Same-day discharge after craniotomy for brain tumor resection: enhancing patient selection through a prognostic scoring system.

OBJECTIVE: Neurosurgery, among other surgical fields, is amid a shift in patient management with enhanced recovery and same-day discharge (SDD) protocols slowly becoming more popular and feasible. While such protocols reduce the risk of nosocomial complications and improve patient satisfaction, appropriate patient selection remains an area of debate. The authors aimed to better quantify selection criteria through a prospective follow-up study of patients undergoing brain tumor resection with SDD. METHODS: Three arms of analysis were carried out. First, clinical data of SDD patients were prospectively collected between August 2021 and August 2022. In parallel, a retrospective analysis of patients who qualified for SDD but were excluded at surgeon clinical discretion over the same period was performed. Third, a comparative analysis of the pilot and follow-up studies was done from which a clinical scoring system for patient selection was derived. RESULTS: Over the duration of the study, 31 of 334 patients were selected for SDD while 59 qualified for SDD by previously defined criteria but were not selected at the surgeon's discretion. There was no difference in outcomes between the two groups, and there were no postoperative complications among the SDD group within 30 days of surgery. Preoperative clinical characteristics found to be significantly different between the two cohorts (left-sided lesion, extra-axial pathology, prior treatment of brain tumor, and tumor volume ≤ 11.75 cm3) were included in a predictive scoring system for successful SDD. The scoring system was found to significantly predict high or low likelihood for successful SDD when tested on the mixed prospective cohort. CONCLUSIONS: This study provides a straightforward clinical scoring system for appropriate selection of candidates for SDD after craniotomy for brain tumor resection. This clinical tool aims to aid clinicians in appropriate admission course selection and builds on the growing literature surrounding same-day and outpatient cranial neurosurgery.

Intraoperative 5-ALA fluorescence-guided resection of high-grade glioma leads to greater extent of resection with better outcomes: a systematic review.

IMPORTANCE: High-grade gliomas (HGG) are the most aggressive and common malignant brain tumors in adults. They have a dismally fatal prognosis. Even if gross total resection of the enhancing tumor is achieved, inevitably, invading tumor cells that are indistinguishable to the un-aided eye are left behind, which eventually leads to tumor recurrence. 5-aminolevulinic acid (5-ALA) is an increasingly utilized intraoperative fluorescent imaging agent for patients with HGG. It enhances visualization of HGG tissue. Despite early promising randomized clinical trial data suggesting a survival benefit for 5-ALA-guided surgery, the growing body of literature must be analyzed to confirm efficacy on patient outcomes. OBJECTIVE: To perform a systematic review of the literature to evaluate whether there is a beneficial effect upon survival and extent of resection due to the utilization of 5-ALA in HGG surgery. EVIDENCE REVIEW: Literature regarding 5-ALA usage in HGG surgery was reviewed according to the PRISMA guidelines. Two databases, PubMed and SCOPUS, were searched for assorted combinations of the keywords "5-ALA," "high-grade glioma," "5-aminolevulinic acid," and "resection" in July 2020 for case reports and retrospective, prospective, and randomized clinical trials assessing and analyzing 5-ALA intraoperative use in patients with HGG. Entailed studies on PubMed and SCOPUS were found for screening using a snowball search technique upon the initially searched papers. Systematic reviews and meta-analyses were excluded from our PRISMA table. FINDINGS: 3756 previously published studies were screened, 536 of which were further evaluated, and ultimately 45 were included in our systematic review. There were no date restrictions on the screened publications. Our literature search was finalized on July 16, 2020. We found an observed increase in the overall survival (OS) and progression-free survival (PFS) of the 5-ALA group compared to the white light group, as well as an observed increase in the OS and PFS of complete resections compared to incomplete resections. Of the studies that directly compared the use of 5-ALA to white light (13 of the total analyzed 45, or 28.9%), 5-ALA lead to a better PFS and OS in 88.4 and 67.5% of patients, respectively. When the studies that reported postoperative neurologic outcomes of surgeries using 5-ALA vs. white light were analyzed, 42.2% of subjects demonstrated 5-ALA use was associated with less post-op neurological deficits, whereas 34.5% demonstrated no difference between 5-ALA and without. 23.3% of studies showed that intraoperative 5-ALA guided surgeries lead to more post-op neurological deficits. CONCLUSIONS AND RELEVANCE: Utilization of 5-ALA was found to be associated with a greater extent of resection in HGG surgeries, as well as longer OS and PFS. Postop neurologic deficit rates were mixed and inconclusive when comparing 5-ALA groups to white light groups. 5-ALA is a useful surgical adjunct for resection of HGG when patient safety is preserved.

Same-day discharge after brain tumor resection: a prospective pilot study.

PURPOSE: Outpatient brain surgery has many advantages for the psychological and physical wellbeing of patients, as well as reduced costs to the health care system. Compared with inpatient admissions, same day discharges reduce patient exposure to nosocomial infection, thromboembolic complications, and medical error. We aim to establish a prospectively collected quality outcomes database to examine the outcomes of patients that undergo brain tumor resection and are discharged home the same day as surgery. METHODS: We have established a prospectively collected quality outcomes database to examine the outcomes of all patients that underwent brain tumor resection by a single neurosurgeon (R.J.K) at our institution from August 2020 to August 2021 and were discharged home the same day as surgery. RESULTS: Over the one-year period this study was conducted, 37 of 334 patients met inclusion criteria for the outpatient protocol. Thirty-two patients were discharged on the same day as surgery. Five patients (14%) were considered eligible for outpatient surgery but were ultimately admitted to the hospital postoperatively and were discharged after an overnight observation. No postoperative complications were noted at two-week postoperative follow-up. CONCLUSION: In select patients undergoing brain tumor surgery, same day discharge should be considered. Establishing a multidisciplinary team of physicians, nurses, radiologists, and physical therapists is critical to achieving this aim. Physicians should have a low threshold to admit a patient with concerning exam findings, complications, or complicated past medical history. Once discharged, open communication with the patient and their family is critical to detect complications that should trigger rehospitalization and intervention.

Homoharringtonine inhibits melanoma cells proliferation in vitro and vivo by inducing DNA damage, apoptosis, and G2/M cell cycle arrest.

Homoharringtonine (HHT), an approved anti-leukemic alkaloid, has been reported effectively in many types of tumor cells. However, its effect on melanoma cells has not been investigated. And the anti-melanoma mechanism of HHT is still unknown. In this study, we detected the effects of HHT on two melanoma cell lines (A375 and B16F10) and on the A375 xenograft mouse model. HHT significantly inhibited the proliferation of melanoma cells as investigated by the CCK8 method, cell cloning assay, and EdU experiment. HHT induced A375 and B16F10 cells DNA damage, apoptosis, and G2/M cell cycle arrest as proved by TdT-mediated dUTP Nick-End Labeling (TUNEL) and flow cytometry assay. Additionally, the loss of mitochondrial membrane potential in HHT-treated cells were visualized by JC-1 fluorescent staining. For the molecule mechanism study, western blotting results indicated the protein expression levels of ATM, P53, p-P53, p-CHK2, γ-H2AX, PARP, cleaved-PARP, cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, Aurka, p-Aurka, Plk1, p-Plk1, Cdc25c, CDK1, cyclin B1, and Myt1 were regulated by HHT. And the relative mRNA expression level of Aurka, Plk1, Cdc25c, CDK1, cyclin B1, and Myt1 were ascertained by q-PCR assay. The results in vivo experiment showed that HHT can slow down the growth rate of tumors. At the same time, the protein expression levels in vivo were consistent with that in vitro. Collectively, our study provided evidence that HHT could be considered an effective anti-melanoma agent by inducing DNA damage, apoptosis, and cell cycle arrest.

Evodiamine inhibits vasculogenic mimicry in HCT116 cells by suppressing hypoxia-inducible factor 1-alpha-mediated angiogenesis.

Evodiamine (Evo), a quinazoline alkaloid and one of the most typical polycyclic heterocycles, is mainly isolated from Evodia rugulosa. Vasculogenic mimicry (VM) is a newly identified way of angiogenesis during tumor neovascularization, which is prevalent in a variety of highly invasive tumors. The purpose of this study was to investigate the effect and mechanism of Evo on VM in human colorectal cancer (CRC) cells. The number of VM structures was calculated by the three-dimensional culture of human CRC cells. Wound-healing was used to detect the migration of HCT116 cells. Gene expression was detected by reverse transcription-quantitative PCR assay. CD31/PAS staining was used to identify VM. Western blotting and immunofluorescence were used to detect protein levels. The results showed that Evo inhibited the migration of HCT116 cells, as well as the formation of VM. Furthermore, Evo reduced the expression of hypoxia-inducible factor 1-alpha (HIF-1α), VE-cadherin, VEGF, MMP2, and MMP9. In a model of subcutaneous xenotransplantation, Evo also inhibited tumor growth and VM formation. Our study demonstrates that Evo could inhibit VM in CRC cells HCT116 and reduce the expression of HIF-1α, VE-cadherin, VEGF, MMP2, and MMP9.

Current experimental therapies for atypical and malignant meningiomas.

INTRODUCTION: Atypical (WHO grade II) and malignant meningiomas (WHO Grade III) are a rare subset of primary intracranial tumors. Given their relatively high recurrence rate after surgical resection and radiotherapy, there has been a recent push to explore other adjuvant treatment options for these treatment-refractory tumors. Recent advances in molecular sequencing of tumors have elucidated new pathways and drug targets which are currently being studied. This article provides a thorough overview of novel investigational therapeutics including targeted therapy, immunotherapy, and new technological modalities for atypical and malignant meningiomas. METHODS: We performed a comprehensive review of the available literature regarding preclinical and clinical evidence for emerging treatments for high grade meningiomas from 1980 to 2020 including contemporaneous clinical trials. RESULTS: There is encouraging preclinical evidence regarding the efficacy of the emerging treatments discussed in this article. Several clinical trials are currently recruiting patients to translate targeted molecular therapy for meningiomas. Several clinical studies have suggested a clinical benefit of combinatorial treatment for these treatment-refractory tumors. CONCLUSION: With numerous active clinical trials for high grade meningiomas, a meaningful improvement in the outcomes for these tumors may be on the horizon.

Age of diagnosis clinically differentiates atypical teratoid/rhabdoid tumors diagnosed below age of 3 years: a database study.

BACKGROUND: Atypical teratoid/rhabdoid tumor (ATRT) is a rare and largely pediatric diagnosis, with poor survival. Diagnosis below the age of 3 years is characteristically seen as a poor prognostic sign. However, elucidating if clinical differences exist within this niche age group has never been attempted before. Correspondingly, we sought to characterize clinical profile of ATRT diagnoses before the age of 3 years based on separate ages of diagnosis. METHODS: All pediatric ATRT patients aged < 3 years in the US National Cancer Database (NCDB) between 2005 and 2016 were retrospectively reviewed. Age groups were divided based on diagnoses at ages 0-1 years in group 1, 1-2 years in group 2, and 2-3 years in group 3. Data were summarized, and overall survival (OS) was modeled using Kaplan-Meier and Cox regression analyses. RESULTS: A total of 354 ATRT diagnoses were made before the age of 3 years, with surgery used in 316 (89%) cases, chemotherapy in 242 (68%) cases, and radiation therapy in 118 (33%) cases. In terms of diagnosis age, there were 153 (43%) in group 1, 137 (39%) in group 2, and 64 (18%) in group 3. With respect to OS, median value was 9.9 months in group 1, 28.4 months in group 2, and 15.9 months in group 3. Upon multivariate analysis, receiving radiation therapy was the only parameter shared amongst all three groups as independently prognostic of longer OS (HR 0.53, P = 0.01 in group 1; HR 0.34, P < 0.01 in group 2; HR 0.31, P < 0.01 in group 3). In group 1, surgery (HR 0.47, P < 0.01) and chemotherapy (HR 0.44, P < 0.01) were also independently prognostic of longer OS. In group 3, multiple socioeconomic parameters were identified to independently predict longer OS. There were no additional predictive parameters identified in group 2. CONCLUSION: Although ATRT diagnosed before the age of 3 is typically viewed a poor prognostic age category, our findings demonstrate that the clinical profile of this pediatric niche is highly heterogeneous based on age of diagnosis. Survival of only those diagnosed between 0 and 1 years is independently prognosticated by all three treatment modalities; patients diagnosed between 1 and 2 years trend towards longest survival, and socioeconomic parameters are most influential in those diagnosed between 2 and 3 years.

Augmented reality head-mounted display-based incision planning in cranial neurosurgery: a prospective pilot study.

OBJECTIVE: Monitor and wand-based neuronavigation stations (MWBNSs) for frameless intraoperative neuronavigation are routinely used in cranial neurosurgery. However, they are temporally and spatially cumbersome; the OR must be arranged around the MWBNS, at least one hand must be used to manipulate the MWBNS wand (interrupting a bimanual surgical technique), and the surgical workflow is interrupted as the surgeon stops to "check the navigation" on a remote monitor. Thus, there is need for continuous, real-time, hands-free, neuronavigation solutions. Augmented reality (AR) is poised to streamline these issues. The authors present the first reported prospective pilot study investigating the feasibility of using the OpenSight application with an AR head-mounted display to map out the borders of tumors in patients undergoing elective craniotomy for tumor resection, and to compare the degree of correspondence with MWBNS tracing. METHODS: Eleven consecutive patients undergoing elective craniotomy for brain tumor resection were prospectively identified and underwent circumferential tumor border tracing at the time of incision planning by a surgeon wearing HoloLens AR glasses running the commercially available OpenSight application registered to the patient and preoperative MRI. Then, the same patient underwent circumferential tumor border tracing using the StealthStation S8 MWBNS. Postoperatively, both tumor border tracings were compared by two blinded board-certified neurosurgeons and rated as having an excellent, adequate, or poor correspondence degree based on a subjective sense of the overlap. Objective overlap area measurements were also determined. RESULTS: Eleven patients undergoing craniotomy were included in the study. Five patient procedures were rated as having an excellent correspondence degree, 5 had an adequate correspondence degree, and 1 had poor correspondence. Both raters agreed on the rating in all cases. AR tracing was possible in all cases. CONCLUSIONS: In this small pilot study, the authors found that AR was implementable in the workflow of a neurosurgery OR, and was a feasible method of preoperative tumor border identification for incision planning. Future studies are needed to identify strategies to improve and optimize AR accuracy.

Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines.

The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation.

Testing the mid-spatial frequency error of a large aperture long-focal-length lens with CGH.

We present the use of a computer-generated hologram (CGH) to test the mid-spatial frequency error of a large aperture long-focal-length lens. In order to verify this test approach, a 450 mm × 450 mm reflective CGH is designed and fabricated for testing the 440 mm × 440 mm spatial filter lens. Both 0th and 1st order diffraction wavefront of CGH are measured, and the 0th order diffraction wavefront is used to calibrate the substrate error. The mid-spatial frequency wavefront error caused by the CGH fabrication errors are evaluated using the binary linear grating model and power spectral density (PSD) theory. Experimental results and error analysis show that the CGH test approach is also feasible for the measurement of mid-spatial frequency error, and the measurement accuracy of PSD1 can reach 0.8832 nm RMS.

Resection versus biopsy in the treatment of multifocal glioblastoma: a weighted survival analysis.

OBJECT: Diffuse tumor invasion in multifocal/multicentric GBM (mGBM) often foreshadows poor survival outcome. The correlation between extent of resection in gliomas and patient outcome is well described. The objective of this study was to assess the effect of gross total resection compared to biopsy for mGBM on patient overall survival and progression free survival. METHODS: Thirty-four patients with mGBM received either biopsy or resection of their largest enhancing lesion from 2011 to 2019. Relevant demographic, peri-operative, and radiographic data were collected. Tumor burden and extent of resection was assessed through measurement of pre-operative and post-operative contrast-enhancing volume. An adjusted Kaplan-Meier survival analysis was conducted using inverse probability of treatment weighting (IPTW) to account for the covariates of age, number of lesions, satellite tumor volume, total pre-operative tumor volume, degree of spread, and location. RESULTS: Thirty-four patients were identified with sixteen (47.1%) and eighteen (52.9%) patients receiving resection and biopsy respectively. Patients receiving resection exhibited greater median overall survival but not progression free survival compared to biopsy on IPTW analysis (p = 0.026, p = 0.411). Greater than or equal to 85% extent of resection was significantly associated with increased median overall survival (p = 0.016). CONCLUSION: Overall, our study suggests that resection of the largest contrast-enhancing lesion may provide a survival benefit. Our volumetric analysis suggests that a greater degree of resection results in improved survival. Employing IPTW analysis, we sought to control for selection bias in our retrospective analysis. Thus, aggressive surgical treatment of mGBM may offer improved outcomes. Further clinical trials are needed.

Survival benefit of lobectomy for glioblastoma: moving towards radical supramaximal resection.

PURPOSE: Extent of resection remains a paramount prognostic factor for long-term outcomes for glioblastoma. As such, supramaximal resection or anatomic lobectomy have been offered for non-eloquent glioblastoma in an attempt to improve overall survival. Here, we conduct a propensity-matched analysis of patients with non-eloquent glioblastoma who underwent either lobectomy or gross total resection of lesion to investigate the efficacy of supramaximal resection of glioblastoma. METHODS: Patients who underwent initial surgery for gross total resection or lobectomy for non-eloquent glioblastoma at our tertiary care referral center from 2010 to 2019 were included for this propensity-matched survival analysis. Propensity scores were generated with the following covariates: age, location, preoperative KPS, product of perpendicular maximal tumor diameters, and product of perpendicular FLAIR signal diameters. Inverse probability of treatment weighting (IPTW) with generated propensity scores was used to compare progression-free survival and overall survival. RESULTS: Sixty-nine patients were identified who underwent initial resection of glioblastoma for non-eloquent glioblastoma from 2010 to 2019 (GTR = 37, lobectomy = 32). Using IPTW, overall survival (30.7 vs. 14.1 months) and progression-free survival (17.2 vs. 8.1 months were significantly higher in the lobectomy cohort compared to the GTR group (p < 0.001). There was no significant difference in pre-op or post-op KPS or complication rates between the two groups. CONCLUSION: Our propensity-matched study suggests that lobectomy for non-eloquent glioblastoma confers an added survival benefit compared to GTR alone. For patients with non-eloquent glioblastoma, a supramaximal resection by means of an anatomic lobectomy should be considered as a primary surgical treatment in select patients if feasible.

Minimally invasive resection of intracranial lesions using tubular retractors: a large, multi-surgeon, multi-institutional series.

PURPOSE: Lesions located in subcortical areas are difficult to safely access. Tubular retractors have been increasingly used successfully with low complication profile to access lesions by minimizing brain retraction trauma and distributing pressure radially. Both binocular operative microscope and monocular exoscope are utilized for lesion visualization through tubular retractors. We present the largest multi-surgeon, multi-institutional series to determine the efficacy and safety profile of a transcortical-transtubular approach for intracranial lesion resections with both microscopic and exoscopic visualization. METHODS: We reviewed a multi-surgeon, multi-institutional case series including transcortical-transtubular resection of intracranial lesions using either BrainPath (NICO, Indianapolis, Indiana) or ViewSite Brain Access System (VBAS, Vycor Medical, Boca Raton, Florida) tubular retractors (n = 113). RESULTS: One hundred thirteen transtubular resections for intracranial lesions were performed. Patients presented with a diverse number of pathologies including 25 cavernous hemangiomas (21.2%), 15 colloid cysts (13.3%), 26 GBM (23.0%), two meningiomas (1.8%), 27 metastases (23.9%), 9 gliomas (7.9%) and 9 other lesions (7.9%). Mean lesion depth below the cortical surface was 4.4 cm, and mean lesion size was 2.7 cm. A gross total resection was achieved in 81 (71.7%) cases. Permanent complication rate was 4.4%. One patient (0.8%) experienced one early postoperative seizure (< 1 week postop). No patients experienced late seizures (> 1 week follow-up). Mean post-operative hospitalization length was 4.1 days. CONCLUSION: Tubular retractors provide a minimally invasive operative corridor for resection of intracranial lesions. They provide an effective tool in the neurosurgical armamentarium to resect subcortical lesions with a low complication profile.

Incidence of high grade gliomas presenting as radiographically non-enhancing lesions: experience in 111 surgically treated non-enhancing gliomas with tissue diagnosis.

PURPOSE: Although non-enhancing lesions suspicious for glioma are usually assumed to be low grade glioma (LGG), some high grade glioma (HGG) do not enhance, which may lead to a delay in biopsy and/or resection, diagnosis, and treatment initiation. Thus, there is a clear need for a large-sample study that quantifies the rate of malignant, non-enhancing gliomas. METHODS: We retrospectively reviewed our series of 561 consecutive surgically treated gliomas with tissue diagnosis, 111 of which were non-enhancing, to determine the prevalence of high-grade histology in radiographically presumed LGG. Relative expression of tumor markers were also reported for non-enhancing lesions to investigate genetic correlates. RESULTS: We identified 561 surgically treated gliomas with tissue diagnosis from August 2012 to July 2018 and found that 111 patients (19.8%) demonstrated non-enhancing lesions suspicious for glioma on preoperative MRI. Thirty-one (27.9%) of the non-enhancing lesions were classified as HGGs (WHO Grade III or IV). Non-enhancing lesions were four times more likely to be HGG in patients older than 60 years than patients younger than 35 years (41.2% vs. 11.4%, Pearson Chi2 p < 0.001). Binomial logistic regression showed a significant inverse effect of age on the presence of IDH mutation in non-enhancing HGGs (p = 0.007). CONCLUSION: A clinically significant proportion (27.9%) of non-enhancing lesions were found to be HGG on final pathologic diagnosis. Thus, in patients with good functional and health status, especially those older than 60 years, we recommend obtaining tissue diagnosis of all lesions suspected to be glioma, even those that are non-enhancing, to guide diagnosis as well as early initiation of chemotherapy and radiation therapy.

Spontaneous preoperative pituitary adenoma resolution following apoplexy: a case presentation and literature review.

Purpose: We aim to more fully understand the incidence and natural history of spontaneously resolving non-functioning pituitary adenomas (NFPAs).Methods: We report a case of spontaneous complete resolution of a NFPA revealed by preoperative magnetic resonance imaging. In addition, we searched all major databases and neurosurgery journals to perform a comprehensive literature review of all previously reported cases of spontaneously resolving NFPAs. We discuss how these cases may contribute to our understanding of the natural course for non-functional pituitary adenomas.Results: To date, only twelve cases of spontaneously resolving nonfunctional pituitary adenomas have previously been reported. The presented case is the first reported spontaneously resolved nonfunctioning pituitary adenoma to recur. In all cases, apoplexy resulted in resolution of mass effect, obviating the need for surgical decompression.Conclusions: In all NFPA cases, the preoperative MRI should always be studied closely before surgery is initiated. Additionally, because we have demonstrated that the adenoma may regrow after spontaneous regression following apoplexy, these patients should be followed with regular serial MRIs to monitor for recurrence.

A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury.

BACKGROUND: Neuroinflammation is an essential player in many neurological diseases including traumatic brain injury (TBI). Recent studies have identified that inflammasome complexes are responsible for inflammatory responses in many pathological conditions. Inflammasomes are intracellular multiprotein complexes which regulate the innate immune response, activation of caspase-1, production of pro-inflammatory cytokines IL-1ß and IL-18, and induction of cell death (pyroptosis). Among inflammasome family members, the nucleotide-binding domain leucine-rich repeats family protein 3 (NLRP3) is the most extensively studied and its activation is induced following TBI. As a novel target, drug development targeting the formation and activation of NLRP3 inflammasome is a prospective therapy for TBI. We have recently developed a small molecule JC124 with specificity on NLRP3 inflammasome. In this study, we explored the therapeutic value of JC124 for TBI treatment. METHODS: Adult male Sprague-Dawley rats were subjected to a moderate cortical impact injury. Following TBI, animals received 4 doses of JC124 treatment with the first dose starting at 30 min, the second dose at 6 h after TBI, the third and fourth doses at 24 or 30 h following TBI, respectively. Animals were sacrificed at 2 days post-injury. Brain tissues were processed either for ELISA and western blotting analysis for inflammatory response, or for histological examination to assess degenerative neurons, acute inflammatory cell response and lesion volume. RESULTS: We found that post-injury treatment with JC124 significantly decreased the number of injury-induced degenerating neurons, inflammatory cell response in the injured brain, and cortical lesion volume. Injured animals treated with JC124 also had significantly reduced protein expression levels of NLRP3, ASC, IL-1 beta, TNFα, iNOS, and caspase-1. CONCLUSION: Our data suggest that our novel NLRP3 inhibitor has a specific anti-inflammatory effect to protect the injured brain following TBI.

Evodiamine inhibits migration and invasion by Sirt1-mediated post-translational modulations in colorectal cancer.

Colorectal cancer (CRC) is one of the most difficult cancers to cure. An important prognostic factor is metastasis, which precludes curative surgical resection. Recent evidences show that Evodiamine (EVO) exerts an inhibitory effect on cancer cell apoptosis, migration, and invasion. In this study, we investigated the effects of EVO on the metastasis of CRC cells in vitro and in vivo. In vitro, wound-healing and transwell assay showed that migration and invasion of HT-29 and HCT-116 CRC cells were inhibited significantly by EVO. Western blot and RT-PCR showed that EVO reduced the expression of matrix metalloproteinase-9 in a dose-dependent manner. In EVO-induced cells, the intracellular NAD+/NADH ratio was increased, the level of Sirt1 was increased, and acetyl-NF-κB P65 was decreased. This process was inhibited by nicotinamide, an inhibitor of Sirt1. In vivo, EVO reduced tumor metastasis markedly. These findings provide evidences that EVO suppresses the migration and invasion of CRC cells by inhibiting the acetyl-NF-κB p65 by Sirt1, resulting in suppression of metalloproteinase-9 expression in vitro and in vivo.

Network connectivity separate from the hypothesized irritative zone correlates with impaired cognition and higher rates of seizure recurrence.

INTRODUCTION: Surgery remains an essential option for the treatment of medically intractable temporal lobe epilepsy (TLE). However, only 66% of patients achieve postoperative seizure freedom, perhaps attributable to an incomplete understanding of brain network alterations in surgical candidates. Here, we applied a novel network modeling algorithm and measured key characteristics of epileptic networks correlated with surgical outcomes and objective measures of cognition. METHODS: Twenty-two patients were prospectively included, and relevant demographic information was attained. Resting state functional magnetic resonance imaging (rsfMRI) and electroencephalography (EEG) data were recorded and preprocessed. Using our novel algorithm, patient-specific epileptic networks were mapped preoperatively, and geographic spread was quantified. Global functional connectivity was also determined using a volumetric functional atlas. Neuropsychological pre- and postsurgical raw and standardized scores obtained blinded to epileptic network status. Key demographic data and features of epileptic networks were then correlated with surgical outcome using Pearson's product-moment correlation. RESULTS: At an average follow-up of 18.4 months, 15/22 (68%) patients were seizure-free. Connectivity was measured globally using a functional 3D atlas. Higher mean global connectivity correlated with worse scores in preoperative neuropsychological testing of executive functioning (Ruff Figural Fluency Test [RFFT]-ER; R = 0.943, p = 0.005). A higher ratio of highly correlated connections between regions of interest (ROIs) in the hemisphere contralateral to the seizure onset correlated with impairment in executive functioning (RFFT-ER; R = 0.943, p = 0.005). Higher numbers of highly correlated connections between ROIs in the contralateral hemisphere correlated with impairment in both short- and long-term measures of verbal memory (Rey Auditory Verbal Learning Test Trials 6, 7 [RAVLT6, RAVLT7]; R = -0.650, p = 0.020, R = -0.676, p = 0.030). Epilepsy networks were modeled in each patient, and localization of the epilepsy network in the bitemporal lobes correlated with lower scores in neuropsychological tests measuring verbal learning and short-term memory (RAVLT6; R = -0.671, p = 0.024). Higher rates of seizure recurrence correlated with localization of the epilepsy network bitemporally (R = -0.542, p = 0.014), with the stronger correlation found with localization to the contralateral temporal lobe from side of surgery (R = - 0.530, p = 0.016). CONCLUSION: Increased connectivity contralateral to seizure onset and epilepsy network spread in the bitemporal lobes correlated with lower measures of executive functioning and verbal memory. Epilepsy network localization to the bitemporal lobes, in particular, the contralateral temporal lobe, is associated with higher rates of seizure recurrence. These findings may reflect network-level disruption that has infiltrated the contralateral hemisphere and the bitemporal lobes contributing to impaired cognition and relatively worse surgical outcomes. Further identification of network parameters that predict patient outcomes may aid in patient selection, resection planning, and ultimately the efficacy of epilepsy surgery.

Testing the transmitted wavefront of large aperture and long-focal-length lens with computer-generated hologram.

A method for testing the transmitted wavefront of large aperture and long-focal-length lens with a multizone computer-generated hologram (CGH) is proposed. The multizone CGH has 5 zones: one main zone for the null testing of long-focal-length lens and four auxiliary zones for the pre-alignment of measured lens. Both 1st order wavefront and 0th order wavefront of CGH are measured, and 0th order wavefront is used to calibrate the substrate error. To verify this test approach, a 450mm × 450mm multizone CGH is designed and fabricated for testing the spatial filter lens. Experiments and error analysis are carried out. The results show that the desired precision can be reached with use of CGH.

Identification of Biological Targets of Therapeutic Intervention for Hepatocellular Carcinoma by Integrated Bioinformatical Analysis.

BACKGROUND We screened the potential molecular targets and investigated the molecular mechanisms of hepatocellular carcinoma (HCC). MATERIAL AND METHODS Microarray data of GSE47786, including the 40 µM berberine-treated HepG2 human hepatoma cell line and 0.08% DMSO-treated as control cells samples, was downloaded from the GEO database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed; the protein-protein interaction (PPI) networks were constructed using STRING database and Cytoscape; the genetic alteration, neighboring genes networks, and survival analysis of hub genes were explored by cBio portal; and the expression of mRNA level of hub genes was obtained from the Oncomine databases. RESULTS A total of 56 upregulated and 8 downregulated DEGs were identified. The GO analysis results were significantly enriched in cell-cycle arrest, regulation of transcription, DNA-dependent, protein amino acid phosphorylation, cell cycle, and apoptosis. The KEGG pathway analysis showed that DEGs were enriched in MAPK signaling pathway, ErbB signaling pathway, and p53 signaling pathway. JUN, EGR1, MYC, and CDKN1A were identified as hub genes in PPI networks. The genetic alteration of hub genes was mainly concentrated in amplification. TP53, NDRG1, and MAPK15 were found in neighboring genes networks. Altered genes had worse overall survival and disease-free survival than unaltered genes. The expressions of EGR1, MYC, and CDKN1A were significantly increased, but expression of JUN was not, in the Roessler Liver datasets. CONCLUSIONS We found that JUN, EGR1, MYC, and CDKN1A might be used as diagnostic and therapeutic molecular biomarkers and broaden our understanding of the molecular mechanisms of HCC.