A comparison of [18F]AlF- and 68Ga-labeled dual targeting heterodimer FAPI-RGD in malignant tumor: preclinical evaluation and pilot clinical PET/CT imaging.

Due to the heterogeneity of tumors, strategies to improve the effectiveness of dual-targeting tracers in tumor diagnostics have been intensively practiced. In this study, the radiolabeled [18F]AlF-NOTA-FAPI-RGD (denoted as [18F]AlF-LNC1007), a dual-targeting heterodimer tracer targeting both fibroblast activation protein (FAP) and integrin αvß3 to enhance specific tumor uptake and retention, was synthesized and evaluated. The tracer was compared with [68Ga]Ga-LNC1007 in preclinical and clinical settings. METHODS: The preparation of [18F]AlF- and 68Ga-labeled FAPI-RGD was carried out with an optimized protocol. The stability was tested in PBS and fetal bovine serum (FBS). Cellular uptake and in vivo distribution of the two products were compared and carried out on the U87MG cell line and its xenograft model. The safety and dosimetry of [18F]AlF-LNC1007 PET/CT scan were evaluated in six patients with malignant tumors. RESULTS: Two radiolabeling protocols of [18F]AlF-/[68Ga]Ga-LNC1007 were developed and optimized to give a high yield of tracers with good stability. In vivo microPET images showed that the two tracers exhibited comparable pharmacokinetic characteristics, with high tumor uptake and prolonged tumor retention. In vivo distribution data showed that the target-to-non-target ratios of [18F]AlF-LNC1007 were similar to[68Ga]Ga-LNC1007. A total of six patients underwent [18F]AlF-LNC1007 PET/CT evaluation while two had head-to-head [18F]FDG PET/CT scans. The total body effective dose was 9.94E-03 mSv/MBq. The biodistribution curve showed optimal normal organ uptake with high tumor uptake and long retention of up to 3h p.i., and notably, the tumor-to-background ratio increased over time. CONCLUSION: We successfully prepared an [18F]AlF-LNC1007 dual-targeting PET probe with comparable performances as [68Ga]Ga-LNC1007. With prolonged tumor retention and tumor specificity, it produced good imaging quality in preclinical and clinical translational studies, indicating that [18F]AlF-LNC1007 is a promising non-invasive tracer for detecting tumors expressing FAP and/or integrin avß3, with the prospect of clinical implementation.

Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013.

Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy. METHODS: Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. RESULTS: The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection. CONCLUSION: Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.

A phase 1 trial to determine the maximum tolerated dose and patient-specific dosimetry of [177Lu]Lu-LNC1003 in patients with metastatic castration-resistant prostate cancer.

PURPOSE: This translational study aimed to determine the maximum tolerated dose (MTD), safety, dosimetry, and therapeutic efficacy of 177Lu-PSMA-EB-01 (denoted as [177Lu]Lu-LNC1003) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A total of 13 patients with mCRPC were recruited in this study. A standard 3 + 3 dose escalation protocol was performed. The following dose levels were ultimately evaluated: 1.11, 1.85, and 2.59 GBq/cycle. Patients received [177Lu]Lu-LNC1003 therapy for up to two cycles at a 6-week interval. RESULTS: Patients received fractionated doses of [177Lu]Lu-LNC1003 ranging from 1.11 to 2.59 GBq per cycle. Myelosuppression was dose-limiting at 2.59 GBq, and 1.85 GBq was determined to be the MTD. The total-body effective dose for 177Lu-LNC1003 was 0.35 ± 0.05 mSv/MBq. The salivary glands were found to receive the highest estimated radiation dose, which was calculated to be 3.61 ± 2.83 mSv/MBq. The effective doses of kidneys and red bone marrow were 1.88 ± 0.35 and 0.22 ± 0.04 mSv/MBq, respectively. The tumor mean absorbed doses for bone and lymph node metastases were 8.52 and 9.51 mSv/MBq. Following the first treatment cycle, PSA decline was observed in 1 (33.3%), 4 (66.7%), and 2 (50.0%) patients at dose levels 1 (1.11 GBq), 2 (1.85 GBq), and 3 (2.59 GBq), respectively. Compared with the baseline serum PSA value, 1 (33.3%) at dose level 1 and 4 (66.6%) patients at dose level 2, presented a PSA decline after the second treatment cycle. CONCLUSION: This phase 1 trial revealed that the MTD of [177Lu]Lu-LNC1003 is 1.85 GBq. The treatment with multiple cycles at the dose of 1.11 GBq /cycle and 1.85 GBq /cycle was well tolerated. [177Lu]Lu-LNC1003 has higher tumor effective doses in bone and lymph nodes metastases while the absorbed dose in the red bone marrow should be closely monitored in future treatment studies with higher doses and multiple cycles. The frequency of administration also needs to be further explored to assess the efficacy and side effects of [177Lu]Lu-LNC1003 treatment. TRIAL REGISTRATION: 177Lu-PSMA-EB-01 in patients with metastatic castration-resistant prostate cancer (NCT05613738, Registered 14 November 2022). URL of registry https://classic. CLINICALTRIALS: gov/ct2/show/NCT05613738.

Homodimeric peptide radiotracer [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 imaging of cervical cancer patients.

PURPOSE: Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2. METHODS: In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N', N″-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30-45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2. RESULTS: Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. CONCLUSION: The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. TRIAL REGISTRATION: ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).

CircHOMER1 inhibits porcine adipogenesis via the miR-23b/SIRT1 axis.

Fat deposition is critical to pork quality. However, the mechanism of fat deposition remains to be elucidated. Circular RNAs (circRNAs) are ideal biomarkers and are involved in adipogenesis. Here, we investigated the effect and mechanism of circHOMER1 on porcine adipogenesis in vitro and in vivo. Western blotting, Oil red O staining, and HE staining were used to assess the function of circHOMER1 in adipogenesis. The results showed that circHOMER1 inhibited adipogenic differentiation of porcine preadipocytes and suppressed adipogenesis in mice. Dual-luciferase reporter gene, RIP, and pull-down assays demonstrated that miR-23b directly bound to circHOMER1 and the 3'-UTR of SIRT1. Rescue experiments further illustrated the regulatory relationship among circHOMER1, miR-23b, and SIRT1. Conclusively, we demonstrate that circHOMER1 plays an inhibitory role in porcine adipogenesis through miR-23b and SIRT1. The present study revealed the mechanism of porcine adipogenesis, which may be helpful to improve pork quality.

Clinical outcomes of patients undergoing reoperation with solitary fibrous tumors/hemangiopericytomas and malignant progression of tumors.

OBJECTIVE: The purpose of this study was to analyze the clinical outcomes and malignant progression of tumors in patients who underwent reoperation for recurrent solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs). METHODS: We identified 48 patients who underwent reoperation because of tumor recurrence at Tangdu Hospital between January 2010 and December 2021 and analyzed the clinical outcomes, namely, the rate of gross total resection (GTR), progression-free survival (PFS), overall survival (OS), malignant progression of tumors and radiotherapy. The survival curves for each group were plotted using the Kaplan‒Meier method and compared using log-rank tests. RESULTS: Of the 48 patients (25 men and 23 women, mean age 49.5 ± 14.3 years), 25 experienced a second recurrence or metastasis, 15 of whom underwent a third surgery, and the remaining 10 patients who did not undergo surgery ultimately died after tumor progression. The median time (95% CI) to tumor recurrence was 40.0 (32.3-47.7) months after reoperation, with 3-, 5- and 10-year PFS rates of 54.6%, 29.5% and 14.8%, respectively. The median (95% CI) survival time was 70.0 (46.6-93.4) months, with 3-, 5- and 10-year survival rates of 67.9%, 55.1% and 36.7%, respectively. Among the 48 patients who underwent reoperation, 27 (56.3%) achieved GTR, and 21 (43.8%) achieved STR. Twelve patients in the GTR group (12/27, 44.4%) received radiotherapy after surgery, and 18 patients in the STR group (18/21, 85.7%) received radiotherapy. Of the 48 recurrent SFTs, 24 were classified as WHO grade 1, 14 were classified as WHO grade 2, and 10 were classified as WHO grade 3 based on 2021 WHO classification after the primary operation. After reoperation, 9 tumors developed malignant progression, including 4 WHO grade 1 tumors progressing to WHO grade 2 tumors, 1 WHO grade 1 tumor progressing to a WHO grade 3 tumor and 4 WHO grade 2 tumors progressing to WHO grade 3 tumors. CONCLUSIONS: GTR after reoperation was associated with better PFS and OS compared to STR. However, the PFS after the third surgery was significantly shorter than that after the second surgery, and the rate of GTR also decreased. Malignant progression may occur after second or third tumor recurrence. Furthermore, compared with WHO grade 1 SFTs, WHO grade 2 and grade 3 SFTs significantly decreased PFS, but OS did not differ among the three groups. Radiotherapy did not prolong PFS or OS in patients who underwent reoperation.

Development of [177Lu]Lu-LNC1003 for radioligand therapy of prostate cancer with a moderate level of PSMA expression.

PURPOSE: Evans blue as an albumin binder has been widely used to improve pharmacokinetics and enhance tumor uptake of radioligands, including prostate-specific membrane antigen (PSMA) targeting agents. The goal of this study is to develop an optimal Evans blue-modified radiotherapeutic agent that could maximize the absolute tumor uptake and tumor absorbed dose thus the therapeutic efficacy to allow treatment of tumors even with moderate level of PSMA expression. METHODS: [177Lu]Lu-LNC1003 was synthesized based on PSMA-targeting agent and Evans blue. Binding affinity and PSMA targeting specificity were verified through cell uptake and competition binding assay in 22Rv1 tumor model that has moderate level of PSMA expression. SPECT/CT imaging and biodistribution studies in 22Rv1 tumor-bearing mice were performed to evaluate the preclinical pharmacokinetics. Radioligand therapy studies were conducted to systematically assess the therapeutic effect of [177Lu]Lu-LNC1003. RESULTS: LNC1003 showed high binding affinity (IC50 = 10.77 nM) to PSMA in vitro, which was comparable with that of PSMA-617 (IC50 = 27.49 nM) and EB-PSMA-617 (IC50 = 7.91 nM). SPECT imaging of [177Lu]Lu-LNC1003 demonstrated significantly improved tumor uptake and retention as compared with [177Lu]Lu-EB-PSMA and [177Lu]Lu-PSMA-617, making it suitable for prostate cancer therapy. Biodistribution studies further confirmed the remarkably higher tumor uptake of [177Lu]Lu-LNC1003 (138.87 ± 26.53%ID/g) over [177Lu]Lu-EB-PSMA-617 (29.89 ± 8.86%ID/g) and [177Lu]Lu-PSMA-617 (4.28 ± 0.25%ID/g) at 24 h post-injection. Targeted radioligand therapy results showed noteworthy inhibition of 22Rv1 tumor growth after administration of a single dose of 18.5 MBq [177Lu]Lu-LNC1003. There was no obvious antitumor effect after [177Lu]Lu-PSMA-617 treatment under the same condition. CONCLUSION: In this study, [177Lu]Lu-LNC1003 was successfully synthesized with high radiochemical purity and stability. High binding affinity and PSMA targeting specificity were identified in vitro and in vivo. With greatly enhanced tumor uptake and retention, [177Lu]Lu-LNC1003 has the potential to improve therapeutic efficacy using significantly lower dosages and less cycles of 177Lu that promises clinical translation to treat prostate cancer with various levels of PSMA expression.

Clinical outcomes and safety of large or giant vestibular schwannoma in older patients undergoing microsurgery: a matched cohort study.

OBJECTIVE: To compare the clinical outcomes of large or giant vestibular schwannomas (VSs) between older patients and younger patients who underwent microsurgery and to explore whether the incidence of postoperative complications increased and whether the postoperative hospital stay was prolonged. METHODS: We conducted a retrospective matched cohort study based on the surgical approach, maximum tumor diameter and extent of resection. Older patients (≥ 60 years) and a matched group (<60 years) who had undergone microsurgery for VSs between January 2015 and December 2021 were included. Clinical data, surgical outcomes and postoperative complications were analyzed statistically. RESULTS: Forty-two older patients (≥ 60 years, 66.0 ± 3.8 years) were identified and matched to younger patients (<60 years, 43.9 ± 11.2 years), and they all underwent microsurgery through a retrosigmoid approach. There were twenty-nine patients with 3-4 cm VSs and thirteen patients with > 4 cm VSs in both groups. The older patients had a higher proportion of imbalance (P = 0.016) and lower American Society of Anesthesiology scores (P = 0.003) before surgery than the younger patients. There was no significant difference in facial nerve function one week (p = 0.851) and one year (p = 0.756) after surgery and no difference in the postoperative complication incidence (40.5% vs. 23.8%, p = 0.102) between the older patients and controls. Furthermore, the older patients had longer postoperative hospital stays than the younger patients (p = 0.043). In the older group, six patients with near total resection and five with subtotal resection were administered stereotactic radiotherapy, and one had recurrence three years after surgery and received conservative treatment. The postoperative follow-up time ranged from 1 to 83 months, with an average of 33.5 ± 21.1 months. CONCLUSIONS: For older patients (≥ 60 years) with symptomatic, large or giant -VSs, microsurgery is the only effective method to prolong lifespan, alleviate clinical symptoms and cure the tumor. However, radical resection of VSs may result in a decreased preservation rate of facial-acoustic nerve function and an increased postoperative complication incidence. Therefore, subtotal resection followed by stereotactic radiotherapy should be recommended.

The incidence and risk factors of unplanned reoperation in endoscopic endonasal surgeries: a single center study.

The incidence of unplanned reoperation after surgery during the same hospitalization is considered one of most important evaluation indicators for health care quality. The purpose of this study was to determine the incidence and risk factors related to unplanned reoperation after an endoscopic endonasal approach (EEA). All patients who underwent elective endoscopic endonasal surgery from January 2016 to December 2021 in the Department of Neurosurgery, Tangdu Hospital, Air Force Military Medical University, were included. We identified the patients who underwent an unplanned reoperation and those who did not and divided them into two groups. The demographic data and risk factors were compared between the groups by univariate and multivariate logistic regression analyses. Of the 1783 patients undergoing EEA for various lesions of the skull base, the incidence of unplanned reoperation was 2.3%. The most common unplanned reoperations were repair of cerebrospinal fluid (CSF) leakage (39%), sellar hematoma evacuation (34.1%), hemostasis of epistaxis (14.6%) and external ventricular drainage for obstructive hydrocephalus (9.8%). The maximum diameter of tumor ≥ 3 cm (OR 2.654, CI 1.236-5.698; p = 0.012), meningioma (OR 4.198, CI 1.169-15.072; p = 0.028), craniopharyngioma (OR 5.020, CI 2.020-12.476; p = 0.001) and other sellar lesions (OR 4.336, CI 1.390-13.527; p = 0.012) and an operation time ≥ 240 min (OR 2.299, CI 1.170-4.518; p = 0.016) were the independent risk factors for unplanned reoperations in multivariate regression analysis. Of the 41 patients undergoing unplanned reoperation, 16 patients died, twenty-one patients had panhypopituitarism, 13 patients had transient and 6 had permanent diabetes insipidus, and 11 patients presented with intracranial infection and 6 of these patients were cured. By reviewing our department's data, we stated the incidence and risk factors for unplanned reoperation. It is important for the hospital administration and neurosurgeons to place more emphasis on these indicators. Furthermore, we suggest some effective quality improvement initiatives to reduce the incidence of unplanned reoperation.

CircRNA Profiling of Skeletal Muscle in Two Pig Breeds Reveals CircIGF1R Regulates Myoblast Differentiation via miR-16.

Muscle development is closely related to meat quality and production. CircRNAs, with a closed-ring structure, have been identified as a key regulator of muscle development. However, the roles and mechanisms of circRNAs in myogenesis are largely unknown. Hence, in order to unravel the functions of circRNAs in myogenesis, the present study explored circRNA profiling in skeletal muscle between Mashen and Large White pigs. The results showed that a total of 362 circRNAs, which included circIGF1R, were differentially expressed between the two pig breeds. Functional assays showed that circIGF1R promoted myoblast differentiation of porcine skeletal muscle satellite cells (SMSCs), while it had no effect on cell proliferation. In consideration of circRNA acting as a miRNA sponge, dual-luciferase reporter and RIP assays were performed and the results showed that circIGF1R could bind miR-16. Furthermore, the rescue experiments showed that circIGF1R could counteract the inhibitory effect of miR-16 on cell myoblast differentiation. Thus, circIGF1R may regulate myogenesis by acting as a miR-16 sponge. In conclusion, this study successfully screened candidate circRNAs involved in the regulation of porcine myogenesis and demonstrated that circIGF1R promotes myoblast differentiation via miR-16, which lays a theoretical foundation for understanding the role and mechanism of circRNAs in regulating porcine myoblast differentiation.

Successful implementation of an enhanced recovery after surgery (ERAS) protocol reduces nausea and vomiting after infratentorial craniotomy for tumour resection: a randomized controlled trial.

BACKGROUND: Infratentorial craniotomy patients have a high incidence of postoperative nausea and vomiting (PONV). Enhanced Recovery After Surgery (ERAS) protocols have been shown in multiple surgical disciplines to improve outcomes, including reduced PONV. However, very few studies have described the application of ERAS to infratentorial craniotomy. The aim of this study was to examine whether our ERAS protocol for infratentorial craniotomy could improve PONV. METHODS: We implemented an evidence-based, multimodal ERAS protocol for patients undergoing infratentorial craniotomy. A total of 105 patients who underwent infratentorial craniotomy were randomized into either the ERAS group (n = 50) or the control group (n = 55). Primary outcomes were the incidence of vomiting, nausea score, and use of rescue antiemetic during the first 72 h after surgery. Secondary outcomes included postoperative anxiety level, sleep quality, and complications. RESULTS: Over the entire 72 h post-craniotomy observation period, the cumulative incidence of vomiting was significantly lower in the ERAS group than in the control group. Meanwhile, the incidence of vomiting was significantly lower in the ERAS group on postoperative days (PODs) 2 and 3. Notably, the proportion of patients with mild nausea (VAS 0-4) was higher in the ERAS group as compared to the control group on PODs 2 or 3. Additionally, the postoperative anxiety level and quality of sleep were significantly better in the ERAS group. CONCLUSION: Successful implementation of our ERAS protocol in infratentorial craniotomy patients could attenuate postoperative anxiety, improve sleep quality, and reduce the incidence of PONV, without increasing the rate of postoperative complications. TRIAL REGISTRATION: ChiCTR-INR-16009662, 27 Oct 2016, Clinical study on the development and efficacy evaluation of Enhanced Recovery After Surgery (ERAS) in Neurosurgery.

Tonsillectomy with modified reconstruction of the cisterna magna with and without craniectomy for the treatment of adult Chiari malformation type I with syringomyelia.

BACKGROUND: In light of the controversies regarding the surgical treatment of adult Chiari malformation type I (CM-I) with syringomyelia, a retrospective study was conducted to evaluate the safety and efficacy of tonsillectomy followed by modified reconstruction of the cisterna magna with or without craniectomy. METHODS: Between 2008 and 2017, 78 adult CM-I patients (36 males and 42 females, mean age 40.6 years old) with syringomyelia were treated with posterior fossa decompression (PFD) with tonsillectomy and modified reconstruction of the cisterna magna. Patients were divided into two study groups: group A (n = 40) underwent cranioplasty with replacement of the bone flap; group B (n = 38) underwent suboccipital craniectomy. Neurological outcomes were evaluated by traditional physician assessment (improved, unchanged, and worsened) and the Chicago Chiari Outcome Scale (CCOS). Syringomyelia outcomes were assessed radiologically. RESULTS: The procedure was successfully performed in all patients, and restoration of normal cerebrospinal fluid (CSF) flow was confirmed by intraoperative ultrasonography. The median postoperative follow-up was 20.3 months (range 18-60 months). Clinical improvement was evident in 66 (84.6%) patients, with no significant differences between the two groups (85.0% vs. 84.2%, P = 0.897). According to the CCOS, 36 patients (90.0%) in group A were labeled as "good" outcome, compared with that of 34 (86.8%) in group B (P = 0.734). Improvement of syringomyelia was also comparable between the groups, which was observed in 35 (87.5%) vs. 33 (86.8%) patients (P = 0.887). The postoperative overall (7.5% vs. 23.7%, P = 0.048) and CSF-related (2.5% vs. 18.4%, P = 0.027) complication rates were significantly lower in group A than group B. CONCLUSIONS: Tonsillectomy with modified reconstruction of the cisterna magna without craniectomy seems to be a safe and effective surgical option to treat adult CM-I patients with syringomyelia, though future well-powered prospective randomized studies are warranted to validate these findings.

The Impact of Simulated Weightlessness on Endothelium-Dependent Angiogenesis and the Role of Caveolae/Caveolin-1.

BACKGROUND/AIMS: The potential role of caveolin-1 in modulating angiogenesis in microgravity environment is unexplored. METHODS: Using simulated microgravity by clinostat, we measured the expressions and interactions of caveolin-1 and eNOS in human umbilical vein endothelial cells. RESULTS: We found that decreased caveolin-1 expression is associated with increased expression and phosphorylation levels of eNOS in endothelial cells stimulated by microgravity, which causes a dissociation of eNOS from caveolin-1 complexes. As a result, microgravity induces cell migration and tube formation in endothelial cell in vitro that depends on the regulations of caveolin-1. CONCLUSION: Our study provides insight for the important endothelial functions in altered gravitational environments.

Activation of G protein-coupled estrogen receptor 1 (GPER-1) ameliorates blood-brain barrier permeability after global cerebral ischemia in ovariectomized rats.

G protein-coupled estrogen receptor 1 (GPER-1) plays important roles in estrogen-mediated neuroprotection. However, protective effects of GPER-1 on blood-brain barrier (BBB) after ischemic stroke have not been determined. The aim of present study was to determine whether GPER-1 activation ameliorates BBB permeability in ovariectomized rats with induced global cerebral ischemia (GCI). GCI was induced by 4-vessel occlusion for 20 min followed by 24 h reperfusion period. The GPER-1 agonist (G1) was bilaterally administered immediately upon reperfusion by intracerebroventricular (icv) injection. We found that the GPER-1 agonist could significantly decrease immunoglobulin G (IgG) extravasation and increase the levels of tight junctions (occludin and claudin-5) in the CA1 at 24 h of reperfusion after GCI. Further, protein levels of vascular endothelial growth factor A (VEGF-A) was significantly decreased in the ischemic CA1 by G1. Our results suggest that GPER-1 activation reduce tight junctions disruption via inhibition of VEGF-A expression after ischemic injury.

Neuroprotective effects of a chromatin modifier on ischemia/reperfusion neurons: implication of its regulation of BCL2 transactivation by ERα signaling.

An understanding of the molecular mechanisms involved in the regulation of estrogen receptor alpha (ERα)-mediated neuroprotective effects is valuable for the development of therapeutic strategy against neuronal ischemic injury. Here, we report the upregulated expression of metastasis-associated protein 1 (MTA1), a master chromatin modifier and transcriptional regulator, in the murine middle cerebral artery occlusion (MCAO) model. Inhibition of MTA1 expression by in vivo short interfering RNA treatment potentiated neuronal apoptosis in a caspase-3-dependent manner and thereafter aggravated MCAO-induced neuronal damage. Mechanistically, the pro-survival effects of MTA1 required the participation of ERα signaling. We also provide in vitro evidence that MTA1 enhances the binding of ERα with the BCL2 promoter upon ischemic insults via recruitment of HDAC2 together with other unidentified coregulators, thus promoting the ERα-mediated transactivation of the BCL2 gene. Collectively, our results suggest that the augmentation of endogenous MTA1 expression during neuronal ischemic injury acts additionally to an endocrinous cascade orchestrating intimate interactions between ERα and BCL2 pathways and operates as an indispensable defensive mechanism in response to neuronal ischemia/reperfusion stress. Future studies in this field will shed light on the modulation of the complicated neuroprotective effects by estrogen signaling.

Complement C5a is detrimental to histological and functional locomotor recovery after spinal cord injury in mice.

Based on the studies on the role of complements C3, C1q and factor B, we hypothesized that complement C5a is detrimental to locomotor recovery at the early stage of secondary injury after spinal cord injury (SCI). To test this hypothesis, we investigated the effect of inhibition of complement C5a receptor (C5aR) by using C5aR antagonist PMX53 (C5aRA) and deficiency of complement C5a receptor (C5aR-/- mice) on histological and locomotor recovery after SCI in mice. We demonstrated that the Basso Mouse Scale scores in the mice injected with C5aRA (C5aRA-mice) at 45min before and 24h after SCI and the C5aR-/- mice were markedly higher than those in the mice treated with saline (Saline-mice) and the C5aR+/+ mice respectively between 7 and 28days after SCI. Also, expression of TNF-α and IL-1ß in C5aRA-mice was significantly lower than that in Saline-mice from 1 to 24h after SCI. In addition, the percentage of microglia/macrophage in C5aRA mice and C5aR-/- mice was significantly lower than those in their corresponding control groups from 1 to 14days after SCI. Furthermore, C5aRA mice and C5aR-/- mice had less GFAP expression in the injured spinal cord epicenter as compared to Saline mice and C5aR+/+ mice at day 28 after SCI. These findings provided evidence that inhibition or deficiency of C5aR could significantly improve histological and functional locomotor recovery after SCI in mice.

CX3CR1 RNAi inhibits hypoxia-induced microglia activation via p38MAPK/PKC pathway.

There is accumulating evidence which demonstrates that chronic cerebral ischaemia can induce white matter lesions (WMLs), and microglia-activation-mediated cytokines and proteases releasing during the ischaemia might play a vital role in pathogenesis. In addition, hypoxia-induced upregulated expression of fractalkine promotes the activation of microglia and their migration to the lesions through interaction with its receptor CX3CR1. However, the specific mechanisms involved in fractalkine/CX3CR1-mediated microglial activation have not been fully identified. In the present study, we constructed lentivirus encoding shRNA against CX3CR1 and transduced into microglial cells in under hypoxic conditions. Moreover, we analysed the proliferation, cytokine secretion and signal-pathway activation of the microglia. We found that CX3CR1 RNAi-mediated gene downregulation could attenuate hypoxic-induced microglial proliferation, cytokine secretion [including tumuor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß)] and matrix metalloproteinase-2 (MMP-2) synthesis. These effects were shown to be nediated through p38MAPK/PKC activation. Therefore, our results reveal a novel mechanism of fractalkine/CX3CR1 involvement in activation of microglia. Thus CX3CR1 RNAi might provide a therapeutic strategy which could be useful in chronic cerebral ischaemia.

Activation of GPER-1 Attenuates Traumatic Brain Injury-Induced Neurological Impairments in Mice.

This study aimed to investigate the effects of G1-activated G protein-coupled estrogen receptor 1 (GPER1) on neurological impairments and neuroinflammation in traumatic brain injury (TBI) mice. The controlled cortical impingement (CCI) method was used to establish the TBI model. The mice were subjected to ovariectomy (OVX) for two weeks prior to modeling. GPER1 agonist G1 was administered by intracerebroventricular injection. Brain tissue water content was detected by wet/dry method, and blood-brain barrier damage was detected by Evans blue extravasation. The neurological impairments in mice were evaluated by open field test, Y-maze test, nest-building test, object location memory test and novel object recognition test. Ionized calcium-binding adapter molecule 1 (Iba1) staining was used to indicate the activation of microglia. Expression of M1/M2-type microglia markers and inflammatory factors were evaluated by ELISA and qRT-PCR. The G1 administration significantly reduced cerebral edema and Evans blue extravasation at injury ipsilateral cortex and basal ganglia in TBI mice. Activation of GPER1 by G1 improved the anxiety behavior and the cognitive dysfunction of mice induced by TBI. G1 administration significantly decreased Iba1-positive staining cells and the mRNA levels of CD86, macrophage cationic peptide 1 (Mcp-1), nitric oxide synthase 2 (Nos2), interleukin 1 beta (IL-1ß), and macrophage inflammatory protein-2 (MIP-2), while increased the mRNA levels of interleukin 10 (IL-10), arginase1 (Arg-1) and CD206. Activation of GPER1 through G1 administration has the potential to ameliorate cognitive dysfunction induced by TBI in mice. It may also inhibit the activation of M1 microglia in cortical tissue resulting from TBI, while promoting the activation of M2 microglia and contributing to the regulation of inflammatory responses.