Biomarker study of symptomatic intracranial atherosclerotic stenosis in patients with acute ischemic stroke.

Objective: Acute ischemic stroke (AIS) is characterized by high rates of morbidity, disability, mortality, and recurrence, often leaving patients with varying degrees of sequelae. Symptomatic intracranial atherosclerotic stenosis (sICAS) is a significant contributor to AIS pathogenesis and recurrence. The formation and progression of sICAS are influenced by pathways such as lipid metabolism and inflammatory response. Given its high risk of clinical recurrence, timely assessment of intracranial vascular stenosis in AIS is crucial for diagnosing sICAS, treating stroke, and preventing stroke recurrence. Methods: Fourteen AIS patients were divided into stenosis and control groups based on the presence or absence of intracranial vessel stenosis. Initially, 4D Label-free proteome quantification technology was employed for mass spectrometry analysis to identify differential proteins between the groups. Subsequently, functional enrichment analysis, including GO classification, KEGG pathway, and Domain, revealed trends related to differential proteins. The STRING (v.11.5) protein interaction network database was used to identify differential protein interactions and target proteins. Finally, parallel reaction monitoring (PRM) validated the selected target proteins. Results: Mass spectrometry identified 1,096 proteins, with 991 being quantitatively comparable. Using a p-value <0.05 and differential expression change thresholds of >1.3 for significant up-regulation and < 1/1.3 for significant down-regulation, 46 differential proteins were identified: 24 significantly up-regulated and 22 significantly down-regulated. PRM experiments validated five proteins related to lipid metabolism and inflammatory response: namely alpha-2-macroglobulin (A2M), lipopolysaccharide-binding protein (LBP), cathepsin G (CTSG), cystatin (CST)3, and fatty acid-binding protein (FABP)1. Conclusion: The detection of changes in these five proteins in AIS patients can aid in the diagnosis of sICAS, inform stroke treatment, and assist in preventing stroke recurrence. Moreover, it can contribute to the development of drugs for preventing AIS recurrence by integrating traditional Chinese and Western medicine.

A multicenter real-world study comparing the clinical equivalence of trastuzumab biosimilar HLX02 and reference trastuzumab in the treatment of HER-2-positive breast cancer.

As the first trastuzumab biosimilar introduced in China, there are few studies on the clinical application of HLX02, especially in combination with other antitumour drugs, for the treatment of HER-2-positive breast cancer. A multicenter retrospective study was conducted in three hospitals in China to select patients with HER-2-positive breast cancer who met the inclusion criteria and received HLX02 or the reference trastuzumab. Ninety-six patients diagnosed with HER-2-positive breast cancer were finally included and divided into two groups and treated with HLX02 or the reference trastuzumab. The results showed no significant differences in pathological complete response (70.0% vs. 76.2%; P=1.000) and overall response rate (91.9% vs. 94.9%; P=0.673) between the two groups. Kaplan-Meier survival curves also showed no significant difference in time-to-event variables between the two groups (log-rank P=0.48). Safety was also comparable in both groups. In conclusion, among patients with HER2-positive breast cancer, HLX02 demonstrated equivalent efficacy and safety to its reference trastuzumab, both in neoadjuvant chemotherapy and in postoperative adjuvant therapy. However, clinical equivalence studies between HLX02 and the original trastuzumab drug remain challenging. Future research should focus on the clinical exchange between biosimilars and original drugs, as well as the extrapolation of biosimilars' indications.

Long Noncoding RNA MIATNB Regulates Hyperosmotic Stress-induced Corneal Epithelial Cell Injury by Inhibiting Autophagy in Dry Eye Disease.

PURPOSE: Dry eye disease (DED) has a complex etiology and the roles of long noncoding RNAs (lncRNAs) in its pathophysiology are not completely understood. Autophagy is a self-eating process important for cell survival and homeostasis. The present study explored the role of myocardial infarction-associated transcript neighbor (MIATNB) long non-coding RNA in hyperosmolarity-induced autophagy and apoptosis in human corneal epithelial cell (HCEC)-based model of dry eye disease. METHODS: In vitro assays were performed with a human SV40 immortalized corneal epithelial cell line. Different concentrations of NaCl were used to create hyperosmolarity. HCECs were cultured in presence of 70-120 mM NaCl for 24 h to create an in vitro model of dry eye. RT-qPCR was performed to assess the expression of dry eye related LC3B, ATG16L, BECN1, ATG1, ATG7, ATG13, ATG5, ATG10, and ATG101 mRNAs and western blot analysis of LC3B and P62 and RFP -GFP-tagged LC3. Flow cytometry and western blot analysis of caspase 3, BCL2 and BAX were performed to detect apoptosis. Chloroquine (CQ) was used to inhibit autophagy pharmacologically. RESULTS: Autophagy flux was activated in HCECs subjected to hyperosmotic stress. Hyperosmolarity activated apoptosis and inhibited HCEC migration and autophagy. Hyperosmolarity upregulated MIATNB expression, while MIATNB knockdown inhibited autophagosome degradation and promoted HCEC apoptosis. Under hyperosmolar conditions, MIATNB knockdown also inhibited the degradation of autophagolysosomes and stimulated HCEC apoptosis. CONCLUSION: MIATNB plays a vital role in dry eye pathogenesis and serves as a bridge between autophagy and apoptosis. Targeting MIATNB for DED treatment should be further evaluated.

Clarifying the mechanism of apigenin against blood-brain barrier disruption in ischemic stroke using systems pharmacology.

Currently, recombinant tissue plasminogen activator (rtPA) is an effective therapy for ischemic stroke (IS). However, blood-brain barrier (BBB) disruption is a serious side effect of rtPA therapy and may lead to patients' death. The natural polyphenol apigenin has a good therapeutic effect on IS. Apigenin has potential BBB protection, but the mechanism by which it protects the BBB integrity is not clear. In this study, we used network pharmacology, bioinformatics, molecular docking and molecular dynamics simulation to reveal the mechanisms by which apigenin protects the BBB. Among the 146 targets of apigenin for the treatment of IS, 20 proteins were identified as core targets (e.g., MMP-9, TLR4, STAT3). Apigenin protects BBB integrity by inhibiting the activity of MMPs through anti-inflammation and anti-oxidative stress. These mechanisms included JAK/STAT, the toll-like receptor signaling pathway, and Nitrogen metabolism signaling pathways. The findings of this study contribute to a more comprehensive understanding of the mechanism of apigenin in the treatment of BBB disruption and provide ideas for the development of drugs to treat IS.

In vivo confocal microscopy of sub-basal corneal nerves and corneal densitometry after three kinds of refractive procedures for high myopia.

PURPOSE: To observe corneal nerve fibers and densitometry after small incision lenticule extraction (SMILE), femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) and laser-assisted subepithelial keratomileusis (LASEK) for high myopia. METHODS: This is a prospective, cross-sectional research study. Patients with high myopia (equivalent spherical lens: -6.00 and -11.00D) who underwent laser corneal refractive surgery were divided into three groups: SMILE, FS-LASIK and LASEK. Scheimpflug imaging of corneal nerves in five areas was observed by confocal microscopy before and 6, 12 months after surgery. Corneal densitometry was measured by Pentacam anterior segment analysis system. RESULTS: Overall, 59 patients were enrolled. The nerve density in the central area did not recover to the preoperative level in three groups until 12 months. The density and length of corneal nerves in central and lower area were better in the SMILE group 6 months postoperatively (p = 0.01), while nerve density did not differ significantly among three groups 12 months postoperatively (p = 0.18). Nerve fibers in central and temporal region were wider in LASEK than that in other two groups at 6- and 12-month follow-up. Corneal densitometry in the central 6 mm diameter was significantly higher in the LASEK group compared with other two groups 6 months postoperatively (p = 0.04). Twelve months postoperatively, corneal densitometry in range of all zone was lower in SMILE than in FS-LASIK and LASEK (p = 0.01, 0.03, 0.04). CONCLUSIONS: Compared with FS-LASIK and LASEK, SMILE-treated eyes with high myopia had certain advantages in nerve density, length and nerve connection way and had better corneal transparency after operation.

Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis.

BACKGROUND AND OBJECTIVE: Epimedii has long been used as a traditional medicine in Asia for the treatment of various common diseases, including Alzheimer's disease, cancer, erectile dysfunction, and stroke. Studies have reported the ameliorative effects of Icariside II (ICS II), a major metabolite of Epimedii, on acute ischemic stroke (AIS) in animal models. Based on network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we conducted a systematic review to evaluate the effects and neuroprotective mechanisms of ICS II on AIS. METHODS: First, we have searched 6 databases using studies with ICS II treatment on AIS animal models to explore the efficacy of ICS II on AIS in preclinical studies. The literature retrieval time ended on March 8, 2022 (Systematic Review Registration ID: CRD42022306291). There were no restrictions on the language of the search strategy. Systematic review follows the Patient, Intervention, Comparison and Outcome (PICO) methodology and framework. SYCLE's RoB tool was used to evaluate the the risk of bias. In network pharmacology, AIS-related genes were identified and the target-pathway network was constructed. Then, these targets were used in the enrichments of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO). Molecular docking and MD simulation were finally employed between ICS II and the potential target genes. RESULTS: Twelve publications were included describing outcomes of 1993 animals. The literature details, animal strains, induction models, doses administered, duration of administration, and outcome measures were extracted from the 12 included studies. ICS II has a good protective effect against AIS. Most of the studies in this systematic review had the appropriate methodological quality, but some did not clearly state the controlling for bias of potential study. Network pharmacology identified 246 targets with SRC, CTNNB1, HSP90AA1, MAPK1, and RELA as the core target proteins. Besides, 215 potential pathways of ICS II were identified, such as PI3K-Akt, MAPK, and cGMP-PKG signaling pathway. GO enrichment analysis showed that ICS II was significantly enriched in subsequent regulation such as MAPK cascade. Molecular docking and MD simulations showed that ICS II can closely bind with important targets. CONCLUSIONS: ICS II is a promising drug in the treatment of AIS. However, this systematic review reveals key knowledge gaps (i.e., the protective role of ICS II in women) that ICS II must address before it can be used for the treatment of human AIS. Our study shows that ICS II plays a protective role in AIS through multi-target and multi-pathway characteristics, providing ideas for the development of drugs for the treatment of AIS.

Case Report: Primary Indolent Epstein-Barr Virus-Positive T-Cell Lymphoproliferative Disease Involving the Central Nervous System.

Background: T-cell lymphoproliferative disease (T-LPD), characterized by primary Epstein-Barr virus (EBV) infection and clonal proliferation of T cells, occurs both in systemic and non-lymphatic organs. However, isolated indolent EBV-positive T-LPD involving the central nervous system has not been reported. Case Presentation: A 48-year-old male who complained of headache, blurred vision, and weakness of the left lower limb for 1 month was hospitalized in our department. Neither neurological deficit nor palpable lymphadenopathy had been found. Bone marrow and laboratory tests had shown no abnormality as well. Enhanced MRI demonstrated enhanced cotton-like lesions up to 20 mm in diameter located in the right frontal, temporal, parietal and left parietal, occipital lobes with perifocal edema. Neuronavigation-assisted mini-craniotomy was performed to achieve total excision of the right temporal superficial lesion and identify the diagnosis. Pathological and EBV analysis described the lesion as indolent EBV-positive T-cell lymphoproliferative disease of the central nervous system (CNS). Then, a therapeutic regimen including whole-brain irradiation, chemotherapy, prednisolone, and aciclovir was given. Serial radiological imaging showed no signal of recurrence at 5 months' follow-up. Conclusion: Primary indolent T-LPD in the central nervous system is quite rare, and it needs to be distinguished from aggressive cerebral T-cell lymphoma, metastatic tumors, and other CNS lesions.

Gospel of malignant Glioma: Oncolytic virus therapy.

Glioma accounts for nearly 80% of all intracranial malignant tumors. It is a major challenge to society as it is causes to impaired brain function in many patients. Currently, gliomas are mainly treated with surgery, postoperative radiotherapy, and chemotherapy. However, the curative effects of these treatments are not satisfactory. Oncolytic virus (OV) is a novel treatment which works by activating the immune functions and inducing apoptosis of tumor cells. The OV propagates indefinitely in the host cell, eventually leading to the death of host cell. Subsequently, a large number of antigens and signal molecules are released which exert antitumor immunity. Several preclinical and clinical studies have shown that G207, DNX2401, Zika and other viruses have important roles in malignant tumors. For example, these viruses can reduce the growth of tumor cells without causing severe complications. However, the known OVs have not been clearly classified. Herein, we divided OVs into neurotropic and non-neurophilic OVs based on whether the OVs are naturally neurotropic or not. The therapeutic effects of each group were compared. Finally, challenges encountered in the clinical application of OVs in the treatment of malignant gliomas were summarized.

Improved strategy for post-traumatic hydrocephalus following decompressive craniectomy: Experience of a single center.

Background: Patients with head trauma may develop hydrocephalus after decompressive craniectomy. Many studies have referred one-stage cranioplasty (CP) and ventriculoperitoneal shunt (VPS) was applied to treat cranial defect with post-traumatic hydrocephalus (PTH), but the safety and efficiency of the procedure remain controversial. Methods: This is a retrospective cohort study including 70 patients of PTH following decompressive craniectomy who underwent simultaneous (50) and separated (20) procedures of cranioplasty and VPS from March 2014 to March 2021 at the authors' institution with at least 30 days of follow-up. Patient characteristics, clinical findings, and complications were collected and analyzed. Results: Fifty patients with PTH underwent improved simultaneous procedures and 20 patients underwent staged surgeries. Among the cases, the overall complication rate was 22.86%. Complications suffered by patients who underwent one-stage procedure of CP and VPS did not differ significantly, compared with patients in the group of staged procedures (22% vs. 25%, p = 0.763). The significant difference was not observed in the two groups, regarding the complications of subdural/epidural fluid collection (4%/6% vs. 0/2%, p = 1.000/1.000), epidural hemorrhage (6% vs. 4%, p = 0.942), dysfunction of shunting system (0 vs. 2%, p = 0.286), postoperative seizure (8% vs. 4%, p = 1.000), and reoperation case (0 vs. 2%, p = 0.286). No case of subdural hemorrhage, incision/intracranial/abdominal infection, shunting system dysfunction, or reoperation was observed in the group of simultaneous procedure. Complications including subdural/epidural fluid collection, subdural hemorrhage, and incision/intracranial infection were not shown in the case series of the staged procedure group. Conclusion: The improved simultaneous procedure of cranioplasty and VPS is effective and safe to treat cranial defect and post-traumatic hydrocephalus with low risk of complications.