Risk of spontaneous intracerebral hemorrhage associated with NOACs compared with aspirin and warfarin: A long-term single hospital follow-up study.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are currently the mainstay treatment for preventing thrombosis-induced ischemic stroke in patients with atrial fibrillation (AF), deep vein thrombosis (DVT), or previous infarction. However, such management may potentially induce antithrombotic-associated intracranial hemorrhage, leading to significantly adverse clinical outcomes. To investigate the risk of spontaneous intracranial hemorrhage (sICH) in patients under therapeutic anticoagulation. METHODS: This retrospective cohort study used a database established by Kaohsiung Veterans General Hospital to estimate the risk of first onset sICH in patients with AF, DVT or previous stroke who were 18 years old or older, and who had been on at least three months continuous long-term treatment with the oral anticoagulants aspirin, warfarin, or NOACs. In addition, we used propensity-score matching to minimize bias and Cox proportional hazards ratio to compare the risk of sICH among patients prescribed these anticoagulants. RESULTS: We analyzed the data of 546 patients (182 aspirin users, 182 warfarin users, and 182 NOAC users). 180 (20 taking aspirin, 74 warfarin, and 86 NOACs) developed new onset sICH before seven years. No new onset cases were found after 7 years. Importantly, those taking NOACs were found to be at a higher risk of early onset hemorrhage (47.80 %) compared to the groups taking aspirin (11.10 %) and warfarin (47.80 %) with a median time-to-occurrence being 2.50, 4.00, and 4.40 years, respectively. CONCLUSIONS: Though NOACs prevented ischemic stroke, they were used with a higher risk of early onset spontaneous ICH at our large medical center.

An Analysis of Emergency Surgical Outcomes for Pediatric Traumatic Brain Injury: A Ten-Year Single-Institute Retrospective Study in Taiwan.

Background and Objectives: Pediatric traumatic brain injury (pTBI) remains a major pediatric public health problem, despite well-developed injury prevention programs. The purpose of this study is to analyze the emergency surgical outcomes of pTBI in a single institute ten-year retrospective study to offer a real-world clinical result. Materials and Methods: Our institute presented a clinical retrospective, single-institute research study of 150 pediatric TBI cases that were diagnosed and underwent emergency surgical treatment from 2010 to 2019. Results: The incidence of radiological findings is detailed as follows: brain edema (30%, 45/150), followed by acute subdural hematoma (27.3%, 41/150), epidural hematoma (21.3%, 32/150), chronic subdural hemorrhage (10%, 15/150), skull fracture (6.7%, 10/150), and traumatic subarachnoid hemorrhage (4.7%, 7/150). Surgical intervention data revealed that decompressive craniectomy was still the main effective surgical method. The results showed longer hospital stays and higher morbidity rates in the brain edema, acute subdural hematoma, and chronic subdural hemorrhage groups, which were viewed as poor surgical outcome groups. Epidural hematoma, skull fracture and traumatic subarachnoid hemorrhage were categorized into good surgical outcome groups. Notably, the data revealed gross improvement in Glasgow Coma Scale/Score (GCS) evolution after surgical interventions, and the time to cranioplasty was a significant factor in the development of post-traumatic hydrocephalus (PTH). Conclusions: Our study provided real-world data for the distribution of etiology in pTBI and also categorized it into six groups, indicating disease-orientated treatment. In addition, our data supported that decompressive craniectomy (DC) remains a mainstay surgical treatment in pTBI and early cranioplasty could decrease the incidence of PTH.

Hyperbaric Oxygen Therapy as a Novel Approach to Modulating Macrophage Polarization for the Treatment of Glioblastoma.

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with a poor prognosis despite current treatments. This is partially attributed to the immunosuppressive environment facilitated by tumor-associated macrophages, which predominantly underlie the tumor-promoting M2 phenotype. This study investigated the potential of hyperbaric oxygen (HBO) therapy, traditionally used to treat conditions such as decompression sickness, in modulating the macrophage phenotype toward the tumoricidal M1 state and disrupting the supportive tumor microenvironment. HBO has direct antiproliferative effects on tumor cells and reduces hypoxia, which may impair angiogenesis and tumor growth. This offers a novel approach to GBM treatment by targeting the role of the immune system within the tumor microenvironment. The effects of HBO on macrophage polarization and GBM cell viability and apoptosis were evaluated in this study. We detected that HBO promoted M1 macrophage cytokine expression while decreasing GBM cell viability and increasing apoptosis using GBM cell lines and THP-1-derived macrophage-conditioned media. These findings suggest that HBO therapy can shift macrophage polarization toward a tumoricidal M1 state. This can improve GBM cell survival and offers a potential therapeutic strategy. In conclusion, HBO can shift macrophages from a tumor-promoting M2 phenotype to a tumoricidal M1 phenotype in GBM. This can facilitate apoptosis and, in turn, improve treatment outcomes.

High PGC-1α Expression as a Poor Prognostic Indicator in Intracranial Glioma.

Gliomas are the most common primary brain tumors in adults. Despite multidisciplinary treatment approaches, the survival rates for patients with malignant glioma have only improved marginally, and few prognostic biomarkers have been identified. Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) is a crucial regulator of cancer metabolism, playing a vital role in cancer cell adaptation to fluctuating energy demands. In this study, the clinicopathological roles of PGC-1α in gliomas were evaluated. Employing immunohistochemistry, cell culture, siRNA transfection, cell viability assays, western blot analyses, and in vitro and in vivo invasion and migration assays, we explored the functions of PGC-1α in glioma progression. High PGC-1α expression was significantly associated with an advanced pathological stage in patients with glioma and with poorer overall survival. The downregulation of PGC-1α inhibited glioma cell proliferation, invasion, and migration and altered the expression of oncogenic markers. These results conclusively demonstrated that PGC-1α plays a critical role in maintaining the malignant phenotype of glioma cells and indicated that targeting PGC-1α could be an effective strategy to curb glioma progression and improve patient survival outcomes.

The crude extract obtained from Cinnamomum macrostemon Hayata regulates oxidative stress and mitophagy in keratinocytes.

Four ethanol fractionated crude extracts (EFCEs [A-D]) purified from the leaves of Cinnamomum macrostemon Hayata were screened for antioxidative effects and mitochondrial function in HaCaT cells. The higher cell viability indicated that EFCE C was mildly toxic. Under the treatment of 50 ng/mL EFCE C, the hydrogen peroxide (H2O2)-induced cytosolic and mitochondrial reactive oxygen species levels were reduced as well as the H2O2-impaired cell viability, mitochondrial membrane potential (MMP), ATP production, and mitochondrial mass. The conversion of globular mitochondria to tubular mitochondria is coincident with EFCE C-restored mitochondrial function. The mitophagy activator rapamycin showed similar effects to EFCE C in recovering the H2O2-impaired cell viability, MMP, ATP production, mitochondrial mass, and also mitophagic proteins such as PINK1, Parkin, LC3 II, and biogenesis protein PGC-1α. We thereby propose the application of EFCE C in the prevention of oxidative stress in skin cells.

Hyperbaric Oxygen Therapy Adjuvant Chemotherapy and Radiotherapy through Inhibiting Stemness in Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor in adults. Despite the advances in GBM treatment, outcomes remain poor, with a 2-year survival rate of less than 5%. Hyperbaric oxygen (HBO) therapy is an intermittent, high-concentration, short-term oxygen therapy used to increase cellular oxygen content. In this study, we evaluated the effects of HBO therapy, alone or combined with other treatment modalities, on GBM in vitro and in vivo. In the in vitro analysis, we used a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess the effects of HBO therapy alone, a colony formation assay to analyze the effects of HBO therapy combined with radiotherapy and with temozolomide (TMZ), and a neurosphere assay to assess GBM stemness. In the in vivo analysis, we used immunohistochemical staining and in vivo bioluminescence imaging to assess GBM stemness and the therapeutic effect of HBO therapy alone or combined with TMZ or radiotherapy, respectively. HBO therapy did not affect GBM cell viability, but it did reduce the analyzed tumors' ability to form cancer stem cells. In addition, HBO therapy increased GBM sensitivity to TMZ and radiotherapy both in vitro and in vivo. HBO therapy did not enhance tumor growth and exhibited adjuvant effects to chemotherapy and radiotherapy through inhibiting GBM stemness. In conclusion, HBO therapy shows promise as an adjuvant treatment for GBM by reducing cancer stem cell formation and enhancing sensitivity to chemotherapy and radiotherapy.

Role of Nucleobindin-2 in the Clinical Pathogenesis and Treatment Resistance of Glioblastoma.

Glioblastoma (GBM) stands as the most prevalent primary malignant brain tumor, typically resulting in a median survival period of approximately thirteen to fifteen months after undergoing surgery, chemotherapy, and radiotherapy. Nucleobindin-2 (NUCB2) is a protein involved in appetite regulation and energy homeostasis. In this study, we assessed the impact of NUCB2 expression on tumor progression and prognosis of GBM. We further evaluated the relationship between NUCB2 expression and the sensitivity to chemotherapy and radiotherapy in GBM cells. Additionally, we compared the survival of mice intracranially implanted with GBM cells. High NUCB2 expression was associated with poor prognosis in patients with GBM. Knockdown of NUCB2 reduced cell viability, migration ability, and invasion ability of GBM cells. Overexpression of NUCB2 resulted in reduced apoptosis following temozolomide treatment and increased levels of DNA damage repair proteins after radiotherapy. Furthermore, mice intracranially implanted with NUCB2 knockdown GBM cells exhibited longer survival compared to the control group. NUCB2 may serve as a prognostic biomarker for poor outcomes in patients with GBM. Additionally, NUCB2 not only contributes to tumor progression but also influences the sensitivity of GBM cells to chemotherapy and radiotherapy. Therefore, targeting NUCB2 protein expression may represent a novel therapeutic approach for the treatment of GBM.

High Thioredoxin Domain-Containing Protein 11 Expression Is Associated with Tumour Progression in Glioma.

Glioblastoma (GBM) is the most common primary brain malignancy in adults. Despite multimodal treatment that involves maximal safe resection, concurrent chemoradiotherapy, and tumour treatment for supratentorial lesions, the prognosis remains poor. The current median overall survival is only <2 years, and the 5-year survival is only 7.2%. Thioredoxin domain-containing protein 11 (TXNDC11), also known as EF-hand binding protein 1, was reported as an endoplasmic reticulum stress-induced protein. The present study aimed to elucidate the prognostic role of TXNDC11 in GBM. We evaluated the clinical parameters and TXNDC11 scores in gliomas from hospitals. Additionally, proliferation, invasion, migration assays, apoptosis, and temozolomide (TMZ)-sensitivity assays of GBM cells were conducted to evaluate the effects of short interfering RNA (siRNA) on these processes. In addition, these cells were subjected to Western blotting to detect the expression levels of N-cadherin, E-cadherin, and Cyclin D1. High levels of TXNDC11 protein expression were significantly associated with World Health Organization (WHO) high-grade tumour classification and poor prognosis. Multivariate analysis revealed that in addition to the WHO grade, TXNDC11 protein expression was also an independent prognostic factor of glioma. In addition, TXNDC11 silencing inhibited proliferation, migration, and invasion and led to apoptosis of GBM cells. However, over-expression of TXNDC11 enhanced proliferation, migration, and invasion. Further, TXNDC11 knockdown downregulated N-cadherin and cyclin D1 expression and upregulated E-cadherin expression in GBM cells. Knock-in TXNDC11 return these. Finally, in vivo, orthotopic xenotransplantation of TXNDC11-silenced GBM cells into nude rats promoted slower tumour growth and prolonged survival time. TXNDC11 is a potential oncogene in GBMs and may be an emerging therapeutic target.

Galectin-3 Mediates Tumor Progression in Astrocytoma by Regulating Glycogen Synthase Kinase-3ß Activity.

Numerous studies have considered galectin-3 or Glycogen synthase kinase 3 beta (GSK3B) as a potential prognosis marker for various cancers. However, the correlation between the protein expression of galectin-3/GSK3B and the clinical parameters of astrocytoma has not been reported. This study aims to validate the correlation between the clinical outcomes and protein expression of galectin-3/GSK3B in astrocytoma. Immunohistochemistry staining was performed to detect galectin-3/GSK3B protein expression in patients with astrocytoma. The Chi-square test, Kaplan-Meier evaluation, and Cox regression analysis were used to determine the correlation between clinical parameters and galectin-3/GSK3B expression. Cell proliferation, invasion, and migration were compared between a non-siRNA group and a galectin-3/GSK3B siRNA group. Protein expression in galectin-3 or GSK3B siRNA-treated cells was evaluated using western blotting. Galectin-3 and GSK3B protein expression were significantly positively correlated with the World Health Organization (WHO) astrocytoma grade and overall survival time. Multivariate analysis revealed that WHO grade, galectin-3 expression, and GSK3B expression were independent prognostic factors for astrocytoma. Galectin-3 or GSK3B downregulation induced apoptosis and decreased cell numbers, migration, and invasion. siRNA-mediated gene silencing of galectin-3 resulted in the downregulation of Ki-67, cyclin D1, VEGF, GSK3B, p-GSK3B Ser9 (p-GSK3B S9), and ß-catenin. In contrast, GSK3B knockdown only decreased Ki-67, VEGF, p-GSK3B S9, and ß-catenin protein expression but did not affect cyclin D1 and galectin-3 protein expression. The siRNA results indicated that GSK3B is downstream of the galectin-3 gene. These data support that galectin-3 mediated tumor progression by upregulating GSK3B and ß-catenin protein expression in glioblastoma. Therefore, galectin-3 and GSK3B are potential prognostic markers, and their genes may be considered to be anticancer targets for astrocytoma therapy.

Lumbar paraspinal atypical spindle cell/pleomorphic lipomatous tumor: A report of a rare case.

The atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) was classified as a new tumor by the World Health Organization (WHO) in 2020. The tumor is benign and commonly occurs in the limbs. Paraspinal presentations are rare. A 38-year-old man presented at our clinic complaining of sudden onset back pain. No neurological deficit was found. The magnetic resonance imaging (MRI) revealed a well-defined heterogeneous mass in the left psoas muscle, from L1 to L3 extending over the L1 and L2 neuroforamen. The tumor was totally excised. Pathology led to an ASPLT diagnosis. Clinical symptoms improved and there was no postsurgical neurological deficit. This case of ASPLT, located in an uncommon location and present an unusual cluster of symptoms, could be treated by surgical excision, usually the first-treatment strategy. Totally, removal was achieved because there was a clear morphological margin. The risk of metastatic dissemination was minimal, though there remains a nonnegligible risk of local recurrence.

AAV-glycine receptor α3 alleviates CFA-induced inflammatory pain by downregulating ERK phosphorylation and proinflammatory cytokine expression in SD rats.

BACKGROUND: Glycine receptors (GlyRs) play key roles in the processing of inflammatory pain. The use of adeno-associated virus (AAV) vectors for gene therapy in human clinical trials has shown promise, as AAV generally causes a very mild immune response and long-term gene transfer, and there have been no reports of disease. Therefore, we used AAV for GlyRα1/3 gene transfer in F11 neuron cells and into Sprague-Dawley (SD) rats to investigate the effects and roles of AAV-GlyRα1/3 on cell cytotoxicity and inflammatory response. METHODS: In vitro experiments were performed using plasmid adeno-associated virus (pAAV)-GlyRα1/3-transfected F11 neurons to investigate the effects of pAAV-GlyRα1/3 on cell cytotoxicity and the prostaglandin E2 (PGE2)-mediated inflammatory response. In vivo experiment, the association between GlyRα3 and inflammatory pain was analyzed in normal rats after AAV-GlyRα3 intrathecal injection and after complete Freund's adjuvant (CFA) intraplantar administration. Intrathecal AAV-GlyRα3 delivery into SD rats was evaluated in terms of its potential for alleviating CFA-induced inflammatory pain. RESULTS: The activation of mitogen-activated protein kinase (MAPK) inflammatory signaling and neuronal injury marker activating transcription factor 3 (ATF-3) were evaluated by western blotting and immunofluorescence; the level of cytokine expression was measured by ELISA. The results showed that pAAV/pAAV-GlyRα1/3 transfection into F11 cells did not significantly reduce cell viability or induce extracellular signal-regulated kinase (ERK) phosphorylation or ATF-3 activation. PGE2-induced ERK phosphorylation in F11 cells was repressed by the expression of pAAV-GlyRα3 and administration of an EP2 inhibitor, GlyRαs antagonist (strychnine), and a protein kinase C inhibitor. Additionally, intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not induce obvious histopathological injury but increased ATF-3 activation in dorsal root ganglion (DRGs). CONCLUSIONS: Antagonists of the prostaglandin EP2 receptor, PKC, and glycine receptor can inhibit PGE2-induced ERK phosphorylation. Intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not significantly induce gross histopathological injury but elicited ATF-3 activation. We suggest that PGE2-induced ERK phosphorylation can be modulated by GlyRα3, and AAV-GlyRα3 significantly downregulated CFA-induced cytokine activation.