Clinical features and surgical outcomes of Rathke cleft cysts with suprasellar components: a single-center experience of 157 cases.

BACKGROUND: Both intrasuprasellar and suprasellar Rathke cleft cysts (RCCs) have suprasellar components, and we aimed to explore their clinical features and surgical outcomes. METHOD: Patients with surgically treated intrasuprasellar or suprasellar RCCs were retrospectively analyzed. All patients with intrasuprasellar RCCs were treated with the standard endoscopic endonasal approach (EEA, group I); the patients with suprasellar RCCs received the extended EEA (group II) or supraorbital keyhole approach (SKA, group III) according to the relevant indications. A surgical strategy of maximal safe resection aiming to protect neuroendocrine function was adopted. In addition, patients (distinguished from the above 3 groups) who had aggressive resection of suprasellar RCC were also enrolled for comparison of different surgical strategies. RESULTS: A total of 157 patients were eligible, including 121 patients with intrasuprasellar RCCs in group I, 19 patients with suprasellar RCCs in group II, and 17 patients with suprasellar RCCs in group III. Preoperatively, the patients with suprasellar RCC (groups II and III) more commonly presented with visual dysfunction, diabetes insipidus (DI), and hyperprolactinemia than the patients with intrasuprasellar RCCs (all p<0.05). A higher incidence of hypopituitarism and a larger diameter were observed for intrasuprasellar RCCs (both p<0.05). Postoperatively, group II had a higher rate of new-onset DI, hyponatremia, and recurrence than group I (all p<0.025) and similar outcomes to group III. For suprasellar RCCs, comparison of the maximal safe resection vs. aggressive resection (supplementary patients: 14 with extended EEA, 12 with SKA) showed similar improvement and recurrence, with higher rates of DI and hyponatremia with the latter strategy (all p<0.05). CONCLUSIONS: Suprasellar RCC is associated with more complicated preoperative presentations, intricate postoperative complications, and frequent recurrence compared with intrasuprasellar RCC. Under rational indications, both extended EEA and SKA achieve satisfactory outcomes. The strategy of maximal safe resection is recommended for greatest functional preservation.

Effects of cruciate embedding fascia-bone flap technique on grade II-III cerebral spinal fluid leak in endoscopic endonasal surgery.

BACKGROUND: Cerebral spinal fluid (CSF) leak remains an important issue in endoscopic endonasal surgery (EES). A standard protocol for skull base closure has not yet been established, and the application of rigid buttress has not been given sufficient attention. To emphasize the functions of support and fixation from rigid buttress in reconstruction, we introduced the cruciate embedding fascia-bone flap (CEFB) technique using autologous bone graft to buttress the fascia lata attachment to the partially sutured skull base dural defect and evaluated its efficacy in a consecutive case series of grade II-III CSF leaks in EES. METHODS: Data from consecutive patients diagnosed with sellar region lesions with grade II-III CSF leaks during EES were collected from May 2015 to May 2020. Skull base reconstructions were performed with the CEFB or the conventional pedicle vascularized nasoseptal flap (PNSF). Related clinical data were analysed. The combined use of the CEFB and PNSF was applied to an additional supplemental case series of patients with grade III leak and multiple high-risk factors. RESULTS: There were 110 and 65 patients included in the CEFB and PNSF groups, respectively. The CEFB demonstrated similar effects on the incidence of postoperative CSF leak (2.7%), intracranial infection (4.5%), and lumbar drainage (LD) placement (5.5%) as PNSF (3.1%, 3.1%, and 6.2%), but with less epistaxis (CEFB: 0%, PNSF: 6.2%) and nasal discomforts (CEFB: 0%, PNSF: 7.7%). The LD duration (CEFB: 6.67 ± 2.16 days, PNSF: 10.50 ± 2.38 days), bed-stay time (CEFB: 5.74 ± 1.58 days, PNSF: 8.83 ± 3.78 days) and hospitalization time (CEFB: 10.49 ± 5.51 days, PNSF: 13.58 ± 5.50 days) were shortened in the CEFB group. The combined use of CEFB and PNSF resulted in 0 postoperative CSF leaks in the supplemental case series of 23 highly susceptible patients. CONCLUSION: This study suggested that the new CEFB technique has the potential to prevent postoperative CSF leak in EES. The results indicated that it can be used effectively without PNSF in suitable cases or applied in addition to a PNSF with high compatibility when necessary. Its effectiveness should be further verified with a larger cohort and better design in the next step. Trial Registration Current Controlled Trials ChiCTR2100044764 (Chinese Clinical Trial Registry); date of registration: 27 March 2020. Retrospectively registered.

Online re-examination of postgraduate medical students during the COVID-19 pandemic.

BACKGROUND: Postgraduate entrance examination (the Unified National Graduate Entrance Examination) is the major way for Chinese medical undergraduate student to apply for postgraduate studies. It consists of two stages: the preliminary basic written test and the re-examination in form of both written tests and interviews. With the spread of COVID-19, the traditional on-site re-examination of postgraduates must be changed to online re-examination. By comparing the re-examination process and admission results of online and on-site re-examination, we studied the feasibility of online re-examination for postgraduates and measures to improve it. METHODS: This was a retrospective cohort study using data from the Unified National Graduate Entrance Examination. Our sample population was the applicants to Peking University Third Hospital (PUTH) who completed re-examinations. In total, 281 records were successively selected from March 2017 to May 2020. By comparing the re-examination process and admission results of the 2020 online re-examination with those of the 2017-2019 on-site re-examinations, we analyzed the process, difficulties and improvement of online re-examination. RESULTS: A total of 281 subjects were included, of whom 77.9% completed an on-site re-examination in 2017-2019 and 22.1% completed the 2020 online re-examination. In the on-site re-examinations, 70.8% of the students were admitted, and in the online re-examination, 74.2% of the students were admitted. There were no significant differences between the students who completed on-site and online re-examinations in terms of gender, recent graduation, cultivation type, graduate from a key university, and admission (P>0.05). The on-site and online re-examination results were very similar among the admitted students. The multivariable logistic regression analysis showed that online re-examination had no effect on student admissions. Students seeking professional degree were less likely to be admitted than those seeking academic degree, and those with a better standardized rank in medicine and a better standardized rank of re-examination score were more likely to be admitted. CONCLUSIONS: The online re-examination implemented in 2020 during the COVID-19 pandemic achieved the same selective effect as on-site re-examination. Effective time management, a standardized test question template, well-trained staff and effective technology are the keys to success.

Treatment with endoscopic transnasal resection of hypothalamic pilocytic astrocytomas: a single-center experience.

BACKGROUNDS: Pilocytic astrocytomas (PAs) are World Health Organization (WHO) grade I tumors, which are relatively common, and are benign lesions in children. PAs could originate from the cerebellum, optic pathways, and third ventricular/hypothalamic region. Traditional various transcranial routes are used for hypothalamic PAs (HPAs). However, there are few studies on hypothalamic PAs treated through the endoscopic endonasal approach (EEA). This study reports the preliminary experience of the investigators and results with HPAs via expanded EEAs. METHODS: All patients with HPAs, undergone EEA in our hospital from 2017 to 2019, were retrospectively reviewed. The demographic data, clinical symptoms, complications, skull base reconstruction, prognosis, and endocrinological data were all recorded and analyzed in detail. RESULTS: Finally, five female patients were enrolled. The average age of patients was 28.6 ± 14.0. All patients had complaints about their menstrual disorder. One patient had severe bilateral visual impairment. Furthermore, only one patient suffered from severe headache due to acute hydrocephalus, although there were four patients with headache or dizziness. Four cases achieved gross-total resection, and one patient achieved subtotal resection. Furthermore, there was visual improvement in one patient (case 5), and postoperative worsening of vision in one patient (case 4). However, only one patient had postoperative intracranial infection. None of the patients experienced a postoperative CSF leak, and in situ bone flap (ISBF) techniques were used for two cases for skull base repair. In particular, ISBF combined with free middle turbinate mucosal flap was used for case 5. After three years of follow-up, three patients are still alive, two patients had no neurological or visual symptoms, or tumor recurrence, and one patient had severe hypothalamic dysfunction. Unfortunately, one patient died of severe postoperative hypothalamus reaction, which presented with coma, high fever, diabetes insipidus, hypernatremia and intracranial infection. The other patient died of recurrent severe pancreatitis at one year after the operation. CONCLUSION: Although the data is still very limited and preliminary, EEA provides a direct approach to HPAs with acceptable prognosis in terms of tumor resection, endocrinological and visual outcomes. ISBF technique is safe and reliable for skull base reconstruction.

Application of PDCA cycle management for postgraduate medical students during the COVID-19 pandemic.

BACKGROUND: The COVID-19 outbreak has exerted an enormous impact on various industries worldwide. During this pandemic, clinical teaching hospitals have faced unprecedented challenges regarding the management of postgraduate medical students since postgraduate students in clinical medicine have both student and resident identity characteristics. The purpose of this study was to explore the management effectiveness of Peking University Third Hospital (PUTH) based on PDCA (plan-do-check-act) cycle management and to further develop the medical student management system during the pandemic. METHODS: The methods of document review, questionnaire surveys and interviews were used to continuously improve the management measures for postgraduate medical students during the COVID-19 pandemic by using the PDCA cycle. RESULTS: Investigations were conducted on the management system, back-to-school arrangements, laboratory management, COVID-19 prevention and control training, online teaching, mentoring, dissertation progress, and emotional state of postgraduate medical students during the COVID-19 pandemic. We found that strengthening public health management knowledge training, increasing infectious-disease-related knowledge training, innovating online teaching methods, improving PDCA management model maps, and formulating improvement programmes are conducive to improving the quality of such management. CONCLUSION: Given the difficulties involved in the management of postgraduate medical students during the COVID-19 pandemic, managers need to comprehensively consider and conduct overall planning and use the PDCA management model to improve the management of postgraduate medical students during this period.

AKT/GSK-3ß/ß-catenin signaling pathway participates in erythropoietin-promoted glioma proliferation.

PURPOSE: Although erythropoietin (EPO) has been proven to significantly promote the proliferation of cancer cells, the mechanism for promoting glioma proliferation is poorly understood. Here, we examined the functional role of the AKT/GSK-3ß/ß-catenin signaling pathway in the EPO-mediated proliferation of glioma. METHODS: The distribution of EPO and Ki-67 among clinical samples with different WHO grades was plotted by Immunological Histological Chemistry analysis. U87 and U251 glioma cell lines were treated with short hairpin RNA targeting (shEPO), recombinant human erythropoietin (rhEPO) and/or AKT-specific inhibitor (MK-2206). The changes in phosphorylated AKT, nuclear ß-catenin, cyclin D1 and p27kip1 expression were detected. Cell cycle distributions and glioma proliferation in vitro and in vivo were analyzed. RESULTS: The expression level of EPO was significantly elevated with the increase of WHO grade and Ki67 in clinical glioma specimens. In vitro, knockdown of endogenous EPO in U87 and U251 cells effectively block the phosphorylation of AKT and GSK-3ß and the expression of nuclear ß-catenin. shEPO treatment also significantly decreased the expression of cyclin D1 and increased the expression of p27kip1. The cell cycle transition then slowed down and the proliferation of glioma cells or mouse xenograft tumors both decreased. Treatment of cells or tumors with extra rhEPO reversed the above biological effects mediated by shEPO. rhEPO-induced activation of the AKT/GSK-3ß/ß-catenin pathway and proliferation were abolished by MK-2206. CONCLUSIONS: Our study identified the AKT/GSK-3ß/ß-catenin axis as a critical mediator of EPO-induced glioma proliferation and further provided a clinically significant dimension to the biology of EPO.

Reconstruction of skull base bone defects using an in situ bone flap after endoscopic endonasal transplanum-transtuberculum approaches.

PURPOSE: The creation of bone flaps which can be later repositioned and fixed in situ for repairing the bone defects during the endoscopic endonasal approaches (EEAs)-similar to transcranial craniotomies-is still a challenge. We present an in situ bone flap (ISBF) closure for the repair of bone defects after endoscopic endonasal transplanum-transtuberculum approaches (EETAs). METHODS: A retrospective analysis of consecutive patients who underwent the EETAs between January 2016 and February 2019 was performed. According to whether or not to use ISBF for skull base reconstruction, these patients were divided into the ISBF group or the non-ISBF group. RESULTS: Of 47 patients in the ISBF group, only one patient (2.1%) developed postoperative cerebrospinal fluid (CSF) leakage, yielding a significantly lower leakage rate in the ISBF group than in the non-ISBF group (6 of 38, 15.8%, P = 0.042). Besides, when only comparing cases of hydrocephalus in the two groups, the CSF leakage rate in the ISBF group was 8.3% (1/12), which was still significantly lower than that in the non-ISBF group (62.5%, 6/8) (P = 0.018). Postoperative CSF leakages in both groups were successfully treated with lumbar drainage alone, and no cases of injury to the internal carotid arteries or optic nerves occurred in either group. CONCLUSIONS: An ISBF closure similar to transcranial craniotomies with repositioning bone flap in situ-is feasible, safe, and reliable. The ISBF closure combining with a pedicled nasoseptal flap (PNSF) provides the cranial base surgeon with an additional repair method that has demonstrated effectiveness at facilitating a more stable and durable reconstruction and reducing CSF leaks.

Clinical and Basic Evaluation of the Prognostic Value of Uric Acid in Traumatic Brain Injury.

Background: As a major antioxidant in serum, uric acid (UA) was once considered only as the leading cause of gout; however, recent studies have validated its neuroprotective role in ischemic stroke. Because the potential protective effects of UA in traumatic brain injury (TBI) remain largely unknown, this study investigated the role of UA in TBI in both clinical patients and experimental animals. Methods: In TBI patients, serum UA concentrations were measured within 3 days after injury. Clinical outcomes at discharge were classified according to the Glasgow Outcome Scale: good outcome (4-5) and poor outcome (1-3). Risk factors for good outcome were identified via backward logistic regression analysis. For the animal study, a controlled cortical impact (CCI) injury model was established in mice. These mice were given UA at different doses intraperitoneally, and subsequent UA concentrations in mouse serum and brain tissue were determined. Neurological function, oxidative stress, inflammatory response, neuronal maintenance, cerebral blood flow, and lesion size were also assessed. Results: The serum UA level was significantly lower in TBI patients who had a good outcome (P<0.01), and low serum UA was an independent predictor of good outcome after TBI (P<0.01; odds ratio, 0.023; 95% confidence interval, 0.006-0.082). Consistently, decreased levels of serum UA were observed in both TBI patients and CCI animals (P<0.05), whereas the UA concentration was increased in CCI brain tissue (P<0.05). Administration of UA further increased the UA level in brain tissue as compared to that in control animals (P<0.05). Among the different doses administered, 16 mg/kg UA improved sensorimotor functional recovery, spatial learning, and memory in CCI mice (P<0.05). Moreover, oxidative stress and the inflammatory response were inhibited by UA treatment (P<0.05). UA treatment also improved neuronal maintenance and cortical blood flow (P<0.05) but not lesion size (P>0.05). Conclusions: UA acted to attenuate neuronal loss, cerebral perfusion impairment and neurological deficits in TBI mice through suppression of neuronal and vascular oxidative stress. Following TBI, active antioxidant defense in the brain may result in consumption of UA in the serum, and thus, a decreased serum UA level could be predictive of good clinical recovery.

Incidence and risk factors of delayed postoperative hyponatremia after endoscopic endonasal surgery for Rathke's cleft cyst: A single-center study.

Backgroud: Delayed postoperative hyponatremia (DPH) is common for sellar lesions. However, the true prevalence and associated factors of DPH after endoscopic endonasal surgery (EES) for Rathke's cleft cyst (RCC) have not been studied in a large patient cohort. Methods: A retrospective analysis was conducted over 6 years at our institution, and patients with RCC treated by EES were enrolled according to our inclusion criteria. Patient demographics, clinical characteristics, images, and surgical procedures were documented. Serum sodium was routinely measured before surgery, on postoperative day 1, and every 2 days thereafter until discharge. For patients with DPH, electrolyte, hematocrit, serum protein levels, and plasma and urinary osmolality were daily measured to explore potential etiology. Results: Of the 149 eligible patients, 25 (16.8%) developed DPH, which was similar to other sellar lesions, except craniopharyngioma, in the same period in our institution. Significant risk factors suggested by univariate analysis were cyst location, requirement of postoperative hydrocortisone therapy, postoperative meningitis, intraoperative cerebrospinal fluid (CSF) leakage, and subtotal resection (STR) of the cyst wall (all p < 0.05). In addition, other supplementary 11 cases of suprasellar RCC with different surgical strategies (aggressive resection) and relevant factors were enrolled into multivariate analysis. Suprasellar location [odds ratio (OR) 8.387, 95% confidence interval (CI) 1.014-69.365, p = 0.049], requirement of postoperative hydrocortisone therapy (OR 4.208, 95%CI 1.246-14.209, p = 0.021), and intraoperative CSF leakage (OR 6.631, 95%CI 1.728-25.440, p = 0.006) were found to be the independent predictors of DPH. Conclusion: DPH is a common complication after EES for RCC. Suprasellar location, requirement of postoperative hydrocortisone therapy, and intraoperative CSF leakage are the most reliable risk factors. Cortisol deficiency and syndrome of inappropriate antidiuretic hormone (SIADH) are considered as the main etiologies of DPH in RCC. Conservative excision of the cyst wall may reduce DPH occurrence.

PTEN and AKT/GSK-3ß/CRMP-2 signaling pathway are involved in neuronal apoptosis and axonal injury in early brain injury after SAH in rats.

In early brain injury (EBI) after subarachnoid hemorrhage (SAH), white matter (WM) axonal injury plays a key role in the prognosis of the disease. The purpose of this study was to investigate the effects of phosphatase and tensin homolog deleted on chromosome ten (PTEN) on axonal injury and neuronal apoptosis post-SAH in rats and to find its underlying mechanism. Adeno-associated virus was injected into the lateral ventricle to suppress or promote PTEN. Neural function post-SAH in animals was determined by the modified Garcia score, beam balance, and Rotarod test, and the blood-brain barrier disruption was assessed by the brain water content. Axonal injury post-SAH was observed by TEM and determined by IF, and neuron apoptosis was measured by TUNEL staining. The mechanism was analyzed by Western blot to detect p-PTEN/PTEN, p-AKT/AKT, p-GSK-3ß/GSK-3ß, p-CRMP-2/CRMP-2, axonal injury marker ß-APP and pro- and anti-apoptosis proteins, including Bax and Bcl-2, expression. We found 1. After knocking down PTEN, neuronal apoptosis and axonal injury were alleviated, and nerve function and blood-brain barrier were protected; accordingly, after overexpression of PTEN, neuronal apoptosis and axon damage were aggravated, and nerve function damage and blood-brain barrier damage were increased. 2. PTEN and AKT/GSK-3ß/CRMP-2 pathway were jointly involved in regulating neuronal apoptosis and WM axon injury after SAH. According to our research, PTEN was a negative factor of EBI, and together with the AKT/GSK-3ß/CRMP-2 signaling pathway aggravates neuronal apoptosis and WM axon damage after SAH. Inhibition of PTEN expression may become a new target for SAH treatment.

Tanshinone IIA reduces AQP4 expression and astrocyte swelling after OGD/R by inhibiting the HMGB1/RAGE/NF-κB/IL-6 pro-inflammatory axis.

This study aimed to investigate the role of tanshinone IIA (TSO IIA) in astrocytic swelling caused by ischemia-reperfusion-like injury in an in vitro model and the molecular mechanisms underlying this effect. Primary brain astrocytes were cultured under conditions of glucose and oxygen deprivation and reoxygenation (OGD/R). The study explored the effects of TSO IIA treatment on cell swelling and injury and the protein levels of aquaporin 4 (AQP4) in the plasma membrane. It then examined the involvement of the high-mobility group box protein 1 (HMGB1)/receptors for advanced-glycation end products (RAGE)/nuclear factor-kappa B (NF-κB)/interleukin-6 (IL-6) pro-inflammatory axis in TSO IIA-mediated protection. The treatment with TSO IIA alleviated OGD/R-induced astrocytic swelling and the overclustering of AQP4 protein in the plasma membrane. In addition, TSO IIA significantly reduced the overexpression of HMGB1 and the high levels of the NF-κB protein in the nucleus and of the IL-6 protein in the cytoplasm and extracellular media induced by OGD/R. The combination of TSO IIA and recombinant HMGB1 reversed these effects. The inhibition of the RAGE, the receptor of HMGB1, induced results similar to those of TSO IIA. In addition, exogenous IL-6 reversed TSO IIA-mediated effect on AQP4 overclustering and cell swelling. TSO IIA significantly reduced astrocyte swelling after OGD/R injury in vitro, via blocking the activation of the HMGB1/RAGE/NF-κB/IL-6 pro-inflammatory axis and thereby decreasing the expression of AQP4 in the plasma membrane.

Diagnosis and treatment of hemorrhagic pituitary adenomas.

We retrospectively analyzed the clinical manifestations, imaging results, and surgical treatment conditions of 72 patients who were diagnosed with hemorrhagic pituitary adenoma between January 2006 and May 2009 at our Department of Neurosurgery. We reached the conclusion that the CT-positive rate was 55.17% and the MRI-positive rate was 94.44%. Sixty-six patients underwent transsphenoidal operations; 6 patients, transfrontal operations; 52, total resections; 10, subtotal resections; and 10, partial resections. All procedures alleviated patients' headaches and stopped vomiting; patients with impaired consciousness gradually became clear-headed after the operations; patients whose preoperative eyesight had been impaired improved to different degrees, and ophthalmoplegia improved. Fifty-six patients were followed, 14 were cured, 32 had alleviated symptoms but 4 did not, and 6 relapsed. Our finding suggests that MRI scanning is superior to CT scanning in the diagnosis of hemorrhagic pituitary adenomas. Surgical decompression should be performed as soon as possible, and transsphenoidal microsurgery is the optimal treatment.

Chronic hydrocephalus after aneurysmal subarachnoid space hemorrhage.

To discuss predisposing factors of chronic hydrocephalus after aneurysmal subarachnoid space hemorrhage (aSAH). Clinical data of treating 32 patients with chronic hydrocephalus after aSAH through operations was retrospectively analyzed and processed. The incidence rate of chronic hydrocephalus of patients with an age above 60 years, Hunt-Hess III-IV level, posterior circulation aneurysm and anterior communicating aneurysm, hemorrhage twice or more and ventricle hematocele is prominently higher than patients with an age below 60 years, Hunt-Hess I-II level, aneurysms on other parts, one hemorrhage and no ventricle hematocele (P < 0.05). An age above 60 years, Hunt-Hess III-IV level, posterior circulation aneurysm and anterior communicating aneurysm, hemorrhage twice or more and ventricle hematocele are predisposing factors of chronic hydrocephalus after aSAH.

A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer.

Programmed cell death 1 ligand (PD-L1) blockade has been used therapeutically in the treatment of ovarian cancer, and potential combination treatment approaches are under investigation to improve the treatment response rate. The increased dependence on glutamine is widely observed in various type of tumors, including ovarian cancer. Kidney-type glutaminase (GLS), as one of the isotypes of glutaminase, is found to promote tumorigenesis. Here, we have demonstrated that the combined treatment with GLS inhibitor 968 and PD-L1 blockade enhances the immune response against ovarian cancer. Survival analysis using the Kaplan-Meier plotter dataset from ovarian cancer patients revealed that the expression level of GLS predicts poor survival and correlates with the immunosuppressive microenvironment of ovarian cancer. 968 inhibits the proliferation of ovarian cancer cells and enhances granzyme B secretion by CD8+ T cells as detected by XTT assay and flow cytometry, respectively. Furthermore, 968 enhances the apoptosis-inducing ability of CD8+ T cells toward cancer cells and improves the treatment effect of anti-PD-L1 in treating ovarian cancer as assessed by Annexin V apoptosis assay. In vivo studies demonstrated the prolonged overall survival upon combined treatment of 968 with anti-PD-L1 accompanied by increased granzyme B secretion by CD4+ and CD8+ T cells isolated from ovarian tumor xenografts. Additionally, 968 increases the infiltration of CD3+ T cells into tumors, possibly through enhancing the secretion of CXCL10 and CXCL11 by tumor cells. In conclusion, our findings provide a novel insight into ovarian cancer cells influence the immune system in the tumor microenvironment and highlight the potential clinical implication of combination of immune checkpoints with GLS inhibitor 968 in treating ovarian cancer.

[Blocking ERK signaling pathway lowers MMP-9 expression to alleviate brain edema after traumatic brain injury in rats].

OBJECTIVE: To investigate the effects of blocking the activation of ERK pathway on the expression of matrix metalloproteinase-9 (MMP-9) and the formation of cerebral edema in SD rats after brain injury. METHODS: Ninety SD rats were randomly divided into 3 equal groups, including a sham-operated group, modified Feeney's traumatic brain injury model group, and ERK inhibition group where the ERK inhibitor SCH772984 (500 µg/kg) was injected via the femoral vein 15 min before brain trauma. At 2 h and 2 days after brain trauma, the permeability of blood-brain barrier was assessed by Evans blue method, the water content of the brain tissue was determined, and the phosphorylation level of ERK and the expression level of MMP-9 mRNA and protein were measured by RT-PCR and Western blotting. RESULTS: Compared with the sham-operated group, the rats with brain trauma exhibited significantly increased level of ERK phosphorylation at 2 h and significantly increased expression of MMP-9 mRNA and protein 2 days after the injury (P < 0.01). Treatment with the ERK inhibitor significantly decreased the phosphorylation level of ERK after the injury (P < 0.01), suppressed over-expression of MMP-9 mRNA and protein 2 days after the injury (P < 0.01). The permeability of blood-brain barrier increased significantly 2 h after brain trauma (P < 0.05) and increased further at 2 days (P < 0.01); the water content of the brain did not change significantly at 2 h (P > 0.05) but increased significantly 2 d after the injury (P < 0.01). Treatment with the ERK inhibitor significantly lowered the permeability of blood-brain barrier and brain water content after brain trauma (P < 0.01). CONCLUSIONS: Blocking the activation of ERK pathway significantly reduced the over-expression of MMP-9 and alleviates the damage of blood-brain barrier and traumatic brain edema, suggesting that ERK signaling pathway plays an important role in traumatic brain edema by regulating the expression of MMP-9.

ATP1A1 Integrates AKT and ERK Signaling via Potential Interaction With Src to Promote Growth and Survival in Glioma Stem Cells.

Glioma stem cells (GSCs) have been considered to be responsible for treatment failure due to their self-renewal and limitless proliferative property. Recently, the Na+/K+-ATPase a1 (ATP1A1) subunit was described as a novel therapeutic target for gliomas. Interestingly, our previous proteomics study revealed that ATP1A1 is remarkably overexpressed in GSCs. In the current study, we investigated the role of ATP1A1 in regulating growth, survival, and tumorigenicity of primary human GSCs and the underlying molecular mechanism. We tested RNA and protein expression of ATP1A1 in glioma tissues and GSCs. In addition, we knocked down ATP1A1 in GSCs and assessed the effects thereof on growth, survival, and apoptosis. The role of ATP1A1 in signaling pathways was investigated in vitro. We found that the ATP1A1 expression level was associated with the grade of glioma. Knockdown of ATP1A1 in GSCs in vitro inhibited cell proliferation and survival, increased apoptosis, and halted cell-cycle progression at the G1 phase. Cell proliferation and survival were resumed upon rescue of ATP1A1 expression in ATP1A1-knockdown GSCs. The ERK1/2 and AKT pathways were inhibited through suppression of Src phosphorylation by ATP1A1 knockdown. Collectively, our findings suggest that ATP1A1 overexpression promotes GSC growth and proliferation by affecting Src phosphorylation to activate the ERK1/2 and AKT signaling pathways.

Endoscopic Endonasal Surgery for Craniopharyngiomas: A Series of 60 Patients.

OBJECTIVE: To report our experience of the management of 60 patients with craniopharyngioma with endoscopic endonasal surgery (EES) and evaluate the feasibility and safety of EES for craniopharyngiomas. METHODS: The clinical data of 60 patients with craniopharyngioma who underwent EES between November 2014 and December 2017 were analyzed retrospectively. All patients had vascularized nasoseptal flaps, and the most recent 4 patients had "in situ bone flaps" for better skull base reconstruction. Visual improvements, tumor resection extents, recurrence rates, endocrine functional changes, and surgical complications were evaluated. RESULTS: The resection rates were as follows: gross total, 68.3% (41 patients); near total (>95% of tumor removed), 15% (9 patients); subtotal (≥80% of tumor removed), 10% (6 patients); and partial (partial resection <80% of tumor removed), 6.7% (4 patients). Fifty-two patients presented with visual impairment; of these, 46 (88.5%) improved or returned to normal after surgery. Regarding the 32 patients with hypopituitarism before surgery, pituitary function was unchanged in 15 (46.8%), improved or normalized in 4 (12.5%), and deteriorated in 13 (40.6%). Eleven patients (18.3%) suffered from diabetes insipidus before treatment, and 27 more patients had this condition after surgery. Twenty-two patients had hyposmia postoperatively, and 17 patients experienced significant weight gain. Four patients had recent memory loss, and 2 of them had a temporary recent mental disorder. Three (5%) patients had cerebro-spinal fluid leakage after surgery. Three patients (5%) contracted meningitis and were cured with antibiotic treatment. One patient showed recurrence by magnetic resonance imaging re-examination, at the mean follow-up time of 22 months (range, 8-45 months; standard deviation, 11 months). CONCLUSIONS: EES can provide surgeons with excellent exposure and can achieve a high extent of removal of most craniopharyngiomas, even those with intraventricular extensions, In our view, vascularized pedicled septal flaps and in situ bony flaps were used in skull base reconstruction.

Evolution of cerebral perfusion in the peri-contusional cortex in mice revealed by in vivo laser speckle imaging after traumatic brain injury.

The role of the cerebrovascular network during the acute and chronic phases after traumatic brain injury (TBI) is poorly defined and emerging evidence suggests that cerebral perfusion is altered. The purpose of this study is to explore how the cortical blood flow is pathologically altered following TBI using a newly developed technique, laser speckle imaging. The controlled cortical impact (CCI) model was established in mice. Then, cerebral blood flow was monitored in vivo laser speckle imaging and vessel painting was labeled by Lectin in the peri-contusional cortex. Lastly, mice were assessed for lesion size and neurological functions. Our results indicated that: 1) In the acute phase of TBI, cerebral blood flow and microvessel counts decreased significantly (P < 0.05) 2) In the chronic phase of TBI, cerebral blood flow and microvessel counts recovered gradually (P < 0.05) 3) Cortical lesion volume reduced significantly in the chronic phase of TBI (P < 0.05) 4) Spontaneous neurocognitive recovery occurred following CCI in mice (P < 0.05). In the acute phase of TBI, there is a reduction in cerebral perfusion at the lesion site. However, this reduction recovers in the chronic phase of TBI ultimately, followed by an improvement of ameliorated neurobehavioral functions and a decrease in the lesion size. The novel approach for cerebral blood flow monitoring by laser speckle imaging can be extended from bench to bedside and provide potential therapeutic strategies for TBI patients.

[Erythropoietin accelerates the proliferation of glioma cells via activating Akt pathway].

OBJECTIVE: To determine whether erythropoietin (EPO) promotes rapid proliferation of glioma through Akt pathway. METHODS: We detected the expression of EPO in human glioma tissues using immunohistochemistry. A nude mouse model bearing human glioma U87 cell xenograft was established and given intraperitoneal injection of EPO or saline every other day, and the tumor growth was observed. In the in vitro experiment, U87 cells were treated with PBS (control), EPO, or EPO with Akt inhibitor, and the expression of p-Akt and cyclin D1 was detected using Western blotting; the cell proliferation rate was determined using cell counting kit-8 and clone formation assay, and the cell cycle changes were analyzed with flow cytometry. RESULTS: Compared with low-grade glioma tissues, high-grade glioma tissues exhibited a significantly increased EPO expression (P=0.0002). In the tumor-bearing mice, EPO treatment significantly increased the expression of EPO (P=0.0006) and p-Akt (P=0.0003) in the tumor and obviously increased the tumor volume (P<0.0001) and weight (P=0.0003). In U87 cells cultured in vitro, EPO treatment obviously accelerated the cell proliferation (P=0.020 on day 3 and 0.028 on day 5), promoted clone formation (P=0.0010), and increased proliferation index (P=0.0028); EPO significantly enhanced the protein expression of p-Akt (P=0.0020) and cyclin D1 (P=0.0022). The application of Akt inhibitor significantly suppressed the effect of EPO in enhancing cyclin D1 and p-Akt expression (both P<0.0001) and promoting cell proliferation. CONCLUSION: EPO can significantly accelerate the proliferation of glioma through Akt pathway.

The Crucial Role of Cyclin-Dependent Kinase-5-Ataxia-Telangiectasia Mutated Axis in ICH-Induced Neuronal Injury of Rat Model.

Cyclin-dependent kinase 5 (CDK5) and ataxia-telangiectasia mutated (ATM) are involved in normal human neurodevelopment and serves as a switch between neuronal survival and death. However, the molecular mechanisms underlying CDK5-ATM-induced neuronal injury caused by intracerebral hemorrhage (ICH) remain unclear. In this work, we used rat ICH models and thrombin-induced cell models to investigate the potential role of CDK5-ATM signals. Our findings revealed that CDK5 protein levels and kinase activities (p-histone H1 expression) were enforced in hematoma-surrounding neuron tissues following ICH. Besides, the expression of p25, p-ATM, and active caspase-3 protein was also upregulated after ICH. According to in vitro assays, the expression of CDK5, p-ATM, and active caspase-3 was all upregulated in cell viability-decreasing ICH cell models. However, blocking of either CDK5 or ATM suppressed the phosphorylation of ATM and the expression of active caspase-3, and attenuated the inhibition of neuronal survival. When p35/p25 was silenced, CDK5-ATM pathway was further inhibited, and cell viability was obviously ameliorated. In conclusion, this work suggested that ATM could be phosphorylated by CDK5 to induce the active caspase-3 and neuronal injury when intracerebral hemorrhage or ischemia occurred. Thus, the CDK5-AMT signal pathway has an important role in ICH process and may be a therapeutic target to prevent brain injury.