ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling.

BACKGROUND: Cyclic nucleotides are critical mediators of cellular signalling in glioblastoma. However, the clinical relevance and mechanisms of regulating cyclic nucleotides in glioblastoma progression and recurrence have yet to be thoroughly explored. METHODS: In silico, mRNA, and protein level analyses identified the primary regulator of cyclic nucleotides in recurrent human glioblastoma. Lentiviral and pharmacological manipulations examined the functional impact of cyclic nucleotide signalling in human glioma cell lines and primary glioblastoma cells. An orthotopic xenograft mice model coupled with aspirin hydrogels verified the in vivo outcome of targeting cyclic nucleotide signalling. RESULTS: Elevated intracellular levels of cGMP, instead of cAMP, due to a lower substrate efflux from ATP-binding cassette sub-family C member 4 (ABCC4) is engaged in the recurrence of glioblastoma. ABCC4 gene expression is negatively associated with recurrence and overall survival outcomes in glioblastoma specimens. ABCC4 loss-of-function activates cGMP-PKG signalling, promoting malignancy in glioblastoma cells and xenografts. Hydrogels loaded with aspirin, inhibiting glioblastoma progression partly by upregulating ABCC4 expressions, augment the efficacy of standard-of-care therapies in orthotopic glioblastoma xenografts. CONCLUSION: ABCC4, repressing the cGMP-PKG signalling pathway, is a tumour suppressor in glioblastoma progression and recurrence. Aspirin hydrogels impede glioblastoma progression through ABCC4 restoration and constitute a viable translational approach.

Unlocking Colchicine's Untapped Potential: A Paradigm Shift in Hepatocellular Carcinoma Prevention.

Background: Liver cancer and notably hepatocellular carcinoma (HCC), results in significantly high mortality rates worldwide. Chronic hepatitis and fatty liver, recognized precursors, underscore the imperative need for effective preventive strategies. This study explores colchicine, traditionally acknowledged for its anti-inflammatory properties and investigates its potential in liver cancer prevention. Methods: Utilizing the iHi Data Platform of China Medical University Hospital, Taiwan, this study analyzed two decades of medical data, incorporating 10,353 patients each in the Colchicine and Non-Colchicine cohorts, to investigate the association between colchicine use and liver cancer risk. Results: The study identified that colchicine users exhibited a 19% reduction in liver cancer risk, with a multivariable-adjusted odds ratio of 0.81 after accounting for confounding variables. Additionally, the influence of gender and comorbidities like diabetes mellitus on liver cancer risk was identified, corroborating the existing literature. A notable finding was that the prolonged use of colchicine was associated with improved outcomes, indicating a potential dose-response relationship. Conclusions: This study proposes a potential new role for colchicine in liver cancer prevention, extending beyond its established anti-inflammatory applications. While the findings are promising, further research is essential to validate these results. This research may serve as a foundation for future studies, aiming to further explore colchicine's role via clinical trials and in-depth investigations, potentially impacting preventive strategies for liver cancer.

Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma.

Tumor hypoxia promotes malignant progression and therapeutic resistance in glioblastoma partly by increasing the production of hydrogen peroxide (H2O2), a type of reactive oxygen species critical for cell metabolic responses due to its additional role as a second messenger. However, the catabolic pathways that prevent H2O2 overload and subsequent tumor cell damage in hypoxic glioblastoma remain unclear. Herein, we present a hypoxia-coordinated H2O2 regulatory mechanism whereby excess H2O2 in glioblastoma induced by hypoxia is diminished by glutathione peroxidase 1 (GPx1), an antioxidant enzyme detoxifying H2O2, via the binding of hypoxia-inducible factor-1α (HIF-1α) to GPx1 promoter. Depletion of GPx1 results in H2O2 overload and apoptosis in glioblastoma cells, as well as growth inhibition in glioblastoma xenografts. Moreover, tumor hypoxia increases exosomal GPx1 expression, which assists glioblastoma and endothelial cells in countering H2O2 or radiation-induced apoptosis in vitro and in vivo. Clinical data explorations further demonstrate that GPx1 expression was positively correlated with tumor grade and expression of HIF-1α, HIF-1α target genes, and exosomal marker genes; by contrast, it was inversely correlated with the overall survival outcome in human glioblastoma specimens. Our analyses validate that the redox balance of H2O2 within hypoxic glioblastoma is clinically relevant and could be maintained by HIF-1α-promoted or exosome-related GPx1.

Astragalus membranaceus Extract Prevents Calcium Oxalate Crystallization and Extends Lifespan in a Drosophila Urolithiasis Model.

Approximately 1 in 20 people develops kidney stones at some point in their life. Although the surgical removal of stones is common, the recurrence rate remains high and it is therefore important to prevent the occurrence of kidney stones. We chose Astragalus membranaceus (AM), which is a traditional Chinese medicine, to study the prevention of urolithiasis using a Drosophila model based on our previous screening of traditional Chinese herbs. Wild-type Drosophila melanogaster Canton-S adult fruit flies were used in this study. Ethylene glycol (EG, 0.5%) was added to food as a lithogenic agent. The positive control agent (2% potassium citrate (K-citrate)) was then compared with AM (2, 8, and 16 mg/mL). After 21 days, the fruit flies were sacrificed under carbon dioxide narcotization, and the Malpighian tubules were dissected, removed, and processed for polarized light microscopy examination to observe calcium oxalate (CaOx) crystallization. Then, the ex vivo dissolution of crystals in the Malpighian tubules was compared between K-citrate and AM. Survival analysis of the EG, K-citrate, and AM groups was also performed. Both 2% K-citrate and AM (16 mg/mL) significantly inhibited EG-induced CaOx crystal formation. Mean lifespan was significantly reduced by the administration of EG, and the results were significantly reversed in the AM (8 and 16 mg/mL) groups. However, AM extract did not directly dissolve CaOx crystals in Drosophila Malpighian tubules ex vivo. In conclusion, AM extract decreased the ratio of CaOx crystallization in the Malpighian tubules and significantly ameliorated EG-induced reduction of lifespan. AM prevented CaOx crystal formation in the Drosophila model.

Incidence of Screw Loosening in Cortical Bone Trajectory Fixation Technique between Single- and Dual-Threaded Screws.

Purpose: This study aims to elucidate the radiological outcome after Cortical bone trajectory (CBT) screw fixation and whether dual-threaded (DT) screws should be used in the fusion surgery. Methods: 159 patients with degenerative lumbar disorder who had undergone midline lumbar inter-body fusion surgery by CBT screw-fixation technique (2014 to 2018). Patient subgroups were based on single-threaded (ST) or DT screw, fixation length, as well as whether fixation involved to sacrum level (S1). Serial dynamic plain films were reviewed and an appearance of a halo phenomenon between screw-bone interfaces was identified as a case of screw loosening. Results: 29 patients (39.7%) in ST group and 10 patients (11.6%) in DT group demonstrated a halo phenomenon (p < 0.0001 ****). After subgrouping with fixation length, the incidence rates of a halo phenomenon in each group were 11.1%:3% (ST-1L vs. DT-1L), 37%:13.8% (ST-2L vs. DT-2L), and 84.2%:23.5% (ST-3L vs. DT-3L). Among the 85 patients with a fixation involved in S1, 26 patients (52%) with single-threaded screw (STS group) and 8 patients (22.8%) with dual-threaded screw (DTS group) demonstrated a halo appearance (p = 0.0078 **). After subgrouping the fixation level, the incidence of a halo appearance in each group was 25%:0% (STS-1L vs. DTS-1L), 40.9%:26.3% (STS-2L vs. DTS-2L), and 87.5%: 30% (STS-3L vs. DTS-3L). Conclusion: Both fixation length and whether fixation involved to S1 contribute to the incidence of screw loosening, the data supports clinical evidence that DT screws had greater fixation strength with an increased fixative stability and lower incidence of screw loosening in CBT screw fixation compared with ST screws. Level of evidence: 2.

Combined posterior and anterior approaches for cervical intradural disc herniation: A case report.

Intradural disc herniation (IDH) is an extremely rare condition. The authors report the case of a 53-year-old female who had neck and right shoulder pain associated with right-sided hemiparesis and hyperesthesia. Magnetic resonance imaging (MRI) of the cervical spine (C-spine) revealed central mass-like lesions that caused the; compression of the right side of the spinal cord. The posterior surgical approach was used to remove two pieces of IDH. After surgery, the muscle strength in the right upper limb improved from Grade 0/5 to 4+/5 without surgery-related complications. Although there are some reports in literature on the radiologic features of cervical IDH (including the Halo sign, Y-sign, hawk-beak sign, and crumble disc sign), it can be difficult to diagnose radiologically. We present the clinical image of the case along with a review of the literature to remind surgeons to consider IDH as a differential diagnosis when patients are affected by anterior intradural lesions.

Level-based analysis of screw loosening with cortical bone trajectory screws in patients with lumbar degenerative disease.

This study aimed to verify the relationship between the number of fusion level and the risk of screw loosening by using cortical bone trajectory (CBT) screws in patients with lumbar degenerative disease.We retrospectively reviewed the serial plain radiograph images of lumbar degenerative disease patients who had undergone posterior fixation and fusion surgery with CBT from 2014. All included patients should have been followed-up with computed tomography scan or plain radiograph for at least 6 months after operation. We individually evaluated the prevalence of screw loosening according to each vertebral level. We also determined whether the number of screw fixation affected the prevalence of screw loosening and whether S1 fixation increased the risk of screw loosening.The screw-loosening rates were high at the S1 level. Moreover, although fixation involved to S1, the loosening rates evidently increased (Fisher exact test, P = .002). The screw-loosening rate was 6.56% in 2 level fusion. However, it increased with the number of fusion levels (3 level: 25.00%, 4 level: 51.16%, and 5 level: 62.50%). To investigate if the number of fusion level affected the S1 screw loosening, we classified the cohort of patients into either involving S1 (S1+ group) or not (S1- group) according to different fusion levels (). The screw loosening between 2 group in 2 (5.56% vs 6.98%) and 3 fusion level (26.32% vs 22.73%) did not exhibit any significant difference. Interestingly, significantly high screw loosening was found in 4 fusion level (60.00% vs 15.38%), indicating that the higher fusion level (4 level) can directly increase the risk of S1 screw loosening.Our data confirmed that the screw-loosening rate increases rate when long segment CBT fixation involves to S1. Therefore, in case of long-segment fixation by using CBT screw, surgeons should be aware of the fusion level of S1.

Cortical Bone Trajectory Instrumentation with Vertebroplasty for Osteoporotic Thoracolumbar Compression Fracture.

BACKGROUND: Osteoporotic spinal fractures commonly occur in elderly patients with low bone mineral density. In these cases, percutaneous vertebroplasty or percutaneous kyphoplasty can provide significant pain relief and improve mobility. However, studies have reported both the recurrence of vertebral compression fractures at the index level after vertebroplasty and the development of new vertebral fractures at the adjacent level that occur without any additional trauma. Pedicle screw fixation combined with percutaneous vertebroplasty has been proposed as an effective procedure for addressing osteoporotic thoracolumbar fractures. However, in osteoporotic populations, pedicle screws can loosen, pullout, or migrate. Currently, the efficacy of cortical bone trajectory screw fixation for osteoporotic fractures remains unclear. Thus, we assessed the effects of using cortical bone trajectory instrumentation with vertebroplasty on patient outcomes. METHOD: We retrospectively reviewed data from 12 consecutively sampled osteoporotic thoracolumbar fracture patients who underwent cortical bone trajectory instrumentation with vertebroplasty. Patients were enrolled beginning in October 2015 and were followed for >24 months. RESULT: The average age was 74 years, and the average dual-energy x-ray absorptiometry T-score was -3.6. The average visual analog scale pain scores improved from 8 to 2.5 after surgery. The average blood loss was 36.25 mL. All patients regained ambulation and experienced reduced pain post-surgery. No recurrent fractures or instrument failures were recorded during follow-up. CONCLUSIONS: Our findings suggest that cortical bone trajectory instrumentation combined with percutaneous vertebroplasty may be a good option for treating osteoporotic thoracolumbar fractures, as it can prevent recurrent vertebral fractures or related kyphosis in sagittal alignment.

Multiple myeloma with intracranial and spinal intradural metastasis: A case report.

Multiple myeloma is a hematopoietic cancer that is multicentric and most commonly involves the spine. Multiple myeloma with extraosseous and intradural involvement is an extremely rare condition. Here we present a rare case of spinal multiple myeloma with intracranial and spinal intradural metastasis causing lumbar spinal nerve compression. We present a 60-year-old woman with progressive weakness of the lower limbs for several weeks. Spinal magnetic resonance imaging (MRI) showed a leptomeningeal tumor with nodularity spreading within the cauda equina. Examination of the brain using MRI showed a lytic skull bone lesion and leptomeningeal enhancement. The patient underwent L3-5 laminectomy. Immunohistological staining confirmed a diagnosis of multiple myeloma of the IgA kappa subtype. After surgery, the patient underwent chemotherapy and rehabilitation exercises. Multiple myeloma has a median survival of 2.5 years, while 75% of patients with spinal involvement die within 1 year of diagnosis. Unfortunately, our patient died 3 months after the diagnosis of multiple myeloma with spinal and intracranial involvement. Intracranial and spinal intradural multiple myeloma invasions are quitely rare. Spine biopsies and cerebrospinal fluid cytology can aid in the diagnosis. Early surgical decompression is necessary, especially when neurological deficits occur.

Long-Term Follow-up in Patients with Spontaneous Intracerebral Hemorrhage Treated With or Without Surgical Intervention: a Large-Scale Retrospective Study.

Debates regarding the most beneficial medical or surgical procedures for patients with spontaneous intracerebral hemorrhage (sICH) are still ongoing. We aimed to evaluate the risk of subsequent vascular disease and mortality in patients with sICH treated with and without surgical intervention, in a large-scale Asian population. Patients hospitalized within 2000 to 2013 who were newly diagnosed with sICH were identified using the National Health Insurance Research Database of Taiwan. Neuroendoscopy and craniotomy groups comprised patients who underwent surgical treatment within 1 week, while those in the control group did not undergo early surgical treatment. Outcomes included subsequent hemorrhagic and ischemic stroke, following acute myocardial infarction, congestive heart failure, and mortality. After propensity score matching, there were 663 patients in each group. Compared to that in the control group, the neuroendoscopy and craniotomy groups had a significantly higher risk of secondary vascular events at 1 to 3 months of follow-up (adjusted HR, 2.08 and 1.95; 95% CI, 1.21-3.58 and 1.13-3.35; p < 0.01 and p < 0.05, respectively), but a significantly lower risk after 3 years of follow-up (adjusted HR, 0.52 and 0.52; 95% CI, 0.35-0.78 and 0.35-0.77; p < 0.01 and p < 0.01, respectively). The mortality rate was higher in the craniotomy group at 6 to 12 months of follow-up (adjusted HR, 2.18; 95% CI, 1.06-4.49; p < 0.05) compared to that in the control group. Thus, a timely surgical intervention for hematoma evacuation is advantageous in preventing secondary vascular events and improving outcomes in the long term. However, greater attention to secondary ischemic stroke following the initial sICH episode is needed.

Minimal invasive surgical technique in midline lumbar inter-body fusion: A technique note.

Midline lumbar inter-body fusion (MIDLF) surgery with cortical bone trajectory (CBT) screw insertion is a modern fusion technique for spinal surgery. The difference in entry point of this trajectory from conventional pedicle screw surgery offers the potential benefits of less soft tissue dissection and reduced blood loss, post-operative wound pain, and infection risks. Because this is a newly developed technique first announced by Santoni in 2009, most surgeons perform this surgery in a mini-open fashion and require more intra-operative fluoroscopy and ionizing radiation exposure during screw placement. In this article, we demonstrate a minimally invasive midline lumbar interbody fusion (MIS-MIDLF) technique with percutaneous CBT screw placement. Using a designed cannulated awl, we only need a single dimensional fluoroscopy view from anterior to posterior (AP view) to achieve an accurate trajectory and therefore reduce radiation exposure. We report our first ten consecutive patients with degenerative spondylolithesis who underwent MISS-MIDLF and were followed up for more than 18 months. The procedure required a single wound of about 3 cm in length in one to two level fusion surgery and only three to four shots of fluoroscopy were needed for each screw placement. There were no screws malpositioned in subsequent plain films or computer tomography scans. We demonstrate a case with detailed surgical procedures and provide this technique as an alternative approach for surgeons performing MILDF surgery.

Risk of posterior circulation stroke in patients with cervical spondylosis: A nationwide, population-based study.

BACKGROUND AND AIMS: Cervical spondylosis (CS) is reported to be associated with vertebrobasilar insufficiency. However, few cohort studies have investigated the association between CS and posterior circulation ischemic stroke. METHODS: The study cohort comprised 27,990 patients aged ≥18 years with a first diagnosis of CS. The controls consisted of patients with propensity score matched for age, sex, and comorbidities at a ratio of 1:1. We investigated the relationships of CS with ischemic stroke and all-cause mortality. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The average follow-up duration was 6.13 (SD = 3.18) and 6.07 (SD = 3.19) years in the CS and non-CS cohorts, respectively. RESULTS: The mean age of CS patients and non-CS patients was 54.9 ±â€¯13.4 and 55.1 ±â€¯14.9 years. Fifty-eight point five percent of CS patients and 59.2% of non-CS patients were women. CS patients were 1.46 folds more likely to develop a posterior circulation ischemic stroke (95% CI, 1.23-1.72) than non-CS patients. CS patients with myelopathy exhibited a 1.50-fold risk (95% CI, 1.21-1.86) of posterior circulation ischemic stroke compared with non-CS patients; CS patients without myelopathy were at a 1.43-fold risk (95% CI, 1.18-1.73) of posterior ischemic stroke compared with non-CS patients. The risk of posterior ischemic stroke was non-significant between non-CS patients and CS patients who had received spinal anterior decompression (adjusted HR, 1.66; 95% CI, 0.78-3.52), while receiving posterior decompression was associated with a 4.23-fold risk of posterior ischemic stroke (95% CI, 1.05-17.0). CONCLUSIONS: This population-based study showed that CS is associated with an increased risk of posterior circulation ischemic stroke. Surgical posterior decompression was associated with the highest risk of posterior ischemic stroke.

Association of Arrhythmia in Patients with Cervical Spondylosis: A Nationwide Population-Based Cohort Study.

BACKGROUND: Sympathetic activity, including cervical ganglia, is involved in the development of cardiac arrhythmias. OBJECTIVE: The present study investigated the association between cervical spondylosis and arrhythmia, which has never been reported before. METHODS: Patients newly diagnosed with cervical spondylosis (CS) with an index date between 2000 and 2011 were identified from the National Health Insurance Research Database. We performed a 1:1 case-control matched analysis. Cases were matched to controls according to their estimated propensity scores, based on demographics and existing risk factors. Cox proportional hazard models were applied to assess the association between CS and arrhythmia. RESULTS: The CS cohort comprised 22,236 patients (males, 42.6%; mean age, 54.4 years) and non-CS cohort comprised 22,236 matched controls. There were 1441 events of arrhythmia in CS cohort and 537 events of arrhythmia in non-CS cohort, which 252 and 127 events of atrial fibrillation in CS and non-CS cohort, 33 and 12 events of ventricular tachycardia in CS cohort and non-CS cohort, 78 and 35 events of supraventricular tachycardia in CS cohort and non-CS cohort. The CS cohort had an arrhythmia incidence of 11.1 per 1000 person-years and a higher risk [adjusted hazard ratio (aHR) = 3.10, 95% confidence interval (CI) = 2.80⁻3.42] of arrhythmia, 2.54-fold aHR of ventricular tachycardia (95% CI = 1.70⁻3.79), and 2.22-fold aHR of atrial fibrillation (95% CI = 1.79⁻2.76) compared with non-CS cohort. CONCLUSIONS: Cervical spondylosis is associated with a higher risk of arrhythmia.

Risk of acute coronary syndrome in patients with cervical spondylosis.

BACKGROUND AND AIMS: Cervical spondylosis (CS) is reported to be associated with increased sympathetic activity and hypertension. However, the cardiovascular (CV) outcomes of patients with CS are largely unknown. METHODS: A national insurance claims dataset of 22 million enrollees in Taiwan during 1999-2010 was used as the research database. We identified 27,948 patients with CS and age-, sex-, and comorbidity-matched controls. By using multivariate logistic regression analysis after adjustment for potential cardiovascular (CV) confounders, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) to quantify the association between CS and acute coronary syndrome (ACS). RESULTS: A total of 744 ACS events were identified among the 27,948 patients with CS. The overall incidence of ACS was 4.27 per 1000 person-years in the CS cohort and 3.90 per 1000 person-years in the non-CS cohort, with an adjusted hazard ratio (aHR) of 1.13 (95% CI = 1.08-1.18). The aHRs of ACS were 1.08 (95% CI = 1.03-1.15) in the CS cohort without myelopathy and 1.20 (95% CI = 1.13-1.28) in the CS cohort with myelopathy, compared with the non-CS cohort. Compared with patients with CS without neurological signs, patients with CS receiving rehabilitation exhibited a 0.67 aHRs of ACS (95% CI = 0.59-0.76), whereas those with neurological signs receiving spinal decompression exhibited 0.73 aHRs of ACS (95% CI = 0.63-0.84). CONCLUSIONS: CS is associated with an increased risk of ACS. Receiving treatment for CS, either rehabilitation or spinal decompression, is associated with less risk of ACS.

Cortical bone trajectory screws fixation in lumbar adjacent segment disease: A technique note with case series.

Lumbar adjacent segment disease after lumbar fusion surgery often requires surgical intervention. However, subsequent surgical treatment often needs to expose and remove all of the previous instruments. This additional surgery leads to significant post-operative pain, muscular fibrosis, poor wound healing and infection, etc. From October 2015 to March 2016, we collected six cases underwent cortical bone trajectory screws fixation with minimal invasive inter-body cage fusion for lumbar adjacent segment disease. Patients in the study all had improvement after surgery without recurrence or instruments failure during follow-up. The technique negates removal of pre-existing instruments and when combined with minimal invasive fusion surgery, the wound length, blood loss and soft tissue damage could be reduced compared with traditional surgery. We introduce the surgical procedures in detail and wish this technique could be an option for spine surgeons who encounter a similar situation.

PG2 for patients with acute spontaneous intracerebral hemorrhage: a double-blind, randomized, placebo-controlled study.

PG2 is an infusible polysaccharide extracted from Astragalus membranaceus, which is a Chinese herb traditionally used for stroke treatment. We investigated the effect of PG2 on patients with spontaneous acute intracerebral hemorrhage (ICH). A total of 61 patients with acute spontaneous ICH were randomized to either the treatment group (TG, 30 patients), which received 3 doses of PG2 (500 mg, IV) per week for 2 weeks, or the control group (CG, 31 patients), which received PG2 placebo. At 84 days after PG2 administration, the percentage of patients with a good Glasgow outcome scale (GOS 4-5) score in the TG was similar to that in the CG (69.0% vs. 48.4%; p = 0.2). The percentage of good mRS scores (0-2) in the TG was similar to that in the CG (62.1% vs. 45.2%; p = 0.3). In addition, no significant differences were seen when comparing differences in the C-reactive protein, erythrocyte sedimentation rate, interleukin-6 (IL-6), IL-1ß, tumor necrosis factor-α, and S100B levels between baseline and days 4, 7, and 14 after PG2 administration (all p > 0.05). The results are preliminary, necessitating a more thorough assessment.

Primary Intraosseous Hemangioma of the Orbital Roof: A Pitfall of Surgery.

A primary intraosseous hemangioma (IOH) of the orbital bone is extremely rare. The preferred method of treatment for IOH is total surgical excision with reconstruction. Herein, the authors describe a patient with an orbital roof IOH and the unexpected complications of ptosis and deteriorated exophthalmos. These findings showed that the total surgical excision and subsequent reconstruction provided adequate decompression and prevented further ocular complications from the orbital wall defect.