Clinical relevance of critical plasma homocysteine levels in predicting rupture risk for small and medium-sized intracranial aneurysms.

Plasma homocysteine (Hcy) has been globally recognized as an independent risk factor for various neurovascular diseases. In this study, the authors investigated the relationship between critical Hcy concentration and the risk of rupture in intracranial aneurysms (IAs). This study collected data from 423 patients with both ruptured and unruptured IAs. We compared demographic data, vascular rupture risk factors, and laboratory test results between the two groups. Multivariable logistic regression analysis was employed to determine the correlation between critical plasma Hcy levels and the risk of rupture in small to medium-sized IAs. A total of 330 cases of ruptured intracranial aneurysms (RIA) and 93 cases of unruptured intracranial aneurysms (UIA) were included. Univariate analysis revealed statistically significant differences between the ruptured and unruptured groups in terms of hypertension, hyperlipidemia, plasma Hcy levels, and IA morphology (all P < 0.05). Multivariable logistic regression analysis indicated that hypertension (odds ratio [OR] 0.504; 95% confidence interval [CI] 0.279-0.911; P = 0.023), hyperlipidemia (OR 1.924; 95% CI 1.079-3.429; P = 0.027), and plasma Hcy levels (OR 1.420; 95% CI 1.277-1.578; P < 0.001) were independently associated with the rupture of small to medium-sized IAs, all with statistical significance (P < 0.05). Our study suggests that critical plasma Hcy levels are an independent risk factor for increased rupture risk in small to medium-sized intracranial aneurysms. Therefore, reducing plasma Hcy levels may be considered a valuable strategy to mitigate the risk of intracranial vascular abnormalities rupture and improve patient prognosis.

Predictors of restenosis after carotid endarterectomy and carotid artery stenting / 国际脑血管病杂志

Carotid artery stenosis is an important cause of ischemic stroke. Carotid endarterectomy and carotid artery stenting are the effective methods for treating carotid artery stenosis, but postoperative restenosis remains a challenge. The pathogenesis of postoperative restenosis is currently not fully understood. However, multiple factors, including biomarkers, imaging features, and surgical related factors, have been proven to be associated with postoperative restenosis and can predict the occurrence of postoperative restenosis. This article reviews the predictors of restenosis after carotid endarterectomy and carotid artery stenting.

Homocysteine and ischemic stroke / 国际脑血管病杂志

Studies have confirmed that homocysteine is associated with ischemic stroke. This article reviews the correlation between homocysteine and ischemic stroke risk, etiological type, severity, outcome, as well as the research progress of reducing homocysteine to prevent ischemic stroke.

Homocysteine and intracerebral hemorrhage / 国际脑血管病杂志

An increasing number of studies have shown that homocysteine is associated with intracerebral hemorrhage. This article reviews the correlation between homocysteine and the incidence risk, clinical characteristics, clinical outcomes of intracerebral hemorrhage, as well as the treatment methods for reducing homocysteine.

Case report: Clinical report of co-occurrence of pituitary adenoma and meningioma in the sellar region after meningioma treatment.

The coexistence of meningioma and pituitary adenoma is very rare, especially in the same location after meningioma surgery. Here, we reported a case of coexisting meningioma and pituitary adenoma secondary to postoperative meningioma in the sellar region in a patient who had not received radiation therapy before the second surgery. A 61-year-old woman underwent craniotomy for tumor resection for sellar meningioma in 2017, and postoperative imaging showed no residual in the surgical area. In 2022, the patient had a history of decreased vision again. MRI showed the possibility of postoperative pituitary adenoma in the sellar region. The patient underwent endoscopic resection of the skull base lesion again. After surgery, the patient's visual symptoms improved. Histology of the sellar tumor showed both meningioma (meningeal epithelial type and WHO grade I) and pituitary adenoma in the same section. The coexistence of meningioma and pituitary adenoma is a very rare surgical entity. This report provides a theoretical basis for the selection of intracerebral tumor surgery and provides a diagnostic basis and treatment reference for patients diagnosed with meningioma and pituitary adenoma at the same time.

The Dolenc technique was used to clip 14 cases of ruptured basilar apex aneurysms and posterior cerebral artery aneurysms.

Objective: To investigate the surgical techniques and their clinical effects for ruptured basilar artery apex and posterior cerebral aneurysms via the Dolenc approach. Methods: We retrospectively analyzed the clinical data of 14 patients with ruptured basilar artery apex and posterior cerebral aneurysms who underwent surgical clipping by the Dolenc approach from July 2017 to June 2020 in Beijing Tiantan Hospital affiliated with Capital Medical University and Lianyungang Hospital affiliated with Xuzhou Medical University. The modified Rankin scale (mRs) scores were used to evaluate the prognosis of patients. Results: All 14 cases of aneurysms were successfully clipped. Overall, 1, 2, and 1 cases of postoperative new-onset visual loss, oculomotor nerve palsy, and contralateral hemiplegia, respectively, were reported. Digital subtraction angiography (DSA) or computed tomography angiography (CTA) examination of the aneurysm within 2 weeks after surgery revealed that the aneurysm was completely clipped without residue. The observations during the follow-up within 12-18 months after surgery were as follows: 1 case of vision loss returned to normal, 2 cases of oculomotor nerve palsy, 1 case of return to normal, 1 case of improved, 1 case of contralateral hemiplegia improved after rehabilitation treatment, and 1 case of hydrocephalus ventriculoperitoneal shunt surgery was performed. Overall, 11, 2, and 1 case had mRs scores of 0, 1, and 2, respectively. No death was reported. Conclusion: For the small number of basilar apical and posterior cerebral aneurysms treated non-invasively, the Dolenc approach may offer advantages over other modalities.

Protection of branches during clipping of low grade internal carotid communicating segment aneurysms via frontolateral keyhole approach / 中华神经医学杂志

Objective:To investigate the clinical experiences and outcomes of protection of branches during clipping of low grade internal carotid communicating segment (C7) aneurysms via frontolateral keyhole approach. Methods:Fifty-two patients with internal carotid C7 aneurysms and Hunt-Hess grading I-III, admitted to our hospital from January 2017 to December 2020, were chosen; 45 patients were with posterior communicating artery (PCoA) aneurysms, 6 patients were with anterior choroidal artery (ACHA) aneurysms, and one patient was with PCoA aneurysm combined with ACHA aneurysm. The relation between origin of the branch arteries and tumor neck was determined during surgery. The relation between shape of the branch arteries and tumor body was investigated in the Spaces II, III and V of the internal carotid artery (indocyanine green fluorescence angiography was used when necessary); the aneurysms were clipped by appropriate aneurysm clip or clips combination; after clipping, microspic or endoscopic exploration and indocyanine green fluorescence angiography were performed, and re-clipping was performed in the misclipped or stenosed branch arteries.Results:During the surgery, the branch arteries of 6 patients (4 from posterior communicating artery, 1 from anterior choroidal artery, and 1 from perforator artery at the bifurcation of internal carotid artery) were misclipped, and therefore, the aneurysm clips were adjusted or replaced and then re-clipped. Aneurysms were successfully clipped in all 52 patients. Brain CT examination within 24 h of surgery showed that focal cerebral infarction in the branch artery feeding area was noted in 5 patients, of which 3 patients were accompanied by contralateral limb muscle strength decline (grading 4, grading 3 and grading 1, respectively) and medication and neurological rehabilitation were given. The other 47 patients had good general condition without special condition. During the follow-up of 9-12 months, the muscle strength of 3 patients with decreased contralateral limb strength recovered to grading 5, 4 and 2, respectively. There were no residual or recurrent aneurysms in all patients. At the last follow-up, 47 patients had Glasgow Outcome scale (GOS) scores of 5, 3 patients had GOS scores of 4, 1 patient had GOS scores of 3, and 1 patient had GOS scores of 2.Conclusion:In the treatment of low-grade internal carotid artery C7 segment aneurysms via frontolateral keyhole approach, multiple protective strategies can be adopted to actively prevent branch artery injury, which can effectively reduce the incidence of postoperative cerebral infarction and improve the prognosis.

FXa cleaves the SARS-CoV-2 spike protein and blocks cell entry to protect against infection with inferior effects in B.1.1.7 variant

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human natural defense mechanisms against SARS-CoV-2 are largely unknown. Serine proteases (SPs) including furin and TMPRSS2 cleave SARS-CoV-2 spike protein, facilitating viral entry. Here, we show that FXa, a SP for blood coagulation, is upregulated in COVID-19 patients compared to non-COVID-19 donors and exerts anti-viral activity. Mechanistically, FXa cleaves the SARS-CoV-2 spike protein, which prevents its binding to ACE2, and thus blocks viral entry. Furthermore, the variant B.1.1.7 with several mutations is dramatically resistant to the anti-viral effect of FXa compared to wild-type SARA-CoV-2 in vivo and in vitro. The anti-coagulant rivaroxaban directly inhibits FXa and facilitates viral entry, whereas the indirect inhibitor fondaparinux does not. In a lethal humanized hACE2 mouse model of SARS-CoV-2, FXa prolonged survival while combination with rivaroxaban but not fondaparinux abrogated this protection. These preclinical results identify a previously unknown SP function and associated anti-viral host defense mechanism and suggest caution in considering direct inhibitors for prevention or treatment of thrombotic complications in COVID-19 patients.

The K18-hACE2 Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 in Response to Infectious Dose of SARS-CoV-2 Virus

A comprehensive analysis and characterization of a SARS-CoV-2 infection model that mimics non-severe and severe COVID-19 in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start. We found that intranasal inoculation with higher viral doses (2x103 and 2x104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lungs, liver, and kidney, while lower doses (2x101 and 2x102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this humanized hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in biopsy samples from COVID-19 patients. Finally, the mice that recovered after infection with a low dose of virus also survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human biopsy samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19. ImportanceThe pandemic of COVID-19 has reached 112,589,814 cases and caused 2,493,795 deaths worldwide as of February 23, 2021, has raised an urgent need for development of novel drugs and therapeutics to prevent the spread and pathogenesis of SARS-CoV-2. To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 virus to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of anti-viral drugs and therapeutics.

Effects of Fe₃O₄ on the denitrification performance of Pseudomonas stutzeri / 生物工程学报

Biological denitrification is the most widely used technology for nitrate removal in wastewater treatment. Conventional denitrification requires long hydraulic retention time, and the nitrate removal efficiency in winter is low due to the low temperature. Therefore, it is expected to develop new approaches to enhance the denitrification process. In this paper, the effect of adding different concentrations of Fe₃O₄ nanoparticles on the denitrification catalyzed by Pseudomonas stutzeri was investigated. The maximum specific degradation rate of nitrate nitrogen improved from 18.0 h⁻¹ to 23.7 h⁻¹ when the concentration of Fe₃O₄ increased from 0 mg/L to 4 000 mg/L. Total proteins and intracellular iron content also increased along with increasing the concentration of Fe₃O₄. RT-qPCR and label-free proteomics analyses showed that the relative expression level of denitrifying genes napA, narJ, nirB, norR, nosZ of P. stutzeri increased by 55.7%, 24.9%, 24.5%, 36.5%, 120% upon addition of Fe₃O₄, and that of denitrifying reductase Nap, Nar, Nir, Nor, Nos increased by 85.0%, 147%, 16.5%, 47.1%, 95.9%, respectively. No significant difference was observed on the relative expression level of denitrifying genes and denitrifying reductases between the bacteria suspended and the bacteria adhered to Fe₃O₄. Interestingly, the relative expression level of electron transfer proteins of bacteria adhered to Fe₃O₄ was higher than that of the bacteria suspended. The results indicated that Fe₃O₄ promoted cell growth and metabolism through direct contact with bacteria, thereby improving the denitrification. These findings may provide theoretical support for the development of enhanced denitrification.

Chinese expert consensus on the management of immune-related adverse events of hepato-cellular carcinoma treated with immune checkpoint inhibitors (2021 edition) / 中华消化外科杂志

The clinical application of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of hepatocellular carcinoma (HCC) patients. With the widespread applica-tion of ICIs in HCC, the management of immune-related adverse events (irAE) gained more and more attention. However, the complicated disease characteristics and various combination therapies in HCC throw out challenges to irAE management. Therefore, the editorial board of the 'Chinese expert consensus on the management of immune-related adverse events of hepatocellular carcinoma treated with immune checkpoint inhibitors (2021 edition)' organizes multidisciplinary experts to discuss and formulate this consensus. The consensus focuses on issues related to HCC irAE manage-ment, and puts forward suggestions, in order to improve standardized and safety clinical medication, so as to maximize the benefits of immunotherapy for patients.

Application of anatomy of anterior clinoid process and anterior clinoidectomy in neurosurgery / 中华神经医学杂志

The anterior clinoid process (ACP) is an important anatomical structure of the skull base. Some surgeries for intracranial lesions require to remove the ACP in order to achieve visual field exposure of the lesions and surrounding anatomical structure, and provide sufficient operating space. In this paper, the research progress in anatomy and variation of the ACP, methods of anterior clinoidectomy, and applications of anterior clinoidectomy in neurosurgical surgerys are summarized as follows.

Efficacy of fluorescein angiography assisted occlusion via lateral-orbital keyhole approach in internal carotid bifurcation aneurysms / 中华神经医学杂志

Objective:To investigate the efficacy and clinical experiences of fluorescein angiography assisted occlusion via lateral-orbital keyhole approach in internal carotid bifurcation aneurysms. Methods:The clinical data of 16 patients with internal carotid artery bifurcation aneurysms admitted to our hospital from January 2016 to December 2020 were retrospectively analyzed. All patients accepted fluorescein angiography assisted occlusion via lateral-orbital keyhole approach. The patients were followed up at one, 3, and 6 months after surgery by medical imaging. The therapeutic efficacy of these patients was assessed by Glasgow outcome scale (GOS). Results:All aneurysms in these 16 patients were clipped at one-stage operation. Intraoperative fluorescein angiography and FLOW 800 showed that the aneurysms were completely clipped without residual, and the blood flow of the parent artery and perforating arteries was unobstructed. Six months after surgery, 14 patients recovered well (GOS scores of 5), and 3 developed limb hemiplegia (GOS scores of 4).Conclusion:Intraoperative fluorescein angiography assisted occlusion via lateral-orbital keyhole approach is safe and effective in internal carotid bifurcation aneurysms.

Effect of NACK knockdown on the proliferation and apoptosis of T-cell acute lymphoblastic leukemia Jurkat cells / 中华实用儿科临床杂志

Objective:To investigate the effect and mechanism of NACK knockdown on the proliferation and apoptosis of T-cell acute lymphoblastic leukemia (T-ALL) Jurkat cells. Methods:Lentivirus transfection technology was used to transfect Jurkat cells and knock down NACK gene.Real time fluorescent quantitative PCR and Western blot were used to detect the silencing efficiency of NACK gene.CCK-8 method and flow cytometry were used to detect the effects of NACK knockdown on the proliferation and apoptosis of Jurkat cells.The expressions of protein related with Notch1 pathway, such as Hes1 and c-Myc, were detected by Western blot. Results:After NACK-shRNA was successfully transfected into Jurkat cells by lentiviral vector, the expression of NACK mRNA and protein was reduced signi-ficantly ( P<0.05). Compared with the negative control group and the blank control group, the CCK-8 method showed that the cell proliferation in the experimental group was significantly inhibited [The inhibition rates of cell proliferation in the experimental group, negative control group and blank control group were (37.27±4.48)%, (4.25±2.10)% and (2.43±1.40)%, respectively]( F=132.640, P<0.05), and the flow cytometry test showed that the apoptosis in the experimental group increased significantly [The apoptosis rates of experimental group, negative control group and blank control group were (26.38±3.03)%, (6.07±2.61)% and (3.40±1.98)%, respectively]( F=90.534, P<0.05). Western blot results confirmed that the expression of Notch1 pathway-related proteins Hes1 and c-Myc was down-regulated compared with the negative control group and the blank control group, and the difference was statistically significant ( P<0.05). Conclusions:Targeting silent NACK can down-regulate the expression of Notch1 pathway-related proteins, which leads to the inhibition of Jurkat cell proliferation and increased apoptosis, thereby exerting its anti-T-ALL effect.

Clipping of 27 patients with partial complicated posterior communicating artery aneurysms via Dolenc approach: a clinical efficacy analysis / 中华神经医学杂志

Objective:To explore the clinical experiences and treatment outcomes of partial complicated posterior communicating artery aneurysms (PCoAs) via Dolenc approach.Methods:The clinical data of 27 patients with partial complicated PCoAs accepted clipping via Dolenc approach in our hospitals from July 2014 to June 2019 were retrospectively reviewed. The clinical efficacies were analyzed and the surgical experiences were summarized in these patients.Results:Among 27 patients with partial complicated PCoAs, 26 accepted clipping successfully via Dolenc approach, and one accepted clipping and wrapping. For clinical ourcomes, 2 out of 3 patients with preoperative oculomotor paralysis got improvement after surgery, and one was without change; in 4 patients with new-onset oculomotor paralysis after surgery, 2 returned to normal after conservative treatment, one got improvement, and one was without change. After surgery, 2 had basal ganglia focal cerebral infarction and one had ventriculoperitoneal shunt due to hydrocephalus. DSA or CTA examination within two weeks after surgery showed all 26 aneurysms were completely clipped and without residual. During the 9-12 months of follow up, Glasgow outcome scale (GOS) showed that 20 patients had GOS 5 scores, 3 had GOS 4 scores, 2 had GOS 3 scores, one had GOS 2 scores, and one died. No patients showed aneurysm recurrent in the imaging examination.Conclusion:Via Dolenc approach, anterior clinoid process and its surrounding bony structures are drilled off via extradural way, and proximal of parent artery is exposed well, therefore, more operation space can be provided to deal with partial complicated PCoAs.

Effectiveness of multi-disciplinary treatment for reducing carbapenem-resistant Enterobacteriaceae infections in intensive care unit / 中华临床感染病杂志

Objective:To evaluate the effectiveness of multi-disciplinary treatment (MDT) for reducing carbapenem-resistant Enterobacteriaceae (CRE) infections in intensive care unit(ICU).Methods:Patients admitted in the emergency ICU (EICU) and neurosurgical ICU (NICU) of the First People’s Hospital of Lianyungang during January 2018 to December 2019 were enrolled in the study, which was analyzed by historical control study. For patients admitted in 2018, the conventional method was adopted for prevention and control of drug-resistant bacteria (control group, n=1, 076), and for patients admitted in 2019, the MDT was adopted for the prevention and control of CRE (intervention group, n=1, 237). Chi-square test was used to compare the incidence rate of CRE infection, CRE detection rate, rate of rational antibiotic use and compliance with implementation of prevention and control measures between two groups. Results:Compared to control group, the incidence rate of CRE infection in EICU and NICU decreased from 3.45% (14/406) and 3.58% (24/670) to 1.65% (9/547) and 2.32% (16/690) in intervention group, respectively; while the detection rate of CRE decreased from 66.21% (96/145) and 57.72% (86/149) to 41.11% (51/124) and 33.06% (40/121), the pathogens were mainly carbapenem-resistant Klebsiella pneumoniae (CRKP). The rational medication rate of carbapenem antibiotics was significantly increased from 65.00%(78/120) in 2018 to 92.73%(319/344) in 2019 ( χ2=55.382, P<0.05). In addition, the single room isolation rate, the rate of specialized nursing care, the cleaning and disinfection quality of bench surface and the special use rate of articles were also significantly improved( χ2=21.646, 18.116, 39.869 and 19.713, P<0.01). Conclusion:The establishment of multi-department collaborative management based on MDT can effectively improve the prevention and control effect of CRE in ICU and significantly reduce the prevalence of CRE infection.

Signaling pathways of cerebral vasospasm after aneurysmal subarachnoid hemorrhage / 国际脑血管病杂志

Aneurysmal subarachnoid hemorrhage (aSAH) has high disability and mortality.Cerebral vasospasm is the main cause of ischemic neurological deficit and even cerebral infarction after aSAH.At present,there are many studies on molecular signaling pathways of cerebral vasospasm.This article reviews the signaling pathways of cerebral vasospasm after aSAH.

Treatment of ischemic stroke with bone marrow mesenchymal stem cells:directional differentiation of neural lineage / 国际脑血管病杂志

Studies have shown that bone marrow mesenchymal stem cells (BMSCs) transplantation can restore the sensory and motor function of patients with ischemic stroke. BMSCs transplantation is a promising therapeutic strategy because of its ability to differentiate into neuron-like cells. This article reviews the inducers that promote BMSCs to differentiate into neuron-like cells in vitro.

Efficacy prediction and molecular mechanism of thyroid hormone levels and multi-target TKI therapy for renal cell carcinoma and hepatocellular carcinoma / 国际肿瘤学杂志

Hypothyroidism is a common adverse reaction in clinical multi-target tyrosine kinase inhibitor (TKI) and may be used as a predictor of efficacy of TKI drugs.Studies show that hypothyroidism is significantly associated with good prognosis in patients with renal cell carcinoma treated with multi-target TKI,which may be related to inhibition of vascular endothelial growth factor receptor pathway,potential off-target effects and inhibition of cell proliferation.Whereas in the patients with hepatocellular carcinoma who received multi-target TKI therapy,hypothyroidism is an indicator of poor prognosis,which is related to the T3/TR pathway regulating liver cancer growth and invasion.The predictive function and mechanism of thyroid hormone levels in different tumor patients receiving multi-target TKI drugs are different,and further research is still needed.

Effect of Tamibarotene on the proliferation and Tyrosine kinase receptor A,N-myc expressions of neuroblastoma SH-SY5Y cells / 中华实用儿科临床杂志

Objective To study the effect of Tamibarotene on the SH-SY5Y cell proliferation inhibition ability and the mRNA and protein expressions of tyrosine kinase receptor a (TrkA) and N-myc (MYCN) in order to provide some experimental bases for the treatment of neuroblastoma.Methods The SH-SY5Y cells were treated with different concentrations of Am80 (0,10,20,40,80,160 μmol/L) for 48 h,then Cell Counting Kit-8 (CCK-8) was used to test the cell proliferation.Reverse transcription PCR(RT-PCR) and Western blot were used to test the mRNA and protein expressions of TrkA and MYCN at 48 hours.Results When the concentration was 10 μmol/L,Am80 had no significant inhibitory effect on SH-SY5Y cells [(3.51 ± 1.68)％,inhibition ratio ＜ 5 ％];but when the concentration was 20 μmol/L,it showed weak inhibition [(9.60 ± 1.97) ％,inhibition ratio ＜ 10％].The inhibition rate of SH-SY5Y cell proliferation[(57.43 ± 4.95)％] was significantly enhanced at Am80 with a concentration of 80 μmol/L.The concentrations of Am80 could effectively inhibit SH-SY5Y cell proliferation in a dose-dependent manner(P ＜0.05).The expression of TrkA increased with the increase of Am80 concentration.Am80 significantly decreased the expression of MYCN in SH-SY5Y cells(10 μmol/L:0.65 ±0.05 vs.20 μmol/L:0.36 ±0.06),and the difference was statistically significant(P ＜ 0.05).Conclusions It is suggested that Am80 can effectively inhibit SH-SY5Y cell proliferation in a concentration-dependent manner.The underlying mechanism involves increasing the expression of TrkA by down-regulation of MYCN.