Tonsillar herniation as a complication of lumboperitoneal shunt: case report and literature review.

Tonsillar herniation is a rare and seldom reported complication after lumboperitoneal (LP) shunting. There have been only few reports that have presented possible options for treatment with varying degrees of success. In this report, we describe a rare case of tonsillar herniation after LP shunting and review related literature.A 17-year-old girl with hydrocephalus related to a traumatic brain injury underwent implantation of an adjustable pressure shunt (valve setting2.5) and a small lumen peritoneal catheter via the L4-L5 interspinal space. One month later, she was admitted to the emergency room with a Glasgow Coma Scale score ofE1M1Vt and dilated pupil. Image studies demonstrated new-onset tonsillar herniation and a mild cervical syrinx. Emergent suboccipital decompressive craniectomy, C1 laminectomy, and duraplasty were performed. This was followed with ligation of the LP shunt and implantation of a ventriculoperitoneal (VP) shunt a few days later. The patient's Glasgow Coma Scale score gradually recovered to 6, which was her previous neurologic status.Tonsillar herniation as a complication after LP shunting is best treated with decompression, ligation or removal of the LP shunt, and a shift to a VP shunt. The tonsillar herniation should be rapidly addressed to avoid persistent symptoms or progression of the neurologic deficits.

The E3 Ubiquitin Ligase NEDD4-1 Mediates Temozolomide-Resistant Glioblastoma through PTEN Attenuation and Redox Imbalance in Nrf2-HO-1 Axis.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is highly resistant to chemotherapy, and tumor recurrence is common. Neuronal precursor cell-expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ligase that controls embryonic development and animal growth. NEDD4-1 regulates the tumor suppressor phosphatase and tensin homolog (PTEN), one of the major regulators of the PI3K/AKT/mTOR signaling axis, as well as the response to oxidative stress. METHODS: The expression levels of NEDD4-1 in GBM tissues and different cell lines were determined by quantitative real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo assays were performed to explore the biological effects of NEDD4-1 on GBM cells. Temozolomide (TMZ)-resistant U87MG and U251 cell lines were specifically established to determine NEDD4-1 upregulation and its effects on the tumorigenicity of GBM cells. Subsequently, miRNA expression in TMZ-resistant cell lines was investigated to determine the dysregulated miRNA underlying the overexpression of NEDD4-1. Indole-3-carbinol (I3C) was used to inhibit NEDD4-1 activity, and its effect on chemoresistance to TMZ was verified. RESULTS: NEDD4-1 was significantly overexpressed in the GBM and TMZ-resistant cells and clinical samples. NEDD4-1 was demonstrated to be a key oncoprotein associated with TMZ resistance, inducing oncogenicity and tumorigenesis of TMZ-resistant GBM cells compared with TMZ-responsive cells. Mechanistically, TMZ-resistant cells exhibited dysregulated expression of miR-3129-5p and miR-199b-3p, resulting in the induced NEDD4-1 mRNA-expression level. The upregulation of NEDD4-1 attenuated PTEN expression and promoted the AKT/NRF2/HO-1 oxidative stress signaling axis, which in turn conferred amplified defense against reactive oxygen species (ROS) and eventually higher resistance against TMZ treatment. The combination treatment of I3C, a known inhibitor of NEDD4-1, with TMZ resulted in a synergistic effect and re-sensitized TMZ-resistant tumor cells both in vitro and in vivo. CONCLUSIONS: These findings demonstrate the critical role of NEDD4-1 in regulating the redox imbalance in TMZ-resistant GBM cells via the degradation of PTEN and the upregulation of the AKT/NRF2/HO-1 signaling pathway. Targeting this regulatory axis may help eliminate TMZ-resistant glioblastoma.

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.

Minimally Invasive Resection of a Foraminal Lumbar Root Schwannoma.

Background and Importance: This video article reports a rare case of a right L5/S1 foraminal root schwannoma that presents the natural course of the disease, imaging findings, treatment protocol, operative procedure, and highlights some of the possible surgical complications. Clinical Presentation: Magnetic resonance imaging (MRI) revealed an intradural, extramedullary, well-enhanced mass at the right L5/S1 level. The operative procedure involved a right minimal L5/S1 laminotomy/foraminotomy posteriorly to open the right L5 root. The facet joints were preserved to prevent spinal instability. The tumor was located along the root after opening the right L5/S1 foramen. Intraoperative electromyography (IOM) was conducted to detect any nerve injury in the patient. After opening the dura, the tumor was carefully separated from the normal root nerve under IOM monitoring. The mass was removed piece-by-piece using mini-forceps. Conclusion: Histopathological examination confirmed the diagnosis of a schwannoma. The patient recovered without incident after surgery with minimal soreness and numbness in the right leg.

Engineered droplet-forming peptide as photocontrollable phase modulator for fused in sarcoma protein.

The assembly and disassembly of biomolecular condensates are crucial for the subcellular compartmentalization of biomolecules in the control of cellular reactions. Recently, a correlation has been discovered between the phase transition of condensates and their maturation (aggregation) process in diseases. Therefore, modulating the phase of condensates to unravel the roles of condensation has become a matter of interest. Here, we create a peptide-based phase modulator, JSF1, which forms droplets in the dark and transforms into amyloid-like fibrils upon photoinitiation, as evidenced by their distinctive nanomechanical and dynamic properties. JSF1 is found to effectively enhance the condensation of purified fused in sarcoma (FUS) protein and, upon light exposure, induce its fibrilization. We also use JSF1 to modulate the biophysical states of FUS condensates in live cells and elucidate the relationship between FUS phase transition and FUS proteinopathy, thereby shedding light on the effect of protein phase transition on cellular function and malfunction.

Hyperglycemia exacerbates intracerebral hemorrhage via the downregulation of aquaporin-4: temporal assessment with magnetic resonance imaging.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is associated with high mortality and neurological deficits, and concurrent hyperglycemia usually worsens clinical outcomes. Aquaporin-4 (AQP-4) is important in cerebral water movement. Our aim was to investigate the role of AQP-4 in hyperglycemic ICH. METHODS: Hyperglycemia was induced by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg) in adult Sprague-Dawley male rats. ICH was induced by stereotaxic infusion of collagenase/heparin into the right striatum. One set of rats was repeatedly monitored by MRI at 1, 4, and 7 days after ICH induction so as to acquire information on the formation of hematoma and edema. Another set of rats was killed and brains were examined for differences in the degree of hemorrhage and edema, water content, blood-brain barrier destruction, and AQP-4 expression. RESULTS: Hyperglycemia ICH rats exhibited increased brain water content, more severe blood-brain barrier destruction, and greater vasogenic edema as seen on diffusion-weighted MRI. Significant downregulation of AQP-4 was observed in STZ-treated rats after ICH as compared with non-STZ-treated rats. Apoptosis was greater on day 1 after ICH in STZ-treated rats. CONCLUSIONS: The expression of AQP-4 in the brain is downregulated in hyperglycemic rats as compared with normoglycemic rats after ICH. This change is accompanied by increased vasogenic brain edema and more severe blood-brain barrier destruction.

Clinical Outcome and Safety of Lumboperitoneal Shunt in the Treatment of Non-Obstructive Hydrocephalus.

Objective: This study aimed to evaluate the functional outcomes of lumboperitoneal (LP) shunt for the treatment of non-obstructive hydrocephalus. Methods: We retrospectively studied the clinical surgical results of 172 adult patients with hydrocephalus who underwent LP shunt surgery between June 2014 and June 2019. Data regarding the following were collected: pre- and postoperative symptom status, third ventricle width changes, Evans index, and postoperative complications. Additionally, the baseline and follow-up Glasgow Coma Scale (GCS) score, Glasgow Outcome Scale (GOS), and Modified Rankin Scale (mRS) scores were investigated. All patients were followed up for ≥12 months using clinical interview and braining imaging using computed tomography (CT) scan or magnetic resonance imaging (MRI). Results: Majority of patients presented with normal pressure hydrocephalus as the etiology of their disease (48.8%), followed by cardiovascular accident (28.5%), trauma (19.7%), and brain tumor (3%). The mean GCS, GOS, and mRS improved postoperatively. The average period from symptomatic onset to surgery was 402 days. The average width of the third ventricle on CT scan or MRI was 11.43 mm preoperatively and 10.8 mm postoperatively (P<0.001). The Evans index improved from 0.258 to 0.222 after operation. The symptomatic improvement score was 7.0, with a complication rate of 7%. Conclusion: Significant improvement was observed in the functional score and brain image after LP shunt placement. Moreover, the satisfaction with symptomatic improvement after surgery remains high. LP shunt operation is a viable alternative in the treatment of non-obstructive hydrocephalus due to the low complication rate, fast recovery, and high satisfaction.

Efficacy of Non-Invasive Brain Stimulation for Treating Depression in Patients with Traumatic Brain Injury: A Meta-Analysis and Meta-Regression of Randomized Controlled Trials.

OBJECTIVE: This meta-analysis aimed to ascertain the efficacy of non-invasive brain stimulation (NIBS)-comprising repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)-for depression in traumatic brain injury (TBI) patients. METHODS: Comprehensive searches were conducted in PubMed, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials up to 28 January 2023. Random-effects models assessed the treatment effects, and heterogeneity was evaluated through I2 statistics and funnel plot inspection. RESULTS: From 10 trials (234 participants; 8 rTMS, 2 tDCS), NIBS was found significantly more effective than sham in alleviating depressive symptoms (SMD: 0.588, 95% CI: 0.264-0.912; p < 0.001). rTMS, specifically, showed higher efficacy (SMD: 0.707, 95% CI: 0.306-1.108; p = 0.001) compared to sham, whereas tDCS outcomes were inconclusive (SMD: 0.271, 95% CI: -0.230 to 0.771; p = 0.289). Meta-regression found no correlation with the number of sessions, treatment intensity, or total dose. Notably, while post-treatment effects were significant, they diminished 1-2 months post intervention. Adverse events associated with NIBS were minimal, with no severe outcomes like seizures and suicide reported. CONCLUSIONS: rTMS emerged as a potent short-term intervention for depression in TBI patients, while tDCS findings remained equivocal. The long-term efficacy of NIBS is yet to be established, warranting further studies. The low adverse event rate reaffirms NIBS's potential safety.

Single-sized N-functionality graphene quantum dot in tunable dual-modality near infrared-I/II illumination detection and photodynamic therapy under multiphoton nonlinear excitation.

Doping sorted graphene quantum dots (GQDs) with heteroatoms and functionalizing them with amino acid could improve their radiative recombination and two-photon properties-including their excitation-wavelength-independent photoluminescence from the ultraviolet to the near-infrared-I (NIR-I) region, absorption, quantum yield, absolute cross section, lifetime, and radiative-to-nonradiative decay ratio-under two-photon excitation (TPE) at a low excitation energy and short photoexcitation duration, as determined using a self-made optical microscopy system with a femtosecond Ti-sapphire laser. Four types of sorted GQDs were investigated: undoped GQDs, nitrogen-doped GQDs (N-GQDs), amino-functionalized GQDs (amino-GQDs), and N-doped and amino-functionalized GQDs (amino-N-GQDs). Among them, the sorted amino-N-GQDs are effective as a two-photon photosensitizer and generate the highest quantity of reactive oxygen species for the elimination of multidrug-resistant cancer cells through two-photon photodynamic therapy (PDT). Larger amino-N-GQDs result in a greater number of C-N and N-functionalities, leading to a superior photochemical effect and more favorable intrinsic luminescence properties, making the dots effective contrast agents for tracking and localizing cancer cells during in-depth bioimaging in a three-dimensional biological environment under TPE in the NIR-II region. Overall, this study highlights the potential of large amino-N-GQDs as a material for future application to dual-modality two-photon PDT and biomedical imaging.

Intradural lumbar disc herniation: A case report and literature review.

Study design and objection: Intradural disc herniation is a unusual disease associated with spinal surgery. The definitive diagnosis of intradural herniation depends on intraoperative findings. Summary of background data: We present the case of a 63-year-old woman with backache and left sciatica radiation for more than two months. The L2/3 laminectomy and discectomy were performed after magnetic resonance imaging (MRI) study; however, no disc rupture was noted during surgery. Follow-up lumbar spine MRI revealed one large, ruptured disc. The patient underwent revision surgery with durotomy. The large intradural disc was found and removed piece by piece. Methods Results and Conclusions: Intradural disc herniation, especially large herniation, is hard to diagnose specifically despite the progression of neuroradiologic imaging techniques. A durotomy procedure should be considered if there is a missing ruptured disc or a palpable intradural mass during surgery.

Ubiquitin-Specific Protease 6 n-Terminal-like Protein (USP6NL) and the Epidermal Growth Factor Receptor (EGFR) Signaling Axis Regulates Ubiquitin-Mediated DNA Repair and Temozolomide-Resistance in Glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant glioma, with a 30-60% epidermal growth factor receptor (EGFR) mutation. This mutation is associated with unrestricted cell growth and increases the possibility of cancer invasion. Patients with EGFR-mutated GBM often develop resistance to the available treatment modalities and higher recurrence rates. The drug resistance observed is associated with multiple genetic or epigenetic factors. The ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) is a GTPase-activating protein that functions as a deubiquitinating enzyme and regulates endocytosis and signal transduction. It is highly expressed in many cancer types and may promote the growth and proliferation of cancer cells. We hypothesized that USP6NL affects GBM chemoresistance and tumorigenesis, and that its inhibition may be a novel therapeutic strategy for GBM treatment. The USP6NL level, together with EGFR expression in human GBM tissue samples and cell lines associated with therapy resistance, tumor growth, and cancer invasion, were investigated. Its pivotal roles and potential mechanism in modulating tumor growth, and the key mechanism associated with therapy resistance of GBM cells, were studied, both in vitro and in vivo. Herein, we found that deubiquitinase USP6NL and growth factor receptor EGFR were strongly associated with the oncogenicity and resistance of GBM, both in vitro and in vivo, toward temozolomide, as evidenced by enhanced migration, invasion, and acquisition of a highly invasive and drug-resistant phenotype by the GBM cells. Furthermore, abrogation of USP6NL reversed the properties of GBM cells and resensitized them toward temozolomide by enhancing autophagy and reducing the DNA damage repair response. Our results provide novel insights into the probable mechanism through which USP6NL/EGFR signaling might suppress the anticancer therapeutic response, induce cancer invasiveness, and facilitate reduced sensitivity to temozolomide treatment in GBM in an autolysosome-dependent manner. Therefore, controlling the USP6NL may offer an alternative, but efficient, therapeutic strategy for targeting and eradicating otherwise resistant and recurrent phenotypes of aggressive GBM cells.

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.

Prenatal transplantation of human amniotic fluid stem cell could improve clinical outcome of type III spinal muscular atrophy in mice.

Spinal muscular atrophy (SMA) is a single gene disorder affecting motor function in uterus. Amniotic fluid is an alternative source of stem cell to ameliorate SMA. Therefore, this study aims to examine the therapeutic potential of Human amniotic fluid stem cell (hAFSC) for SMA. Our SMA model mice were generated by deletion of exon 7 of Smn gene and knock-in of human SMN2. A total of 16 SMA model mice were injected with 1 × 105 hAFSC in uterus, and the other 16 mice served as the negative control. Motor function was analyzed by three behavioral tests. Engraftment of hAFSC in organs were assessed by flow cytometry and RNA scope. Frequency of myocytes, neurons and innervated receptors were estimated by staining. With hAFSC transplantation, 15 fetuses survived (93.75% survival) and showed better performance in all motor function tests. Higher engraftment frequency were observed in muscle and liver. Besides, the muscle with hAFSC transplantation expressed much laminin α and PAX-7. Significantly higher frequency of myocytes, neurons and innervated receptors were observed. In our study, hAFSC engrafted on neuromuscular organs and improved cellular and behavioral outcomes of SMA model mice. This fetal therapy could preserve the time window and treat in the uterus.

Targeting BC200/miR218-5p Signaling Axis for Overcoming Temozolomide Resistance and Suppressing Glioma Stemness.

Background: Glioblastoma (GB) is one of the most common (~30%) and lethal cancers of the central nervous system. Although new therapies are emerging, chemoresistance to treatment is one of the major challenges in cancer treatment. Brain cytoplasmic 200 (BC200) RNA, also known as BCYRN1, is a long noncoding RNA (lncRNA) that has recently emerged as one of the crucial members of the lncRNA family. BC200 atypical expression is observed in many human cancers. BC200 expression is higher in invasive cancers than in benign tumors. However, the clinical significance of BC200 and its effect on GB multiforme is still unexplored and remains unclear. Methods: BC200 expression in GB patients and cell lines were investigated through RT-qPCR, immunoblotting, and immunohistochemistry analysis. The biological importance of BC200 was investigated in vitro and in vivo through knockdown and overexpression. Bioinformatic analysis was performed to determine miRNAs associated with BC200 RNA. Results: Our findings revealed that in GB patients, BC200 RNA expression was higher in blood and tumor tissues than in normal tissues. BC200 RNA expression have a statistically significant difference between the IDH1 and P53 status. Moreover, the BC200 RNA expression was higher than both p53, a prognostic marker of glioma, and Ki-67, a reliable indicator of tumor cell proliferation activity. Overexpression and silencing of BC200 RNA both in vitro and in vivo significantly modulated the proliferation, self-renewal, pluripotency, and temozolomide (TMZ) chemo-resistance of GB cells. It was found that the expressions of BC200 were up-regulated and that of miR-218-5p were down-regulated in GB tissues and cells. miR-218-5p inhibited the expression of BC200. Conclusions: This study is the first to show that the molecular mechanism of BC200 promotes GB oncogenicity and TMZ resistance through miR-218-5p expression modulation. Thus, the noncoding RNA BC200/miR-218-5p signaling circuit is a potential clinical biomarker or therapeutic target for GB.

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.

MicroRNA-7 targets T-Box 2 to inhibit epithelial-mesenchymal transition and invasiveness in glioblastoma multiforme.

The dysregulation of microRNA expression in cancer has been associated with the epithelial-mesenchymal transition (EMT) that triggers invasive ability and increases therapeutic resistance. Here, we determined the microRNA expression profile of seven tumor tissues from patients with glioblastoma multiforme (GBM) by use of microRNA array analysis. We discovered that microRNA-7 (miR-7) is consistently downregulated in all tumor samples. Using the microRNA.org algorithm, the T-box 2 gene (TBX2) was identified as a candidate gene targeted by miR-7. In contrast to miR-7, TBX2 had an increased expression in GBM tumors and was linked to poor prognosis. We confirmed that TBX2 mRNA and protein production are significantly repressed by overexpressing miR-7 in GBM cells in vitro. The reporter assay showed that miR-7 significantly represses the signal from luciferase with the 3' UTR of TBX2. Furthermore, TBX2 overexpression decreased E-cadherin expression and increased Vimentin expression, causing an increasing number of invaded cells in the invasion assay, as well as pulmonary metastasis in vivo. Our findings demonstrated that overexpression of TBX2 in GBM tumors via the downregulation of miR-7 leads to EMT induction and increased cell invasion.

Preclinical Evidence of STAT3 Inhibitor Pacritinib Overcoming Temozolomide Resistance via Downregulating miR-21-Enriched Exosomes from M2 Glioblastoma-Associated Macrophages.

BACKGROUND: The tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). A dysfunctional TME promotes drug resistance, disease recurrence, and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within the TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins, and microRNAs. RESULTS: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Coculture of GAMs (and GAM-derived exosomes) and GBM cell lines increased GBM cells' resistance against temozolomide (TMZ) by upregulating the prosurvival gene programmed cell death protein 4 (PDCD4) and stemness markers SRY (sex determining region y)-box 2 (Sox2), signal transducer and activator of transcription 3 (STAT3), Nestin, and miR-21-5p and increasing the M2 cytokines interleukin 6 (IL-6) and transforming growth factor beta 1(TGF-ß1) secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed a markedly reduced ability to secret M2 cytokines and reduced miR-21-enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which the tumor suppressor PDCD4 was targeted. We subsequently established patient-derived xenograft (PDX) models where mice bore patient GBM and GAMs. Treatment with pacritinib and the combination of pacritinib and TMZ appeared to significantly reduce the tumorigenesis of GBM/GAM PDX mice as well as overcome TMZ resistance and M2 polarization of GAMs. CONCLUSION: In summation, we showed the potential of pacritinib alone or in combination with TMZ to suppress GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in clinical settings.

Surgical results of cranioplasty using three-dimensional printing technology.

OBJECT: The aim of this research was to evaluate the surgical outcome of a new three-dimensional printing (3DP) technique using prefabrication molds and polymethyl methacrylate (PMMA). PATIENTS AND METHODS: The study included 10 patients with large skull defects (>100 cm2) who underwent cranioplasty. The causes of the skull defects were trauma (6), bone resorption (2), tumor (1), and infection (1). Before the operation, computed tomography (CT) scans were used to create a virtual plan, and these were then converted to 3-dimensional (3-D) images. The field of the skull defect was blueprinted by the technicians and operators, and a prefabricated 3-D model was generated. During the operation, a PMMA implant was created using a prefabricated silicone rubber mold and fitted into the cranial defect. All patients were followed up for at least 2 years, and any complications after the cranioplasty were recorded. RESULTS: Only 1 patient suffered a complication, subdural effusion 2 months after cranioplasty, which was successfully treated with a subdural peritoneal shunt. All patients satisfied the criteria for operative outcome and cosmetic effect. There were no episodes of infection or material rejection. CONCLUSION: The 3DP technology allowed precise, fast, and inexpensive craniofacial reconstruction. This technique may be beneficial for shortening the operation time (and thus reducing exposure time to general anesthesia, and wound exposure time, and blood loss), enhancing preoperative evaluation and simplifying the surgical procedure.

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.