Homeostatic, Non-Canonical Role of Macrophage Elastase in Vascular Integrity.

BACKGROUND: Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm. METHODS: Apoe-/- and Mmp12-/-/Apoe-/- mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH1-5 (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined. RESULTS: Unexpectedly, death from aortic rupture was significantly higher in Mmp12-/-/Apoe-/- mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in Mmp12-/- aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in Mmp12-/- mice pointed to complement overactivation. Treatment with IgG-FH1-5 decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II-infused Mmp12-/- mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II-infused mice. CONCLUSIONS: An MMP-12 deficiency/complement activation/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.

Gamma Knife Radiosurgery for Petroclival Meningioma: Long-Term Outcome and Failure Pattern.

Total removal of petroclival meningioma is difficult, and aggressive extirpation is often associated with significant surgical morbidity and mortality. The aim of this study was to evaluate the long-term outcome and failure pattern of treatment with Gamma Knife radiosurgery (GKRS) in patients with petroclival meningiomas. Eighty-nine consecutive patients with petroclival meningiomas underwent GKRS between 1998 and 2013. Fifty-eight patients received GKRS as a primary treatment and 31 patients underwent GKRS as a secondary treatment after microsurgery. The mean tumor volume was 6.7 cm3 (range, 0.5-46.3 cm3) and the mean marginal dose was 13.2 Gy (range, 8-17 Gy). At the last radiological follow-up, tumor volume was decreased in 50 patients (56.2%), stationary in 34 patients (38.2%), and increased in 5 patients (5.6%). The actuarial progression-free survival after GKRS was 94.7% at 5 years and 88.9% at 10 years. Favorable cranial nerve outcomes were found in 81 patients (91%). A regrowth pattern was present in all 4 patients of the primary treatment group, whereas cyst formation (3 patients) and regrowth (1 patient) were observed in the secondary treatment group. GKRS is an effective and reasonable option as a primary or secondary treatment for petroclival meningioma. Further studies of failure patterns after GKRS for petroclival meningioma are mandatory.

Gamma Knife Surgery for Recurrent or Residual Supratentorial Primitive Neuroectodermal Tumors.

BACKGROUND: Supratentorial primitive neuroectodermal tumors (PNETs) are highly malignant and rare tumors of the central nervous system. OBJECTIVES: The aim of this study was to determine the role of Gamma Knife surgery (GKS) as a salvage treatment option for patients with recurrent or residual supratentorial PNETs. METHODS: Between 1998 and 2014, 11 patients with supratentorial PNETs were retrospectively analyzed. This series consisted of 7 male and 4 female patients. The median age was 17 years. All patients received surgical resection followed by adjuvant therapy. The median time from operation to the first GKS treatment was 72.5 months. The median tumor volume was 17.5 cm3, and the median marginal dose was 11.5 Gy. RESULTS: 15 (65%) of the 23 tumors had been controlled. The actuarial local tumor control rate was 91% at 3 months, 73% at 6 months, and 44% at 12 months. At the time of analysis, 9 (82%) of the patients had died. The median survival time after the first GKS session was 17 months. The median survival time from the initial diagnosis was 65 months. No adverse radiation effect after GKS treatment occurred in any patient. CONCLUSIONS: GKS treatment might be an effective salvage treatment option for recurrent or residual supratentorial PNETs after multimodal treatment.

Prognostic implication of progression pattern after anti-VEGF bevacizumab treatment for recurrent malignant gliomas.

Malignant glioma treated with anti-vascular endothelial growth factor (VEGF) bevacizumab show progression patterns that vary with different mechanisms of resistance. We evaluated the clinico-radiological data of 71 patients with progressive malignant glioma treated with bevacizumab to determine the prognostic value of the differential outcome of each progression pattern. Progression patterns were categorized as three types based on the initial response to bevacizumab and serious changes of MR images i.e., non-enhancing infiltration, flare-up of contrast enhancement (CE) and primary non-responder progression. We analyzed the clinical outcome in each type of progression using Kaplan-Meier survival analysis. Analysis of progression patterns showed that incidence of non-enhancing infiltration progression (28.1 %) was less common than flare-up of CE or primary non-responder pattern. The time from initiation of bevacizumab to development of non-enhancing infiltration or flare-up of CE progression was longer than for progression in primary non-responders. There was no significant difference of overall survival, progression-free survival from start of bevacizumab therapy, survival after bevacizumab failure between non-enhancing infiltration and flare-up of CE patterns. However, in the non-enhancing infiltration pattern, early appearance of enhancement was observed after bevacizumab was discontinued, resulting in poor survival, as compared to flare-up of CE pattern (P = 0.01). Although the appearance of non-enhancing infiltration after bevacizumab does not imply a worse prognosis, discontinuation of therapy can aggravate the clinical course.

The lack of relationship between intracranial pressure and cerebral ventricle indices based on brain computed tomography in patients undergoing ventriculoperitoneal shunt.

BACKGROUND: In this study we investigated whether cerebral ventricle indices based on brain computed tomography (CT) scans are reliable for predicting intracranial pressure (ICP) in hydrocephalic patients. METHODS: Electronic medical records of 221 patients undergoing ventriculoperitoneal shunt due to hydrocephalus were retrospectively reviewed. Cerebral ventricle indices including Evans' index, third ventricle index, cella media index, and ventricular score were calculated from transverse diameters measured at various levels on preoperative brain CT scans. ICP was considered as CSF opening pressure. Patients were categorized into three groups: communicating hydrocephalus, non-communicating hydrocephalus, and normal pressure hydrocephalus (NPH). The non-communicating hydrocephalus group was further divided according to the obstruction site; aqueduct, fourth ventricle outlet, third ventricle, and the foramen of Monro. The primary endpoint was the extent of the correlation between cerebral ventricle indices and ICP in each hydrocephalus group. RESULTS: No cerebral ventricle index correlated with ICP in patients with communicating hydrocephalus (n = 113) and NPH (n = 62). In the non-communicating hydrocephalus group (n = 46), only the third ventricle index revealed moderate negative correlation with ICP (r = -0.395, p < 0.01). In subgroup analyses, the third ventricle index showed a strong negative relationship with ICP only in patients with the third ventricle obstruction (r = -0.779, p < 0.05). CONCLUSIONS: In this study we showed that although an inverse correlation existed between ICP and the third ventricle index only in patients with non-communicating hydrocephalus due to obstruction of the third ventricle, cerebral ventricle indices based on brain CT scan were non-reliable predictors of ICP in hydrocephalic patients.

Extended endoscopic endonasal approach for recurrent or residual adult craniopharyngiomas.

BACKGROUND: The aim of this study was to evaluate the effectiveness of the extended endoscopic endonasal transsphenoidal approach (TSA) for recurrent or residual craniopharyngiomas, focusing on the extent of tumor resection and complications resulting from surgery at a single institution. METHODS: Twelve adult patients (six men and six women) underwent extended endoscopic endonasal TSA for a recurrent or residual craniopharyngioma after a previous surgical intervention at a single institution by a single surgeon. The mean number of surgeries patients had undergone before TSA was 1.3 (range, 1-3). The mean period between patients' most recent surgery and extended TSA was 55.9 months (range, 1-184). The mean preoperative (that is, pre-extended TSA) tumor volume was 2.87 cm³. The mean follow-up period was 15.8 months (range, 4-32). We reviewed clinical and radiological features in each case, focusing on the degree of tumor resection as well as endocrinological and ophthalmological outcomes. RESULTS: Gross total resection was achieved in ten patients (83.3 %), and the mean resection rate was 87 % in the other two cases. There were no significant differences between pre- and postoperative endocrine function, except in one patient who suffered postoperative panhypopituitarism resulting in pituitary stalk resection, which was necessary because of obvious tumor involvement. Three patients suffered transient diabetic insipidus (DI). With respect to ophthalmological outcomes, three patients showed improvement, two others showed decline, and the remainder showed no significant changes. CONCLUSION: The extended endoscopic endonasal transsphenoidal approach is an effective and safe surgical approach for treating recurrent or residual craniopharyngioma.

Increased protection from vaccinia virus infection in mice genetically prone to lymphoproliferative disorders.

Mutations in the genes that encode Fas or Fas ligand (FasL) can result in poor restraints on lymphocyte activation and in increased susceptibility to autoimmune disorders. Because these mutations portend a continuously activated immune state, we hypothesized that they might in some cases confer resistance to infection. To examine this possibility, the immune response to, morbidity caused by, and clearance of vaccinia virus (VACV) Western Reserve was examined in 5- to 7-week-old Fas mutant (lpr) mice, before an overt lymphoproliferative disorder was observable. On day 6 after VACV infection, C57BL/6-lpr (B6-lpr) mice had decreased morbidity, decreased viral titers, and an increased percentage and number of CD4(+) and CD8(+) T cells. As early as day 2 after infection, B6-lpr mice had decreased liver and spleen viral titers and increased numbers of and increased gamma interferon (IFN-γ) production by several different effector cell populations. Depletion of individual effector cell subsets did not inhibit the resistance of B6-lpr mice. Uninfected B6-lpr mice also had increased numbers of NK cells, γδ(+) T cells, and CD44(+) CD4(+) and CD44(+) CD8(+) T cells compared to uninfected B6 mice. Antibody to IFN-γ resulted in increased virus load in both B6 and B6-lpr mice and eliminated the differences in viral titers between them. These results suggest that IFN-γ produced by multiple activated leukocyte populations in Fas-deficient hosts enhances resistance to some viral infections.

Anti-complement 5 antibody ameliorates antibody-mediated rejection after liver transplantation in rats.

Antibody-mediated rejection (AMR) remains a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible liver transplantation (LT), even in the era of pre-transplant rituximab desensitization. This is due to the lack of not only effective post-transplant treatments but also robust animal models to develop/validate new interventions. Orthotopic LT from male Dark Agouti (DA) to male Lewis (LEW) rats was used to develop a rat LT-AMR model. LEW were pre-sensitized by a preceding skin transplantation from DA 4-6 weeks before LT (Group-PS), while sham procedure was performed in non-sensitized controls (Group-NS). Tacrolimus was daily administered until post-transplant day (PTD)-7 or sacrifice to suppress cellular rejections. Using this model, we validated the efficacy of anti-C5 antibody (Anti-C5) for LT-AMR. Group-PS+Anti-C5 received Anti-C5 intravenously on PTD-0 and -3. Group-PS showed increased anti-donor (DA) antibody-titers (P <0.001) and more C4d deposition in transplanted livers than in Group-NS (P <0.001). Alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA), and total bilirubin (T-Bil) were all significantly higher in Group-PS than in Group-NS (all P <0.01). Thrombocytopenia (P <0.01), coagulopathies (PT-INR, P =0.04), and histopathological deterioration (C4d+h-score, P <0.001) were also confirmed in Group-PS. Anti-C5 administration significantly lowered anti-DA IgG (P <0.05), resulting in decreased ALP, TBA, and T-Bil on PTD-7 than in Group-PS (all P <0.01). Histopathological improvement was also confirmed on PTD-1, -3, and -7 (all P <0.001). Of the 9,543 genes analyzed by RNA sequencing, 575 genes were upregulated in LT-AMR (Group-PS vs. Group-NS). Of these, 6 were directly associated with the complement cascades. In particular, Ptx3, Tfpi2, and C1qtnf6 were specific to the classical pathway. Volcano plot analysis identified 22 genes that were downregulated by Anti-C5 treatment (Group-PS+Anti-C5 vs. Group-PS). Of these, Anti-C5 significantly down-regulated Nfkb2, Ripk2, Birc3, and Map3k1, the key genes that were amplified in LT-AMR. Notably, just two doses of Anti-C5 only on PTD-0 and -3 significantly improved biliary injury and liver fibrosis up to PTD-100, leading to better long-term animal survival (P =0.02). We newly developed a rat model of LT-AMR that meets all the Banff diagnostic criteria and demonstrated the efficacy of Anti-C5 antibody for LT-AMR.

CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections.

In this study, we demonstrate complex networks of CD8 T cell cross-reactivities between influenza A virus and EBV in humans and between lymphocytic choriomeningitis virus and vaccinia virus in mice. We also show directly that cross-reactive T cells mediate protective heterologous immunity in mice. Subsets of T cell populations reactive with one epitope cross-reacted with either of several other epitopes encoded by the same or the heterologous virus. Human T cells specific to EBV-encoded BMLF1(280-288) could be cross-reactive with two influenza A virus or two other EBV epitopes. Mouse T cells specific to the vaccinia virus-encoded a11r(198-205) could be cross-reactive with three different lymphocytic choriomeningitis virus, one Pichinde virus, or one other vaccinia virus epitope. Patterns of cross-reactivity differed among individuals, reflecting the private specificities of the host's immune repertoire and divergence in the abilities of T cell populations to mediate protective immunity. Defining such cross-reactive networks between commonly encountered human pathogens may facilitate the design of vaccines.

Private specificities of CD8 T cell responses control patterns of heterologous immunity.

CD8 T cell cross-reactivity between viruses can play roles in protective heterologous immunity and damaging immunopathology. This cross-reactivity is sometimes predictable, such as between lymphocytic choriomeningitis virus (LCMV) and Pichinde virus, where cross-reactive epitopes share six out of eight amino acids. Here, however, we demonstrate more subtle and less predictable cross-reactivity between LCMV and the unrelated vaccinia virus (VV). Epitope-specific T cell receptor usage differed between individual LCMV-infected C57BL/6 mice, even though the mice had similar epitope-specific T cell hierarchies. LCMV-immune mice challenged with VV showed variations, albeit in a distinct hierarchy, in proliferative expansions of and down-regulation of IL-7Ralpha by T cells specific to different LCMV epitopes. T cell responses to a VV-encoded epitope that is cross-reactive with LCMV fluctuated greatly in VV-infected LCMV-immune mice. Adoptive transfers of splenocytes from individual LCMV-immune donors resulted in nearly identical VV-induced responses in each of several recipients, but responses differed depending on the donor. This indicates that the specificities of T cell responses that are not shared between individuals may influence cross-reactivity with other antigens and play roles in heterologous immunity upon encounter with another pathogen. This variability in cross-reactive T cell expansion that is unique to the individual may underlie variation in the pathogenesis of infectious diseases.

Pathological features of heterologous immunity are regulated by the private specificities of the immune repertoire.

Heterologous immunity associated with cross-reactive T-cell responses is proposed to contribute to variations among individuals in the pathogenesis of human viral infections. In genetically identical mice with similar infection histories, marked variations in the magnitude and specificities of T-cell responses under conditions of heterologous immunity occur and have been linked to the private specificity of T-cell repertoires in individual immune mice. Variations in immunopathology in the form of panniculitis are observed in lymphocytic choriomeningitis virus-immune mice after vaccinia virus infection. By adoptively transferring splenocytes from individual lymphocytic choriomeningitis virus-immune donors into paired recipients, we show here that, on vaccinia virus infection, similar levels of panniculitis were generated in recipients from a single donor, but the severity of panniculitis varied among recipients receiving cells from different donors. This indicates that virus-induced immunopathology under conditions of heterologous immunity is a function of the private specificity of the immune repertoire.

Utility of Low-Profile Visualized Intraluminal Support Junior Stent as a Rescue Therapy for Treating Ruptured Intracranial Aneurysms During Complicated Coil Embolization.

BACKGROUND: Coil protrusion occasionally occurs during embolization and can lead to thromboembolic complications. We aimed to evaluate the efficacy of rescue stenting procedures with a low-profile stent system (LVIS Jr.) for treating ruptured intracranial aneurysms during complicated coil embolization. METHODS: We performed a retrospective review to identify patients who had subarachnoid hemorrhage and were treated with LVIS Jr. stent rescue therapy. We enrolled 15 patients with intracranial aneurysms and evaluated the technical success and immediate postprocedural clinical and angiographic outcomes. RESULTS: All 15 patients underwent successful rescue-stent treatment, and no thrombotic or hemorrhagic complications occurred. Immediate postprocedural angiography revealed complete aneurysm occlusion in 40% (6/15) of the patients, whereas 60% (9) of the patients had a residual neck. Among the 12 patients who underwent follow-up angiography, 10 (83.3%) patients had complete aneurysm occlusion, 1 (8.3%) had a residual neck, and 1 (8.3%) showed an increase in the filling status of the aneurysm. There were no thrombotic complications during the follow-up period. CONCLUSIONS: Our findings indicate that LVIS Jr. stent rescue therapy is clinically useful for handling coil protrusion during the embolization of ruptured intracranial aneurysms.

A National Consensus Survey for Current Practice in Brain Tumor Management I: Antiepileptic Drug and Steroid Usage.

BACKGROUND: The Guideline Working Group of the Korean Society for Neuro-Oncology (KSNO) conducted a nationwide questionnaire survey for diverse queries faced in the treatment of brain tumors. As part I of the survey, the aim of this study is to evaluate national patterns of clinical practice about antiepileptic drug (AED) and steroid usage for management of brain tumors. METHODS: A web-based survey was sent to all members of the KSNO by email. The survey included 9 questions of AED usage and 5 questions of steroid usage for brain tumor patients. All questions were developed by consensus of the Guideline Working Group. RESULTS: The overall response rate was 12.8% (54/423). Regarding AED usage, the majority of respondents (95.2%) routinely prescribed prophylactic AEDs for patients with seizure at the peri/postoperative period. However, as many as 72.8% of respondents prescribed AED routinely for seizure-naïve patients, and others prescribed AED as the case may be. The duration of AED prophylaxis showed wide variance according to the epilepsy status and the location of tumor. Levetiracetam (82.9%) was the most preferred AED for epilepsy prophylaxis. Regarding steroid usage, 90.5% of respondents use steroids in perioperative period, including 34.2% of them as a routine manner. Presence of peritumoral edema (90.9%) was considered as the most important factor determining steroid usage followed by degree of clinical symptoms (60.6%). More than half of respondents (51.2%) replied to discontinue the steroids within a week after surgery if there are no specific medical conditions, while 7.3% preferred slow tapering up to a month after surgery. CONCLUSION: The survey demonstrated the prevailing practice patterns on AED and steroid usage in neuro-oncologic field among members of the KSNO. This information provides a point of reference for establishing a practical guideline in the management of brain tumor patients.

A National Consensus Survey for Current Practice in Brain Tumor Management II: Diffuse Midline Glioma and Meningioma.

BACKGROUND: The Guideline Working Group of the Korean Society for Neuro-Oncology (KSNO) conducted a nationwide questionnaire survey for diverse queries faced in the treatment of brain tumors. As part II of the survey, the aim of this study is to evaluate the national patterns of clinical practice for patients with diffuse midline glioma and meningioma. METHODS: A web-based survey was sent to all members of the KSNO by email. The survey included 4 questions of diffuse midline glioma and 6 questions of meningioma (including 2 case scenarios). All questions were developed by consensus of the Guideline Working Group. RESULTS: In the survey about diffuse midline glioma, 76% respondents performed histologic confirmation to identify H3K27M mutation on immunohistochemical staining or sequencing methods. For treatment of diffuse midline glioma, respondents preferred concurrent chemoradiotherapy with temozolomide (TMZ) and adjuvant TMZ (63.8%) than radiotherapy alone (34.0%). In the survey about meningioma, respondents prefer wait-and-see policy for the asymptomatic small meningioma without peritumoral edema. However, a greater number of respondents had chosen surgical resection as the first choice for all large size meningiomas without exception, and small size meningiomas with either peritumoral edema or eloquent location. There was no single opinion with major consensus on long-term follow-up plans for asymptomatic meningioma with observation policy. As many as 68.1% of respondents answered that they would not add any adjuvant therapies for World Health Organization grade II meningiomas if the tumor was totally resected including dura. CONCLUSION: The survey demonstrates the prevailing clinical practice patterns for patients with diffuse midline glioma and meningioma among members of the KSNO. This information provides a point of reference for establishing a practical guideline in the management of diffuse midline glioma and meningioma.

A National Consensus Survey for Current Practice in Brain Tumor Management III: Brain Metastasis and Primary Central Nervous System Lymphoma.

BACKGROUND: The Guideline Working Group of the Korean Society for Neuro-Oncology (KSNO) conducted the nationwide questionnaire survey for diverse queries facing to treat patients with brain tumor. As part III of the survey, the aim of this study is to evaluate the national patterns of clinical practice for patients with brain metastasis and primary central nervous system lymphoma (PCNSL). METHODS: A web-based survey was sent to all members of the KSNO by email. The survey included 7 questions of brain metastasis and 5 questions of PCNSL, focused on the management strategies in specific situations. All questions were developed by consensus of the Guideline Working Group. RESULTS: In the survey about brain metastasis, respondents preferred surgical resection with adjuvant treatment for patients with a surgically accessible single brain metastatic lesion less than 3 cm in size without extracranial systemic lesions. However, most respondents considered radiosurgery for surgically inaccessible lesions. As the preferred treatment of multiple brain metastases according to the number of brain lesions, respondents tended to choose radiotherapy with increasing number of lesions. Radiosurgery was mostly chosen for the brain metastases of less than or equal to 4. In the survey about PCNSL, a half of respondents choose high-dose methotrexate-based polychemotherapy as the first-line induction therapy for PCNSL. The consolidation and salvage therapy showed a little variation among respondents. For PCNSL patients with cerebrospinal fluid dissemination, intrathecal chemotherapy was most preferred. CONCLUSION: The survey demonstrates the prevailing clinical practice patterns for patients with brain metastasis and PCNSL among members of the KSNO. This information provides a point of reference for establishing a practical guideline in the management of brain metastasis and PCNSL.

Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity.

Why some virus-specific CD8 TCR repertoires are diverse and others restricted or "oligoclonal" has been unknown. We show here that oligoclonality and extreme clonal dominance can be a consequence of T cell cross-reactivity. Lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV) encode NP(205-212) epitopes that induce different but highly cross-reactive diverse TCR repertoires. Homologous viral challenge of immune mice only slightly skewed the repertoire and enriched for predictable TCR motifs. However, heterologous viral challenge resulted in a narrow oligoclonal repertoire with dominant clones with unpredictable TCR sequences. This shift in clonal dominance varied with the private, i.e., unique, specificity of the host's TCR repertoire and was simulated using affinity-based computer models. The skewing differences in TCR repertoire following homologous versus heterologous challenge were observed within the same private immune system in mice adoptively reconstituted with memory CD8 T cell pools from the same donor. Conditions driving oligoclonality resulted in an LCMV epitope escape variant in vivo resembling the natural Lassa virus sequence. Thus, T cell oligoclonality, including extremes in clonal dominance, may be a consequence of heterologous immunity and lead to viral escape. This has implications for the design of peptide-based vaccines, which might unintentionally prime for skewed TCR responses to cross-reactive epitopes.

Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction.

The EGF-like domain of smallpox growth factor (SPGF) targets human ErbB-1, inducing tyrosine phosphorylation of certain host cellular substrates via activation of the receptor's kinase domain and thereby facilitating viral replication. Given these findings, low molecular weight organic inhibitors of ErbB-1 kinases might function as antiviral agents against smallpox. Here we show that CI-1033 and related 4-anilinoquinazolines inhibit SPGF-induced human cellular DNA synthesis, protein tyrosine kinase activation, and c-Cbl association with ErbB-1 and resultant internalization. Infection of monkey kidney BSC-40 and VERO-E6 cells in vitro by variola strain Solaimen is blocked by CI-1033, primarily at the level of secondary viral spreading. In an in vivo lethal vaccinia virus pneumonia model, CI-1033 alone promotes survival of animals, augments systemic T cell immunity and, in conjunction with a single dose of anti-L1R intracellular mature virus particle-specific mAb, fosters virtually complete viral clearance of the lungs of infected mice by the eighth day after infection. Collectively, these findings show that chemical inhibitors of host-signaling pathways exploited by viral pathogens may represent potent antiviral therapies.

Cystic Meningiomas: Correlation between Radiologic and Histopathologic Features.

BACKGROUND: Tumors with cysts often correlate with gliomas, metastatic tumors, or hemangioblastomas, which require differentiation. METHODS: Thirty-eight cases of cyst associated-meningioma based on preoperative radiologic studies and histologic confirmations were reviewed from November 1998 to July 2017. RESULTS: A total of 395 cases of meningioma were observed in the 20 years, and surgical treatment of intracranial meningioma was performed in 120 cases. Thirty-eight (9.6%) cases of cyst associated meningiomas were analyzed. Nauta type I was the most common type of cyst (39.5%) and the most frequent histopathological subtype was meningothelial type (36.8%). CONCLUSION: Statistically there were no significant associations between meningioma histopathological type and associated cysts; however, the rate of World Health Organization grade II was higher in cyst associated meningiomas than in unrelated meningiomas. This correlation was weak, in accordance with the meningioma grade.

A subpopulation of cancer stem cells identifies radiographic characteristics in glioblastoma.

Cancer stem cells (CSCs), defined by CD133 expression, harbor heterogeneous subpopulations of cells, including endothelial progenitor cells (EPCs). This study aimed to investigate whether a subpopulation of CSCs could affect the radiographic characteristics of glioblastoma. Tissue samples from 10 patients newly diagnosed with glioblastoma were selected according to the radiographic characteristics of their tumors. The patients were divided into two groups based on preoperative magnetic resonance imaging demonstrating contrast enhancement, necrosis and infiltrative patterns: the enhancement/necrosis group (E/N, n=5) and the non-enhancement/infiltration group (NE/I, n=5). Flow cytometry was used to assess the CSCs while immunohistochemistry was used to study microvessel density and the proliferation index. The EPC (CD34+/CD133+) fraction in CSCs (CD133+) was larger in the NE/I group. However, there was little difference in the angiogenic activity assessed using microvessel density between the two groups. The proliferation index (assessed using the antibody Ki-67) was higher in the E/N group and was negatively correlated with the EPC fraction. The non-EPC (CD34-/CD133+) fraction is a major factor responsible for radiographic characteristics of contrast enhancement, thus establishing an association between a subpopulation fraction of CSCs and radiographic characteristics in glioblastoma. Therefore, the simple non-invasive assessment of studying contrast enhancement lesions in glioblastomas may be used to estimate CSC subpopulations.

Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma.

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is now a widely-used modality for glioblastoma (GBM) treatment. However, intratumoral heterogeneity of fluorescence intensity may reflect different onco-metabolic programs. Here, we investigated the metabolic mechanism underlying the heterogeneity of 5-ALA fluorescence in GBM. Using an in-house developed fluorescence quantification system for tumor tissues, we collected 3 types of GBM tissues on the basis of their fluorescence intensity, which was characterized as strong, weak, and none. Expression profiling by RNA-sequencing revealed 77 genes with a proportional relationship and 509 genes with an inverse relationship between gene expression and fluorescence intensity. Functional analysis and in vitro experiments confirmed glutaminase 2 (GLS2) as a key gene associated with the fluorescence heterogeneity. Subsequent metabolite profiling discovered that insufficient NADPH due to GLS2 underexpression was responsible for the delayed metabolism of 5-ALA and accumulation of protoporphyrin IX (PpIX) in the high fluorescence area. The expression level of GLS2 and related NADPH production capacity is associated with the regional heterogeneity of 5-ALA fluorescence in GBM.