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IntroductionSeveral species of cellulolytic bacteria display cellulosomes, massive multi-cellulase containing complexes that degrade lignocellulosic plant biomass (LCB). A greater understanding of cellulosome structure and enzyme content could facilitate the development of new microbial-based methods to produce renewable chemicals and materials.MethodsTo identify novel cellulosome-displaying microbes we searched 305,693 sequenced bacterial genomes for genes encoding cellulosome proteins; dockerin-fused glycohydrolases (DocGHs) and cohesin domain containing scaffoldins.Results and discussionThis analysis identified 33 bacterial species with the genomic capacity to produce cellulosomes, including 10 species not previously reported to produce these complexes, such as Acetivibrio mesophilus. Cellulosome-producing bacteria primarily originate from the Acetivibrio, Ruminococcus, Ruminiclostridium, and Clostridium genera. A rigorous analysis of their enzyme, scaffoldin, dockerin, and cohesin content reveals phylogenetically conserved features. Based on the presence of a high number of genes encoding both scaffoldins and dockerin-fused GHs, the cellulosomes in Acetivibrio and Ruminococcus bacteria possess complex architectures that are populated with a large number of distinct LCB degrading GH enzymes. Their complex cellulosomes are distinguishable by their mechanism of attachment to the cell wall, the structures of their primary scaffoldins, and by how they are transcriptionally regulated. In contrast, bacteria in the Ruminiclostridium and Clostridium genera produce ‘simple’ cellulosomes that are constructed from only a few types of scaffoldins that based on their distinct complement of GH enzymes are predicted to exhibit high and low cellulolytic activity, respectively. Collectively, the results of this study reveal conserved and divergent architectural features in bacterial cellulosomes that could be useful in guiding ongoing efforts to harness their cellulolytic activities for bio-based chemical and materials production.

Abstract ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

Abstract The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP’s propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.

Evidence suggests that fibrous aggregates of protein tau may be the proximal cause of Alzheimer’s disease. Here, using atomic structures of tau fibrils from brains of people with Alzheimer’s disease, the authors have found small-molecule drug leads that disaggregate tau fibrils in vitro.

An environmentally safe means of mosquito control is the application of Bacillus thuringiensis israelensis, which produces a cocktail of four naturally crystalline proteins exclusively toxic to mosquito. Here the authors report the atomic-resolution structures of Bti Cry11Aa and related Btj Cry11Ba solved de novo through Serial Femtosecond Crystallography on naturally-occurring nanocrystals.

Background: In this study, we aimed at delineating the still ambiguous clinical characteristics and long-term outcomes of basal ganglia (BG) germinoma from the aspect of recurrence-free survival as well as social and intellectual activity., Methods: We retrospectively reviewed medical records and imaging data for 12 patients with BG germinoma diagnosed and treated between 1996 and 2020, collecting the most recent status via medical records or telephone from the patients., Results: The tumors involved the right and left sides and bilateral locations in three, seven, and two cases, respectively. The median follow-up period was 179 months. Six patients exhibited onset neuropsychologic symptoms, for example, cognitive decline or behavior disorder. We evaluated the intelligence quotient (IQ) in 10 patients and observed significantly lower IQ scores in six patients with neuropsychologic symptoms. Patients with right-sided lesions displayed average IQ levels (median 106), whereas those with left-sided or bilateral lesions had reduced IQ (median 67). A complete response was achieved by primary chemoradiotherapy in all patients. Three patients who underwent focal or whole-ventricle irradiation experienced recurrence, whereas no recurrence was observed in patients who received whole-brain irradiation (WBI). Concerning the neurocognitive outcomes, three and six patients with unilateral right and left lesions were living self-independently (Karnofsky Performance Status [KPS] ≧ 70), whereas the three remaining patients (one with left and two with bilateral lesions) had a dependent status (KPS <70)., Conclusions: WBI is crucial for disease control in BG germinoma. Furthermore, lesion laterality might affect neuropsychologic symptoms including IQ at diagnosis and neurocognitive outcomes in BG germinoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

A 68-year-old Japanese man developed a fever, headache, hiccups, and altered consciousness. Brain magnetic resonance imaging revealed a hemorrhagic lesion in the right temporal lobe and multiple high-intensity white matter lesions. A brain biopsy showed pathological findings consistent with acute disseminated encephalomyelitis (ADEM), suggesting a diagnosis of acute hemorrhagic leukoencephalitis (AHLE), an aggressive ADEM variant. The patient also developed myodesopsia and was diagnosed with retinal vasculitis, likely due to a hyperimmune state caused by AHLE. Corticosteroids enabled full recovery. Although AHLE is uncommon in elderly individuals, clinicians should be aware of its occurrence in this patient subgroup and recognize potential retinal manifestations associated with AHLE.

Late gadolinium enhancement (LGE) is a widely used magnetic resonance imaging method for assessing cardiac disease. However, the relationship between different LGE signal thresholds and microscopic tissue staining images is unclear. In this study, we performed cardiovascular MRI on myocardial infarction (MI) model rats and evaluated the relationship between LGE with different signal thresholding methods and tissue staining images. We prepared 16 rats that underwent MRI 14-18 days following a surgery to create an MI model. We captured cine and LGE images of the cardiac short-axis and longitudinal two- and four-chamber views. The mean ± 2SD, ± 3SD, and ± 5SD of the pixel values in the non-infarcted area were defined as the LGE area. We compared areas of Sirius red staining, determined by the color tone, with their respective LGE areas at end-diastole and end-systole. We observed that the LGE area calculated as the mean ± 2SD of the non-infarcted area at end-diastole demonstrated a significant positive correlation with the area of Sirius red staining (Pearson's correlation coefficient in both: 0.81 [p < 0.01]). Therefore, the LGE area calculated as the mean ± 2SD of the non-infarcted area at end-diastole best reflected the MI area in tissue staining., (© 2024. The Author(s).)

Background: With the recent advent of genetic testing, IDH-mutant glioma has been found among adult brainstem gliomas. However, the clinical outcome and prognosis of IDH-mutant brainstem gliomas in adults have not been elucidated. This study aimed to investigate the clinical outcome, radiological findings, and genetic features of adult patients with IDH-mutant diffuse brainstem gliomas., Methods: Data from adult patients with brainstem glioma at Hokkaido University Hospital between 2006 and 2022 were retrospectively analyzed. Patient characteristics, treatment methods, genetic features, and prognosis were evaluated., Results: Of 12 patients with brainstem glioma with proven histopathology, 4 were identified with IDH mutation. All patients underwent local radiotherapy with 54 Gray in 27 fractions combined with chemotherapy with temozolomide. Three patients had IDH1 R132H mutation and one had IDH2 R172G mutation. The median progression-free survival and overall survival were 68.4 months and 85.2 months, respectively, longer than that for IDH-wildtype gliomas (5.6 months and 12.0 months, respectively). At the time of initial onset, contrast-enhanced lesions were observed in two of the four cases in magnetic resonance imaging., Conclusion: As some adult brainstem gliomas have IDH mutations, and a clearly different prognosis from those with IDH-wildtype, biopsies are proactively considered to confirm the genotype., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Purpose: Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using fluorine-18-fluoromisonidazole ( 18 F-FMISO) and fluorine-18-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) could depict the degree of glucose metabolism with hypoxic condition. However, molecular mechanism of glucose metabolism under hypoxia in glioblastoma has been unclear. The aim of this study was to identify the key molecules of hypoxic glucose metabolism., Methods: Using surgically obtained specimens, gene expressions associated with glucose metabolism were analyzed in patients with glioblastoma ( n = 33) who underwent preoperative 18 F-FMISO and 18 F-FDG PET to identify affected molecules according to hypoxic condition. Tumor in vivo metabolic activities were semiquantitatively evaluated by lesion-normal tissue ratio (LNR). Protein expression was confirmed by immunofluorescence staining. To evaluate prognostic value, relationship between gene expression and overall survival was explored in another independent nonoverlapping clinical cohort ( n = 17) and validated by The Cancer Genome Atlas (TCGA) database ( n = 167)., Results: Among the genes involving glucose metabolic pathway, mRNA expression of glucose-6-phosphatase 3 ( G6PC3 ) correlated with 18 F-FDG LNR ( P = 0.03). In addition, G6PC3 mRNA expression in 18 F-FMISO high-accumulated glioblastomas was significantly higher than that in 18 F-FMISO low-accumulated glioblastomas ( P < 0.01). Protein expression of G6PC3 was consistent with mRNA expression, which was confirmed by immunofluorescence analysis. These findings indicated that the G6PC3 expression might be facilitated by hypoxic condition in glioblastomas. Next, we investigated the clinical relevance of G6PC3 in terms of prognosis. Among the glioblastoma patients who received gross total resection, mRNA expressions of G6PC3 in the patients with poor prognosis (less than 1-year survival) were significantly higher than that in the patients who survive more than 3 years. Moreover, high mRNA expression of G6PC3 was associated with poor overall survival in glioblastoma, as validated by TCGA database., Conclusion: G6PC3 was affluently expressed in glioblastoma tissues with coincidentally high 18 F-FDG and 18 F-FMISO accumulation. Further, it might work as a prognostic biomarker of glioblastoma. Therefore, G6PC3 is a potential key molecule of glucose metabolism under hypoxia in glioblastoma., Competing Interests: The authors have no relevant financial or nonfinancial interests to disclose., (Copyright © 2024 Michinari Okamoto et al.)

Objective: CD44 is a major cell surface receptor involved in cell adhesion and migration. The overexpression of CD44 is a poor prognostic factor in many neoplasms, including meningiomas. The aim of this study was to investigate the association between CD44 gene expression and clinical signatures of primary meningiomas., Methods: CD44 gene expression was quantitatively evaluated by snap freezing tumor tissues obtained from 106 patients with primary meningioma. The relationships between CD44 expression and clinical signatures of meningiomas, including histological malignancy, tumor volume, and peritumoral brain edema (PTBE), were analyzed. PTBE was assessed using the Steinhoff classification (SC) system (from SC 0 to SC III)., Results: CD44 gene expression in WHO grade 2 and 3 meningiomas was significantly higher than that in grade 1 meningiomas. In addition, CD44 expression increased with the severity of PTBE. Particularly, among the grade 1 meningiomas or small-sized tumors (maximum tumor diameter < 43 mm), CD44 expression in tumors with severe PTBE (SC II or III) was significantly higher than that in tumors without or with mild PTBE (SC 0 or I). Multivariate logistic regression analysis also revealed that overexpression of CD44 was an independent significant factor of severe PTBE development in primary meningiomas., Conclusions: In addition to tumor cell aggressiveness, CD44 expression promotes the development of PTBE in meningioma. Since PTBE is a strong factor of tumor-related epilepsy or cognitive dysfunction in patients with meningioma, CD44 is thus a potential therapeutic target in meningioma with PTBE.

Background: There is a paucity of literature regarding the clinical characteristics and management of subependymomas of the fourth ventricle due to their rarity. Here, we describe the operative and non-operative management and outcomes of patients with such tumors., Methods: This retrospective single-institution case series was gathered after Institutional Review Board (IRB) approval. Patients diagnosed with a subependymoma of the fourth ventricle between 1993 and 2021 were identified. Clinical, radiology and pathology reports along with magnetic resonance imaging (MRI) images were reviewed., Results: Patients identified (n = 20), showed a male predominance (n = 14). They underwent surgery (n = 9) with resection and histopathological confirmation of subependymoma or were followed with imaging surveillance (n = 11). The median age at diagnosis was 51.5 years. Median tumor volume for the operative cohort was 8.64 cm 3 and median length of follow-up was 65.8 months. Median tumor volume for the non-operative cohort was 0.96 cm 3 and median length of follow-up was 78 months. No tumor recurrence post-resection was noted in the operative group, and no tumor growth from baseline was noted in the non-operative group. Most patients (89 %) in the operative group had symptoms at diagnosis, all of which improved post-resection. No patients were symptomatic in the non-operative group., Conclusions: Surgical resection is safe and is associated with alleviation of presenting symptoms in patients with large tumors. Observation and routine surveillance are warranted for smaller, asymptomatic tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction/aims: Most patients with myasthenia gravis (MG) develop ocular manifestations during their illness and up to 22% may have isolated ocular myasthenia gravis (OMG). Apraclonidine elevates the eyelid by activating alpha-2 receptors on Muller's muscle, an accessory eyelid elevator muscle. In this study we evaluate the effect of apraclonidine in alleviating ptosis secondary to MG., Methods: This clinical trial (NCT05045248) was done at the American University of Beirut Medical Center. Patients with ptosis secondary to MG were administered two drops of apraclonidine 0.5% solution to the most affected eye. We measured palpebral fissure height (PF), marginal reflex distance-1 (MRD1), marginal reflex distance-2 (MRD2), and levator function (LF) before drug administration and at 1, 5, 30, and 60 minutes after administration., Results: Ten participants were enrolled in the study. Improvement in all eyelid measurements was noted in all participants as early as 1 minute after apraclonidine administration. From baseline to 60 minutes after administration, average PF increased from 8.8 ± 1.9 mm to 14.2 ± 2.6 mm, MRD-1 from 1.7 ± 1.4 mm to 5.4 ± 2.9 mm, MRD-2 from 7.1 ± 1.3 mm to 8.8 ± 1.7 mm, and LF from 13.4 ± 2.9 mm to 17.5 ± 2.4 mm. All increases were statistically significant., Discussion: Apraclonidine may alleviate ptosis secondary to MG and may be an effective alternative treatment for this group of patients., (© 2023 Wiley Periodicals LLC.)

Purpose: This study aimed to investigate the ability of creatine-chemical exchange saturation transfer (Cr-CEST) technique assessed through 7-T MRI to evaluate cisplatin-induced testicular damage., Methods: We used 8-10 weeks C57BL/6 mice (n = 10) that were divided into a control group (n = 5) and a cisplatin-treated group (n = 5). The cisplatin group received cisplatin at a dose of 15 mg/kg, via intraperitoneal injection, while the control group received saline. MR images of mouse testes were acquired under anesthesia 18 days after the injection using a horizontal 7-T scanner. The pulse sequence consisted of rapid acquisition with a relaxation enhancement (RARE) with magnetization transfer. The Z-spectra were collected using a 2000-ms saturation pulse at a B 1 amplitude of 1.2 μT, with frequencies varying from -4.8 to +4.8 parts per million (ppm). Maps of magnetization transfer ratio with asymmetric analysis (MTR asym ) were reconstructed at a Cr metabolite concentration of 1.8 ppm., Results: The Cr-CEST effect was significantly reduced in the cisplatin-treated group compared to the control group (MTR asym of control mice vs. cisplatin-treated mice: 6.9 [6-7.5] vs. 5.2 [4-5.5], P = 0.008). Correlation analysis revealed a strong correlation between the Cr-CEST effect and the pathological score (ρ = 0.93, P < 0.001)., Conclusion: Cr-CEST MRI can be useful for the evaluation of cisplatin-induced testicular damage in mice.

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARP)i are emerging as standard oncology treatments in various tumor types. The indications will expand as PARPi are being investigated in various breast cancer subtypes. Currently, except for BRCA1/2 mutation carriers with human epidermal growth factor receptor 2 (HER2)-negative breast cancer, there is inadequate identification of predictive biomarkers of response. We present a 57-year-old woman with metastatic breast cancer, hormone-receptor-positive, HER2 negative with a germline ataxia-telangiectasia mutation with a large brain metastasis with clinical benefit to talazoparib. This case report exemplifies the importance of the multidisciplinary management of patients with brain metastases and personalized biomarker selected treatment., Competing Interests: Conflict of Interest: None.

This study aimed to evaluate an intracerebral hemorrhage (ICH) model using quantitative susceptibility mapping (QSM) and chemical exchange saturation transfer (CEST) with preclinical 7T-magnetic resonance imaging (MRI) and determine the potential of amide proton transfer-CEST (APT-CEST) for use as a biomarker for the early detection of ICH. Six Wistar male rats underwent MRI, and another six underwent histopathological examinations on postoperative days 0, 3, and 7. The ICH model was created by injecting bacterial collagenase into the right hemisphere of the brain. QSM and APT-CEST MRI were performed using horizontal 7T-MRI. Histological studies were performed to observe ICH and detect iron deposition at the ICH site. T 2 -weighted images (T 2 WI) revealed signal changes associated with hemoglobin degeneration in red blood cells, indicating acute-phase hemorrhage on day 0, late-subacute-phase hemorrhage on day 3, and chronic-phase hemorrhage on day 7. The susceptibility alterations in each phase were detected using QSM. QSM and Berlin blue staining revealed hemosiderin deposition in the chronic phase. APT-CEST revealed high magnetization transfer ratios in the acute phase. Abundant mobile proteins and peptides were observed in early ICH, which were subsequently diluted. APT-CEST imaging may be a reliable noninvasive biomarker for the early diagnosis of ICH.

Introduction: The Emergency Medicine Education and Research by Global Experts (EMERGE) network was formed to generate and translate evidence to improve global emergency care. We share the challenges faced and lessons learned in establishing a global research network., Methods: We describe the challenges encountered when EMERGE proposed the development of a global emergency department (ED) visit registry. The proposed registry was to be a six-month, retrospective, deidentified, minimal dataset of routinely collected variables, such as patient demographics, diagnosis, and disposition., Results: Obtaining reliable, accurate, and pertinent data from participating EDs is challenging in a global context. Barriers experienced ranged from variable taxonomies, need for language translation, varying site processes for curation and transfer of deidentified data, navigating institution- and country-specific data protection regulations, and substantial variation in each participating institution's research infrastructure including training in research-related activities. We have overcome many of these challenges by creating detailed data-sharing agreements with bilateral regulatory oversight agreements between EMERGE and participating EDs, developing relationships with and training health informaticians at each site to ensure secure transfer of deidentified data, and formalizing an electronic transfer process ensuring data privacy., Conclusion: We believe that networks like EMERGE are integral to providing the necessary platforms for education, training, and research collaborations for emergency care. We identified substantial challenges in data sharing and variation in local sites' research infrastructure and propose potential approaches to address these challenges.

Glioblastoma is the most common and aggressive primary malignant brain tumour. The prognosis of patients with glioblastoma is poor, and their overall survival averages at 1 year, despite advances made in cancer therapy. The emergence of immunotherapy, a strategy that targets the natural mechanisms of immune evasion by cancerous cells, has revolutionised the treatment of melanoma, lung cancer and other solid tumours; however, immunotherapy failed to improve the prognosis of patients with glioblastoma. This is attributed to the fact that glioblastoma is endowed with numerous mechanisms of resistance that include the intrinsic resistance, which refers to the location of the tumour within the brain and the nature of the blood-brain barrier, as well as the adaptive and acquired resistance that result from the tumour heterogeneity and its immunosuppressive microenvironment. Glioblastoma is notorious for its inter and intratumoral heterogeneity, which, coupled with its spatial and temporal evolution, limits its immunogenicity. In addition, the tumour microenvironment is enriched with immunosuppressive cells and molecules that hinder the reactivity of cytotoxic immune cells and the success of immunotherapies. In this article, we review the mechanisms of resistance of glioblastoma to immunotherapy and discuss treatment strategies to overcome them worthy of further exploration., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Purpose: Recent advances in machine learning have enabled image-based prediction of local tissue pathology in gliomas, but the clinical usefulness of these predictions is unknown. We aimed to evaluate the prognostic ability of imaging-based estimates of cellular density for patients with gliomas, with comparison to the gold standard reference of World Health Organization grading., Materials and Methods: Data from 1181 (207 grade II, 246 grade III, 728 grade IV) previously untreated patients with gliomas from a single institution were analyzed. A pretrained random forest model estimated voxelwise tumor cellularity using MR imaging data. Maximum cellular density was correlated with the World Health Organization grade and actual survival, correcting for covariates of age and performance status., Results: A maximum estimated cellular density of >7681 nuclei/mm 2 was associated with a worse prognosis and a univariate hazard ratio of 4.21 ( P  < .001); the multivariate hazard ratio after adjusting for covariates of age and performance status was 2.91 ( P  < .001). The concordance index between maximum cellular density (adjusted for covariates) and survival was 0.734. The hazard ratio for a high World Health Organization grade (IV) was 7.57 univariate ( P  < .001) and 5.25 multivariate ( P  < .001). The concordance index for World Health Organization grading (adjusted for covariates) was 0.761. The maximum cellular density was an independent predictor of overall survival, and a Cox model using World Health Organization grade, maximum cellular density, age, and Karnofsky performance status had a higher concordance (C = 0.764; range 0.748-0.781) than the component predictors., Conclusions: Image-based estimation of glioma cellularity is a promising biomarker for predicting survival, approaching the prognostic power of World Health Organization grading, with added values of early availability, low risk, and low cost., (© 2022 by American Journal of Neuroradiology.)

Objective: In patients with intracranial germ cell tumors, residual lesions are sometimes observed after completion of primary chemoradiotherapy. Although salvage resection of these end-of-treatment residual lesions is recommended for patients with nongerminomatous germ cell tumors, the necessity of early salvage resection for those with germinoma is not clear. The aim of this study was to investigate the frequency of residual germinoma lesions after primary chemoradiotherapy, as well as their management, long-term consequences, and prognosis., Methods: The authors retrospectively reviewed patients who were primarily treated for germinoma between 2002 and 2021. Residual lesions were evaluated with MRI with and without contrast enhancement within 2 weeks after chemoradiotherapy. The decision to perform salvage resection of residual lesions was at the discretion of the treating physicians. The change in appearance of residual lesions was assessed with serial MRI. Overall survival (OS), progression-free survival (PFS), and recurrence pattern were also investigated., Results: Sixty-nine patients were treated with chemoradiotherapy for germinoma, with a mean follow-up period of 108 months. Residual lesions were radiologically observed in 30 patients (43.5%). Among these, 5 patients (3 with pineal lesions and 2 with basal ganglia lesions) underwent salvage resection. Pathological examination revealed teratomatous components in 3 patients, whereas no tumoral components were identified in 2 patients. One patient with a basal ganglia lesion showed worsening of hemiparesis postoperatively. The remaining 25 patients received watchful observation without surgical intervention. Chronological periodic radiological change in residual lesions was evaluated in 21 patients. One year after primary treatment, the size of the residual lesions was stable and had decreased in 10 and 11 patients, respectively. None of the lesions increased in size. The 10-year PFS and OS rates were 96.7% and 97.3% in patients without residual lesions (n = 39), and 87.1% and 100% in patients with residual lesions (n = 30), respectively. Presence of residual lesions had no significant effect on PFS or OS. All recurrences occurred at distant sites or via dissemination without progression of the primary tumor site, regardless of the presence of residual lesion., Conclusions: End-of-treatment residual lesions are not rare in patients with germinoma, and these residual lesions seldom show progression. Because of the potential risk of surgical complications, the indication for early salvage surgery for residual lesions should be carefully determined. Watchful observation is recommended for the majority of these cases.

Purpose: Subependymomas located within the 4th ventricle are rare, and the literature describing imaging characteristics is sparse. Here, we describe the clinical and radiological characteristics of 29 patients with 4th ventricle subependymoma., Methods: This is a retrospective multi-center study performed after Institutional Review Board (IRB) approval. Patients diagnosed with suspected 4th ventricle subependymoma were identified. A review of clinical, radiology, and pathology reports along with magnetic resonance imaging (MRI) images was performed., Results: Twenty-nine patients, including 6 females, were identified. Eighteen patients underwent surgery with histopathological confirmation of subependymoma. The median age at diagnosis was 52 years. Median tumor volume for the operative cohort was 9.87 cm 3 , while for the non-operative cohort, it was 0.96 cm 3 . Thirteen patients in the operative group exhibited symptoms at diagnosis. For the total cohort, the majority of subependymomas (n = 22) were isointense on T1, hyperintense (n = 22) on T2, and enhanced (n = 24). All tumors were located just below the body of the 4th ventricle, terminating near the level of the obex. Fourteen cases demonstrated extension of tumor into foramen of Magendie or Luschka., Conclusion: To the best of our knowledge, this is the largest collection of 4th ventricular subependymomas with imaging findings reported to date. All patients in this cohort had tumors originating between the bottom of the body of the 4th ventricle and the obex. This uniform and specific site of origin aids with imaging diagnosis and may infer possible theories of origin., (© 2022. The Author(s).)

Pelizaeus−Merzbacher disease (PMD) is an X-linked recessive disorder of the central nervous system. We performed 7 Tesla magnetic resonance imaging of the brain in Tama rats, a rodent PMD model, and control rats, as well as evaluated the diagnostic values. In the white matter of the Tama rats, the T2 values were prolonged, which is similar to that observed in patients with PMD (60.7 ± 1.8 ms vs. 51.6 ± 1.3 ms, p < 0.0001). The apparent diffusion coefficient values in the white matter of the Tama rats were higher than those of the control rats (0.68 ± 0.03 × 10−3 mm2/s vs. 0.64 ± 0.03 × 10−3 mm2/s, p < 0.05). In proton magnetic resonance spectroscopy, the N-acetylaspartate (6.97 ± 0.12 mM vs. 5.98 ± 0.25 mM, p < 0.01) and N-acetylaspartate + N-acetylaspartylglutamate values of the Tama rats were higher (8.22 ± 0.17 mM vs. 7.14 ± 0.35 mM, p < 0.01) than those of the control rats. The glycerophosphocholine + phosphocholine values of the Tama rats were lower than those of the control rats (1.04 ± 0.09 mM vs. 1.45 ± 0.04 mM, p < 0.001). By using Luxol fast blue staining, we confirmed dysmyelination in the Tama rats. These results are similar to those of patients with PMD and other PMD animal models.

This case report describes a fatal outcome due to delayed perforation after cold snare polypectomy in a patient with bullous pemphigoid receiving oral corticosteroids. Cold snare polypectomy has become the standard treatment for small colorectal polyps because of the procedure's safety and simplicity. In this case, however, corticosteroid therapy and vasculitis may have caused local necrosis and tearing of the intestinal wall. Corticosteroids are widely used, and perforation after cold snare polypectomy is extremely rare. However, some patients on corticosteroid therapy may have special pathologies, such as in this case, and we advise physicians to use appropriate judgment and extreme caution in determining the indication for endoscopic therapy., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: Virtual reality surgical simulators provide detailed psychomotor performance data, allowing qualitative and quantitative assessment of hand function. The nondominant hand plays an essential role in neurosurgery in exposing the operative area, assisting the dominant hand to optimize task execution, and hemostasis. Outlining expert-level nondominant hand skills may be critical to understand surgical expertise and aid learner training., Objective: To (1) provide validity for the simulated bimanual subpial tumor resection task and (2) to use this simulation in qualitative and quantitative evaluation of nondominant hand skills for bipolar forceps utilization., Methods: In this case series study, 45 right-handed participants performed a simulated subpial tumor resection using simulated bipolar forceps in the nondominant hand for assisting the surgery and hemostasis. A 10-item questionnaire was used to assess task validity. The nondominant hand skills across 4 expertise levels (neurosurgeons, senior trainees, junior trainees, and medical students) were analyzed by 2 visual models and performance metrics., Results: Neurosurgeon median (range) overall satisfaction with the simulated scenario was 4.0/5.0 (2.0-5.0). The visual models demonstrated a decrease in high force application areas on pial surface with increased expertise level. Bipolar-pia mater interactions were more focused around the tumoral region for neurosurgeons and senior trainees. These groups spent more time using the bipolar while interacting with pia. All groups spent significantly higher time in the left upper pial quadrant than other quadrants., Conclusion: This work introduces new approaches for the evaluation of nondominant hand skills which may help surgical trainees by providing both qualitative and quantitative feedback., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

The aim of this study was to analyze the clinical and radiological characteristics of glioblastomas (GBMs) harboring a BRAF mutation. Sequencing analysis of BRAF, IDH1/2, and TERT promoters was performed on GBM samples of patients older than 15 years. The clinical, pathological, and radiological data of patients were retrospectively reviewed. Patients were classified into three groups according to their BRAF and IDH1/2 status: BRAF group, IDH group, and BRAF/IDH-wild-type (WT) group. Among 179 GBM cases, we identified nine cases with a BRAF mutation and nine with IDH mutation. The WT group had 161 cases. Age at onset in the BRAF group was significantly lower compared to the WT group and was similar to the IDH group. In cases with negative IDH1-R132H staining and age < 55 years, 15.2% were BRAF-mutant cases. Similar to the IDH group, overall survival of the BRAF group was significantly longer compared with the WT group. Among nine cases in the BRAF group, three cases had hemorrhagic onset and prior lesions were observed in two cases. In conclusion, age < 55 years, being IDH1-R132H negative, with hemorrhagic onset or the presence of prior lesions are factors that signal recommendation of BRAF analysis for adult GBM patients., (© 2022. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

Aim: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. Patients & methods: In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. Results: In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T 1/2 was 2-3 h with a dose dependent increase in the C max . Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. Conclusion: Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.

The diagnosis of mosaicism is challenging in patients with neurofibromatosis type 2 (NF2) subset due to low variant allele frequency. In this study, we generated induced pluripotent stem cells (iPSCs) were generated from a patient clinically diagnosed with NF2 based on multiple schwannomas, including bilateral vestibular schwannomas and meningiomas. Genetic analysis of the patient's mononuclear cells (MNCs) from peripheral blood failed to detect NF2 alteration but successfully found p.Q65X (c.193C>T) mutation in all separate tumors with three intracranial meningiomas and one intraorbital schwannoma, and confirming mosaicism diagnosis in NF2 alteration using deep sequencing. Five different clones with patient-derived iPSCs were established from MNCs in peripheral blood, which showed sufficient expression of pluripotent markers. Genetic analysis showed that one of five generated iPSC lines from MNCs had the same p.Q65X mutation as that found in NF2. There was no significant difference in the expression of genes related to NF2 between iPSC clones with the wild-type and mutant NF2. In this case, clonal expansion of mononuclear bone marrow-derived stem cells recapitulated mosaicism's genetic alteration in NF2. Patient-derived iPSCs from mosaic NF2 would contribute to further functional research of NF2 alteration., (© 2022 Wiley Periodicals LLC.)

Purpose: We measured the T 1rho and T 2 values the liver of acute liver inflammation model mice administered carbon tetrachloride (CCl 4 ) after 3 days and 6 days after dispensed, and we compared and examined whether each relaxation time can be used for detect acute liver inflammation., Methods: To create an acute liver inflammation model, a mixture of 0.2 ml / 100 g of CCl 4 with an equal amount of Sesame Oil was administered once intraperitoneally to C57BL / 6JJmsSlc mice (n = 15). On the 3 days and 6 days after administration, we acquired T 1rho mapping images and T 2 mapping images of the liver under respiratory synchronization using for preclinical 7T-MRI, and we measured T 1rho and T 2 values and compared statistically., Results: The liver T 1rho value of control mice was 33.9 ± 2.5 ms before CCl 4 administration, 43.2 ± 4.9 ms (p < 0.01) on the 3 days post CCl 4 injection, and 41.0 ± 1.2 ms (p < 0.001) on the 6 days post CCl 4 injection. The rate showed a significant increase of 27% on the 3 days after, as well as significant increase of 21% on the 6 days after. On the other hand, the liver T 2 value of control mice was 26.7 ± 1.9 ms before CCl 4 administration, 31.5 ± 3.4 ms (p < 0.05) 3 days post CCl 4 injection, and 29.0 ± 2.0 ms (p = 0.06) 6 days post CCl 4 injection. The rate 3 days after CCl 4 administration showed a significant increase of 18%, after 6 days rate increased 9%, but no significant difference was confirmed compared with normal mice., Conclusions: The T 1rho value changed significantly compared to the T 2 value, and a continuous change was observed even after 6 days. T 1rho mapping can diagnose acute liver inflammation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study is to observe a thioacetamide (TAA) administered Hepatic encephalopathy (HE) model rats at three and ten days after TAA administration using liver MRI and brain MR Spectroscopy (MRS) by use of 7T-MRI. Forty-two Wistar rats (control group, n = 14) were intraperitoneally administered at 300 mg/kg (low-dose group, n = 14) or 400 mg/kg (high-dose group, n = 14) doses of TAA for induced of HE. At three days after TAA administration, glutamine (Gln) measured by MRS in high-dose and low-dose TAA groups showed significant increases in comparison to those of the control group (p < 0.05). Other metabolites measured by MRS showed no significant changes. Liver T1ρ and T2 relaxation times significantly increased three days after TAA injection compared to pre-injection. There was a correlation between Gln levels in the brain and the relaxation time of the liver. Furthermore, Gln levels and relaxation time changed depending on the TAA dose. The Gln concentration in the brain increased with the deterioration of liver function, as inferred from the prolonged relaxation time of the liver. The prolonged relaxation time of the liver corresponded with the level of Gln in the brain. Gln concentration for the alterations of brain metabolites and T1ρ relaxation time for the assessment of liver damage are useful markers for inter-organ association analysis in the HE model.