin.

Results: The number of patients with total resolution of PE were 238 (80.1%), 220 (78.0%), and 166 (62.6%), in the nadroparin + rivaroxaban, nadroparin + dabigatra, and nadroparin + warfarin groups, respectively. (p = 0.001) The prevalence of DVT at the 3-month follow-up visit was 18 (6.1%), 14 (5.0%), and 11 (4.2%), in the aforementioned three groups, respectively. (p = 0.559) The NT-proBNP level (pg/ml) at the 3-month follow-up visit was 122.5 (97.4–158.9), 131.7 (102.2–166.3), and 357.8 (275.4–433.2) in the three groups, respectively. (p = 0.001) The D-dimer level (ng/ml) at the 3-month follow-up visit was 387.3 (310.9–465.2), 432.5 (382.4–489.6), and 854.0 (721.5–993.7) in the three groups, respectively (p < 0.001). The number of patients with major bleeding events was 3(0.9%), 6(1.8%), and 18 (5.5%) in the three groups, respectively (p < 0.001).

Conclusion: The regimen of sequential subcutaneous nadroparin at body-weight adjusted dose for a week followed by oral rivaroxaban at a dose of 20 mg once daily for 3 months is effective and safe in the initial treatment of patients with acute pulmonary embolism.
Drug Prescriptions in the Outpatient Management of COVID-19: Evidence-Based Recommendations Versus Real Practice
Authors: Belleudi Valeria , Finocchietti Marco , Fortinguerra Filomena , Di Filippo Aurora , Trotta Francesco , Davoli Marina , Addis Antonio
Published: March 2022

Background: Evidence-based recommendations for outpatient management of COVID-19 were published by the Italian Medicines Agency (AIFA) to limit the use of off-label treatments. The aim of this study is to measure the use of outpatient drug treatments in a COVID-19-positive population, taking into account the Italian regulatory agency’s advices.

Methods: A descriptive observational study was conducted. All patients testing positive for COVID-19 residing in Lazio region, Italy, with diagnosis date between March 2020 and May 2021 were selected, and outpatient medicine prescription patterns were identified.

Results: Independent of AIFA recommendations, the use of drug therapy in the management of outpatient COVID-19 cases was frequent (about one-third of the cases). The most used drug therapy was antibiotics, specifically azithromycin, despite the negative recommendation of AIFA, while the use of corticosteroids increased after the positive recommendation of regulatory agency for the use in subjects with severe COVID-19 disease. The use of hydroxychloroquine was limited to the early pandemic period where evidence on its potential benefit was controversial. Antithrombotics were widely used in outpatient settings, even if their use was recommended for hospitalized patients.

Conclusion: In this study, we show a frequent use of drug therapy in the management of outpatient cases of COVID-19, mainly attributable to antibiotics use. Our research highlights the discrepancy between recommendations for care and clinical practice and the need for strategies to bridge gaps in evidence-informed decision-making.
Exploration of the Specific Pathology of HXMM Tablet Against Retinal Injury Based on Drug Attack Model to Network Robustness
Authors: Xi Yujie , Miao Yan , Zhou Rui , Wang Maolin , Zhang Fangbo , Li Yu , Zhang Yi , Yang Hongjun , Guo Feifei
Published: March 2022

Retinal degenerative diseases are related to retinal injury because of the activation of the complement cascade, oxidative stress-induced cell death mechanisms, dysfunctional mitochondria, chronic neuroinflammation, and production of the vascular endothelial growth factor. Anti-VEGF therapy demonstrates remarkable clinical effects and benefits in retinal degenerative disease patients. Hence, new drug development is necessary to treat patients with severe visual loss. He xue ming mu (HXMM) tablet is a CFDA-approved traditional Chinese medicine (TCM) for retinal degenerative diseases, which can alleviate the symptoms of age-related macular degeneration (AMD) and diabetic retinopathy (DR) alone or in combination with anti-VEGF agents. To elucidate the mechanisms of HXMM, a quantitative evaluation algorithm for the prediction of the effect of multi-target drugs on the disturbance of the disease network has been used for exploring the specific pathology of HXMM and TCM precision positioning. Compared with anti-VEGF agents, the drug disturbance of HXMM on the functional subnetwork shows that HXMM reduces the network robustness on the oxidative stress subnetwork and inflammatory subnetwork to exhibit the anti-oxidation and anti-inflammation activity. HXMM provides better protection to ARPE-19 cells against retinal injury after H2O2 treatment. HXMM can elevate GSH and reduce LDH levels to exhibit antioxidant activity and suppress the expression of IL-6 and TNF-α for anti-inflammatory activity, which is different from the anti-VEGF agent with strong anti-VEGF activity. The experimental result confirmed the accuracy of the computational prediction. The combination of bioinformatics prediction based on the drug attack on network robustness and experimental validation provides a new strategy for precision application of TCM.
Advances and Challenges in Intranasal Delivery of Antipsychotic Agents Targeting the Central Nervous System
Authors: Pandey Manisha , Jain Neha , Kanoujia Jovita , Hussain Zahid , Gorain Bapi
Published: March 2022

Treatment of central nervous system (CNS) disorders is challenging using conventional delivery strategies and routes of administration because of the presence of the blood–brain barrier (BBB). This BBB restricts the permeation of most of the therapeutics targeting the brain because of its impervious characteristics. Thus, the challenges of delivering the therapeutic agents across the BBB to the brain overcoming the issue of insufficient entry of neurotherapeutics require immediate attention for recovering from the issues by the use of modern platforms of drug delivery and novel routes of administration. Therefore, the advancement of drug delivery tools and delivering these tools using the intranasal route of drug administration have shown the potential of circumventing the BBB, thereby delivering the therapeutics to the brain at a significant concentration with minimal exposure to systemic circulation. These novel strategies could lead to improved efficacy of antipsychotic agents using several advanced drug delivery tools while delivered via the intranasal route. This review emphasized the present challenges of delivering the neurotherapeutics to the brain using conventional routes of administration and overcoming the issues by exploring the intranasal route of drug administration to deliver the therapeutics circumventing the biological barrier of the brain. An overview of different problems with corresponding solutions in administering therapeutics via the intranasal route with special emphasis on advanced drug delivery systems targeting to deliver CNS therapeutics has been focused. Furthermore, preclinical and clinical advancements on the delivery of antipsychotics using this intranasal route have also been emphasized.
The Nutraceutical Alliin From Garlic Is a Novel Substrate of the Essential Amino Acid Transporter LAT1 (SLC7A5)
Authors: Scanga Raffaella , Scalise Mariafrancesca , Rovella Filomena , Regina Teresa Maria Rosaria , Galluccio Michele , Indiveri Cesare
Published: March 2022

The plasma membrane transporter LAT1 (SLC7A5) is a crucial player for cell homeostasis because it is responsible for providing cells with essential amino acids and hormones. LAT1 forms a functional heterodimer with the cell surface antigen heavy chain CD98 (also known as 4F2hc and SLC3A2), a type II membrane glycoprotein, which is essential for LAT1 stability and localization to the plasma membrane. The relevance of LAT1 for human metabolism is also related to its altered expression in human diseases, such as cancer and diabetes. These features boosted research toward molecules that are able to interact with LAT1; in this respect, the recent resolution of the LAT1-CD98 3D structure by Cryo-EM has opened important perspectives in the study of the interaction with different molecules in order to identify new drugs to be used in therapy or new substrates of natural origin to be employed as adjuvants and food supplements. In this work, the interaction of LAT1 with alliin, a garlic derivative, has been investigated by using a combined approach of bioinformatics and in vitro transport assays. Alliin is a nutraceutical that has several beneficial effects on human health, such as antidiabetic, anticarcinogenic, antioxidant, and anti-inflammatory properties. The computational analysis suggested that alliin interacts with the substrate binding site of LAT1, to which alliin was docked. These data were then confirmed by the competitive type inhibition measured in proteoliposomes. Interestingly, in the same experimental model, alliin was also revealed to be a substrate of LAT1.
A Tunable low Pass Filter Based on Transmission Lines With Tunable Input/Output Impedance
Authors: Zhang Zhonghai , Zhao Yuekai , Chen Lin , Fang Zhihua , Wu Aiting , Zhang Pengquan
Published: March 2022

A tunable low pass filter (TLPF) based on the tuning of input/output impedance was presented in this letter. The TLPF mainly consisted of improved quarter-wavelength stubs. The input/output impedance of the improved quarter-wavelength stubs can be tuned in a certain range. The design procedure of this TLPF was derived from the filters based on the quarter-wavelength transmission stubs. Through the tuning of the input/output impedance of the transmission lines, the cut-off frequency of the TLPF can be adjusted in a certain range. The TLPF has relatively good designability and can be easily changed to meet other performance levels. Finally, a TLPF was designed, fabricated, and measured. The measured results verify the effectiveness of the design method.
Monoclonal Antibodies as Probes to Study Ligand-Induced Conformations of Troponin Subunits
Authors: Rasmussen Monica , Jin Jian-Ping
Published: March 2022

Striated muscle contraction and relaxation is regulated by Ca2+ at the myofilament level via conformational modulations of the troponin complex. To understand the structure–function relationship of troponin in normal muscle and in myopathies, it is necessary to study the functional effects of troponin isoforms and mutations at the level of allosteric conformations of troponin subunits. Traditional methodologies assessing such conformational studies are laborious and require significant amounts of purified protein, while many current methodologies require non-physiological conditions or labeling of the protein, which may affect their physiological conformation and function. To address these issues, we developed a novel approach using site-specific monoclonal antibodies (mAb) as molecular probes to detect and monitor conformational changes of proteins. Here, we present examples for its application in studies of two subunits of troponin: the Ca2+-binding subunit, TnC, and the tropomyosin-binding/thin filament-anchoring subunit, TnT. Studies using a high-throughput microplate assay are compared with that using localized surface plasmon resonance (LSPR) to demonstrate the effectiveness of using mAb probes to assess ligand-induced conformations of troponin subunits in physiological conditions. The assays utilize relatively small amounts of protein and are free of protein modification, which may bias results. Detailed methodologies using various monoclonal antibodies (mAbs) are discussed with considerations for the optimization of assay conditions and the broader application in studies of other proteins as well as in screening of therapeutic reagents that bind a specific target site with conformational and functional effects.
Effect of Upright Posture on Endothelial Function in Women and Men
Authors: Habib Karim , Fallah Behzad , Edgell Heather
Published: March 2022

Women are more prone to orthostatic intolerance compared to men and have a greater vasodilatory capacity. We investigated the hypothesis that women would have greater peripheral flow-mediated dilation (FMD) while in the upright posture compared to men, which could contribute to this phenomenon. In young healthy women (age: 20 ± 3, BMI: 27 ± 5 kg/m2, n = 10) and men (age = 21 ± 2, BMI: 27 ± 8 kg/m2, n = 8), we assessed FMD of the brachial artery and hemodynamics to determine endothelial function during the supine and 70° head-up tilt postures (randomized). The brachial artery was kept at heart level in both trials. We observed that FMD increased in both sexes during tilt (Women: 11.9 ± 5.3 to 15.7 ± 5.6%; Men: 8.4 ± 3.2 to 14.6 ± 3.4%, Main effect of tilt p = 0.005) which was not due to changes in blood pressure or shear stress. There were no interaction effects between sex and posture. In a second cohort of women (age: 22 ± 3, BMI: 23 ± 3 kg/m2, n = 9) and men (age: 22 ± 2, BMI: 25 ± 8 kg/m2, n = 8), we investigated reactive hyperemia by peripheral arterial tonometry (LnRHI) via EndoPAT. Interestingly, we found that the EndoPAT response was decreased in both sexes during tilt (LnRHI: Men: 0.70 ± 0.28 to 0.59 ± 0.40, Women: 0.52 ± 0.23 to 0.30 ± 0.32, Main effect of tilt p = 0.037). We previously found that FMD is related to coronary responses to acetylcholine and adenosine whereas EndoPAT is related to coronary responses to dobutamine. Therefore, we suggest that sympathetic mediated dilation is attenuated in the upright posture while the increased vasodilatory response as measured by FMD in the tilt posture could be attributed to increasing metabolite production from postural muscles.
Computational Prediction of Phosphoinositide Binding to Hyperpolarization-Activated Cyclic-Nucleotide Gated Channels
Authors: Claveras Cabezudo Ainara , Feriel Khoualdi Asma , D’Avanzo Nazzareno
Published: March 2022

Protein-lipid interactions are key regulators of ion channel function. Numerous ion channels, including hyperpolarization-activated cyclic-nucleotide gated (HCN) channels have been shown to be regulated by phosphoinositides (PIPs), with important implications in cardiac and neuronal function. Specifically, PIPs have been shown to enhance HCN activation. Using computational approaches, we aim to identify potential binding sites for HCN1-PIP interactions. Computational docking and coarse-grained simulations indicate that PIP binding to HCN1 channels is not well coordinated, but rather occurs over a broad surface of charged residues primarily in the HCN-domain, S2 and S3 helices that can be loosely organized in 2 or 3 overlapping clusters. Thus, PIP-HCN1 interactions are more resembling of electrostatic interactions that occur in myristoylated alanine-rich C kinase substrate (MARCKS) proteins, than the specifically coordinated interactions that occur in pleckstrin homology domains (PH domains) or ion channels such as inward rectifier potassium (Kir) channels. Our results also indicate that phosphatidylinositol (PI) interactions with HCN1 are even lower affinity, explaining why unphosphorylated PI have no effect on HCN1 activation unlike phosphorylated PIPs.