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Mission preparation for lunar exploration using landers has been rapidly increasing, and strong demand should arise toward precise understanding of the electrostatic environment. The lunar surface, which has neither a dense atmosphere nor a global magnetic field, gets charged electrically by the collection of surrounding charged particles of the solar wind or the Earth's magnetosphere. As a result of the charging processes, the surface regolith particles behave as "charged dust grains". Dust particles have been suggested to have adverse effects on exploration instruments and living organisms during the lunar landing missions, and their safety evaluation is an issue to be solved for the realization of sustainable manned lunar explorations. It is necessary to develop comprehensive and organized understanding of lunar charging phenomena and the electrodynamic characteristics of charged dust particles.It is widely accepted that the surface potential of the lunar dayside is, "on average" several to 10 V positive due to photoelectron emission in addition to the solar wind plasma precipitation. Recent studies, however, have shown that insulating and rugged surfaces of the Moon tend to make positive and negative charges separated and irregularly distributed, and intense and structured electric fields can be formed around them. This strong electric field lies in the innermost part of the photoelectron sheath and may contribute to mobilizations of the charged dust particles. Since this strong electric field develops on a spatial scale of less than the Debye length and can take various states depending on the lunar surface geometry, it is necessary to update the research approach. In this paper, we will discuss the direction of the near-surface plasma, electrostatic, and dust environment for upcoming lunar landing missions.

Supplementary Data from HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma

Supplementary Figure from HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma

Supplementary document

Supplementary Table 1 Primers used for PCR amplification and sequencing Supplementary Table 2 Results of Multiplex PCR based MGH SNAPShot assay, Pyrosequencing and Sanger sequencing in YMG6 patient and xenograft cells Supplementary Table 3 Analysis of microsatellite instability in YMG6 parent and xenograft tumors Supplementary Table 4 Quantitative analysis for MGMT methylation status in YMG6 cells Supplementary Table 5 Multiplex PCR based MGH SnaPShot assay for oligodendroglial tumors Supplementary Table 6 Correlation of xenograft lethality and phosphorylation of PI3K pathway protein Supplementary Table 7 Phosphorylation in PI3K pathway in oligodendroglioma xenograft model Supplementary Table 8 Clinical characteristics in oligodendroglial tumor patients

Supplementary Figure S1-S7

Supplementary Figure 1. A, Hematoxylin and eosin, Ki-67, and IDH1R132H staining in each specimen. B, Sanger sequencing, immunohistochemical analysis, pyrosequencing, and FISH to identify YMG6 tumors as oligodendroglial tumors. C, Multiplex Ligation-dependent Probe Amplification assay demonstrating chromosome 1p and 19q co-deletion in YMG6R3F (left) and YMG6R3T (right). Bars, 50 �m. Supplementary Figure 2. A, DNA fingerprinting showing matched DNA identification in YMG6R3F (upper), YMG6R3T (middle), and YMG6R3T xenograft (YMG6R3Tsc1, lower). Supplementary Figure 3. Sanger sequencing indicating MSH6Ala1293Ser (left, arrow) and STK11Pro281Leu (right, arrow) in YMG6I. B, Immunohistochemical analysis demonstrating MSH6 expression in YMG6I (left) and YMG6R4T (right). C, Immunohistochemical analysis demonstrating LKB1/STK11 expression in YMG6I (left) and YMG23 (right, positive control). D, Sanger sequencing indicating MSH6Gly409Glu (arrow) in YMG6R4T. E, F, Upper gastrointestinal endoscopy (E) and colonoscopy (F) demonstrating no abnormal lesion in YMG6 patient. G, FDG-PET indicating no abnormal uptake in YMG6 patient. Bars, 50 �m. Supplementary Figure 4. Microsatellite instability (MSI)-PCR indicating microsatellite stable (MSS) in YMG6R2 and YMG6R3T. MSI-H, microsatellite instability high. MSS, microsatellite stable. Supplementary Figure 5. Immunohistochemical analysis demonstrating ATRX expression and weak expression of p53 in YMG6R3T. Supplementary Figure 6. Pyrosequencing indicating PIK3CAE542K (arrows) in YMG6I and YMG6R3T. B, Immunohistochemical analysis demonstrating phospho-AKT, -4EBP1, and -S6K expression in YMG6I and YMG6R1. Supplementary Figure 7. A, Multiplex Ligation-dependent Probe Amplification assay indicating 1p and 19q co-deletion in YMG6R3Tsc1. B, Sanger sequencing showing mutation in IDH1 (arrow; c.395G>A, left) and TERT (arrow; c.-124C>T, right) of YMG6R4Tsc1. Supplementary Figure 8. A, Overview and microscopic view of hematoxylin and eosin (H&E, upper), Ki-67 (middle) and IDH1R132H (lower) in first (YMG6R3Tsc1, left), second (YMG6R3Tsc2, middle), and third (YMG6R3Tsc3, right) generation YMG6R3T xenograft. B, H&E (upper), Ki-67 (middle), and IDH1R132H (lower) in YMG6R4Tsc1 (left), YMG6R4Tsc2 (middle), and YMG6R4Tsc3 (right). C, Sanger sequencing showing mutation of IDH1 (arrows, c.395G>A, left) and TERT (arrows, c.-124C>T, right), and PIK3CA (arrows, c.1624G>A) in YMG6R3Tsc2 (upper), YMG6R4Tsc2 (middle), and YMG6R4Tsc3 (lower). D, Immunohistochemical analysis demonstrating strong expression of phospho-AKT (Ser473, left), phospho-4EBP1 (middle), and phospho-S6K (right) in YMG6R4Tsc3. Bars, 50 �m. Supplementary Figure 9. A, Upper, Sanger sequencing showing IDH1 mutation (arrow, c.395 G>A), TERT (arrow, c.-124C>T), and PIK3CA (arrow, c.3140A>G) in YMG23. Lower, MLPA demonstrating chromosome 1p/19q co-deletion and CDKN2A (chr.9p.21) loss in YMG23 patient tumor. B, Immunohistochemical analysis demonstrating negative expression of p16INK4a/CDKN2A in YMG23 (upper). YMG5 (CDKN2A intact) served as positive control. C, Sanger sequencing showing mutations of IDH1 (arrow, c.395G>A, R132H, left) and TERT (arrow, c.-124C>T) in YMG5. D, Sanger sequencing showing mutations of IDH1 (arrow, c.395G>A), TERT (arrow, c.-124C>T), and PIK3CA (arrow, c.3140A>G) in YMG23sc1. E, MLPA demonstrating chromosome 1p/19q co-deletion and CDKN2A loss (chr.9p.21) in YMG23sc1. F, immunohistochemical analysis demonstrating negative expression of p16INK4a/CDKN2A in YMG23sc1. Bars, 50 �m. Supplementary Figure 10. A, B, C, Sanger sequencing showing IDH1 mutation (arrows, c.395G>A, R132H, left) and TERT promoter mutation (c.-124C>T, C228T or c.-146C>T, C250T), and in YMG46 (A), YMG28 (B) and YMG53 (C). PIK3CA mutation (c.1406A>G, E542G, arrow, A, right) in YMG46. D, Contrast enhancing MRI showing non-enhanced tumor recurrence at right frontal lobe (left). H&E (upper) and IDH1R132H staining (lower) in YMG53 (AOD, middle). Overview of H&E staining indicating no xenograft formation in YMG53sc1 (right). Bars, 50 �m. Supplementary Figure 11. A, Overview and magnification of hematoxylin and eosin staining of second passaged YMG23 xenograft model (YMG23sc2). B, C, Immunohistochemical analysis demonstrating expression of IDHR132H (B, left), Ki-67 (B, right), phospho-AKT (C, left), phospho-4EBP1 (C, middle), and phospho-S6K (C, right) in YMG23sc2. D, Sanger sequencing showing mutations in IDH1 (arrow, c.395 G>A), TERT (arrow, c.-124C>T), and PIK3CA (arrow, c.3140A>G) in YMG23sc2. Bars, 50 �m. Supplementary Figure 12. (A-D) Contrast enhanced MRI of the indicated patients at pre-treatment (left) and post-chemotherapy with/without radiotherapy (right). Supplementary Figure 13. Kaplan Meier Curve indicating no survival difference (P = 0.9) of overall survival in PIK3CA/PIK3RI- mutant (blue) and -wild-type (red) oligodendroglial tumor patients. Supplementary Figure 14. A, Relative cell viability of YMG28 (left) and YMG46 (right) cells after 3-day treatment with FK866 combined with DMSO control (blue bars) or TMZ (200 �M, purple bars). *, P

Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein–Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease.Significance:A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform.

Purpose:Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E-mutant high-grade gliomas (HGG); however, the therapeutic effect is limited by the emergence of drug resistance.Experimental Design:We established multiple paired BRAFV600E-mutant HGG patient-derived xenograft models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment-resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo.Results:We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the reactivation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E-mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3β (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular targeted therapy.Conclusions:The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E-mutant HGG.

Supplementary Table from HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma

Supplementary Table S1-S12

Purpose:Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression.Experimental Design:Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo.Results:A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1R132H and 1p/19q codeletion) and PIK3CAE542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo—evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma.Conclusions:Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

In the tenuous atmospheric bodies of our solar system, space weathering on the celestial surface is an important process for its chemical and physical evolution and ambient environment on timescales of celestial evolution. Space plasma is a dominant energy and material source for space weathering. Plasma irradiation experiment in the laboratory is an effective method for modeling long-term space weathering driven by space plasma. However, comprehensive modeling of plasma space weathering has not yet been conducted because the capabilities of the earlier facilities were not optimized for long-term space weathering; for example, the machine time and number flux of incident particles. Here, we developed a plasma irradiation system, Plasma Irradiation Emulator for Celestial Environments (PIECE) of the solar system bodies, which reproduces long-term plasma space weathering in tenuous atmospheric bodies by exclusive use. We successfully developed a system with high electron and ion number fluxes of ~1013 − 1016 particles cm-2s-1 at any acceleration energy in the range of 1–30 keV, which leads to the first-ever high fluence of ~1019 − 1022 particles cm-2s-1 with a 10-day irradiation time. This fluence corresponds to a plasma irradiation time of ~104–108 years on Europa.

Background The incidence and risk factors of severe anaphylaxis by intravenous anti‐cancer drugs are unclear, whereas those of milder reactions have been reported. Study Design Electronic medical charts of cancer patients who have undergone intravenous chemotherapy between January 2013 and October 2020 in a university hospital were retrospectively reviewed. Non‐epithelial malignancies were also included in the analysis. "Severe anaphylaxis" was judged using Brown's criteria: typical presentation of anaphylaxis and one or more of hypoxia, shock, and neurologic compromise. (UMIN000042887). Results Among 5584 patients (2964 males [53.1%], 2620 females [46.9%], median age 66 years), 88,200 person‐day anti‐cancer drug administrations were performed intravenously, and 27 severe anaphylaxes were observed. The causative drugs included carboplatin (14 cases), paclitaxel (9 cases), and cisplatin, docetaxel, trastuzumab, and cetuximab (1 case each). The person‐based lifetime incidence of severe anaphylaxis for patients who received at least one intravenous chemotherapy was 0.48% (27/5584, 95% confidence interval (CI) 0.30%–0.67%) and the administration‐based incidence was 0.031% (27/88,200, 95% CI 0.019%–0.043%). Among 124 patients who received at least 10 carboplatin administrations, 10 patients experienced carboplatin‐induced severe anaphylaxis (10/124, 8.1%, 95% CI 3.0%–13.1%). Carboplatin caused severe anaphylaxis after at least 9‐min interval since the drip started. Thirteen out of 14 patients experienced carboplatin‐induced severe anaphylaxis within a 75‐day interval from the previous treatment. Paclitaxel infusion caused severe anaphylaxis after a median of 5 min after the first drip of the day at a life‐long incidence of 0.93% (9/968, 95% CI 0.27%–1.59%). Conclusion We elucidated the high‐risk settings of chemotherapy‐induced severe anaphylaxis., 88,200 person‐days of chemotherapy provided for 5584 patients were reviewed. They induced 27 severe anaphylaxes defined by Brown’s criteria. Most were caused by carboplatin (14 cases) or paclitaxel (9 cases).

Background: Brain metastases with hematoma are clinically important as they indicate the potential for rapid neurological deterioration. Non-uterine leiomyosarcoma-derived brain metastases are particularly rare, and their clinical features, including the bleeding rate, are unclear. Herein, we present a rare case of thigh leiomyosarcoma-derived brain metastasis with intratumoral hematoma and review previous case reports. Case Description: A 68-year-old man with a right thigh leiomyosarcoma presented with multiple brain metastases. The patient received stereotactic radiotherapy; however, he reported sudden right-sided hemiparesis. We found a right frontal irradiated lesion with intratumoral hemorrhage and performed gross total tumor resection. Histopathological examination showed highly atypical cells with prominent necrosis and hemorrhage. Abnormal thin-walled vessels were prominent within the brain tumor, and vascular endothelial growth factor was diffusely expressed immunohistopathologically. To date, 11 cases of brain metastasis from non-uterine leiomyosarcoma, including the present case, have been reported. Of note, six patients had hemorrhage. Three out of six patients presented with hemorrhage before therapeutic intervention, three cases were from residual sites after surgery or radiation. Conclusion: More than half the patients with non-uterine leiomyosarcoma-derived brain metastases presented with intracerebral hemorrhage. Furthermore, these patients are at risk of developing rapid neurological deterioration due to intracerebral hemorrhage.

Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein–Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. Significance: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform.

We demonstrated the existence of a distorted plasma depletion region in a satellite wake through 3-D electrostatic particle-in-cell (PIC) plasma simulations. It is commonly known that a wake is formed in the downstream region of a satellite in a magnetized plasma flow. Our simulation shows that the plasma depletion region in the wake is distorted in the plane perpendicular to the static magnetic field. This distortion is asymmetric with respect to the plasma flow direction in the satellite rest frame of reference. We found that the asymmetric structure of the plasma depletion region is caused by nonuniform local drift motion of electrons around the depletion region. By test particle simulations in which electron trajectories are traced in fixed fields obtained in the PIC simulation, we confirmed that cold electrons that have a Larmor radius less than the size of the satellite can cause the asymmetric structure of the plasma depletion in the wake.

Purpose: Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. Experimental Design: Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo. Results: A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1R132H and 1p/19q codeletion) and PIK3CAE542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo—evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma. Conclusions: Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive, extra-nodal non-Hodgkin lymphoma that is confined to the central nervous system (CNS) and the eyes. Most PCNSLs arise in immunocompetent older patients and less frequently in immunocompromised patients with Epstein-Barr virus infection. Although a patient's initial response to chemotherapy and radiation therapy is favorable, the clinical outcome of PCNSL remains poor compared to that of systemic lymphoma. Radiation-induced neurotoxicity is also a critical problem for patients with PCNSL. Therefore, a novel therapeutic strategy is required to overcome these challenges. Recent studies have largely uncovered the genomic landscape and associated histopathological features of PCNSL. Based on this background, novel therapeutic agents, such as Bruton's tyrosine kinase inhibitors and immune checkpoint inhibitors, have been introduced for patients with PCNSL. Here, we provide an overview of the updated histopathological and genomic characterization of PCNSL and summarize the current therapeutic strategies. We also review current preclinical PCNSL models for translational research.

Partial deletions in chromosomes 1p and 19q are found in a subset of astrocytic tumors; however, it remains unclear how these alterations affect their histological features and prognosis. Herein, we present 3 cases of isocitrate dehydrogenase (IDH)-mutant astrocytoma with chromosome 19q13 deletion. In the first case, the primary tumor harbored an IDH1 mutation with chromosome 1p/19q partial deletions, which covered 19q13 and exhibited a durable initial response to radiotherapy and temozolomide (TMZ) treatment. However, the tumor lost the chromosome 1p/19q partial deletions at recurrence and became resistant to TMZ. Histologically, an oligodendroglioma-like feature was found in the primary tumor but not in the recurrent tumor. Capicua transcriptional repressor (CIC), located on 19q13, was less expressed in the primary tumor but was highly expressed in the recurrent tumor. Similar histological findings were observed in 2 other astrocytic tumors with IDH1 or IDH2 mutations. These tumors also had chromosome 19q13 deletion, including the CIC gene, weakly expressed CIC, and oligodendroglioma-like morphology. These tumors recurred at 6 and 32 months, respectively. These findings suggest that IDH-mutant astrocytoma with chromosome 19q13 partial deletion, including the CIC gene, may induce an oligodendroglioma-like phenotype, but the clinical prognosis may not be similar to that of genetically defined oligodendroglioma.

A surprising and unexpected phenomenon observed during Cassini's Grand Finale was the spacecraft charging to positive potentials in Saturn's ionosphere. Here, the ionospheric plasma was depleted of free electrons with negatively charged ions and dust accumulating up to over 95 % of the negative charge density. To further understand the spacecraft-plasma interaction, we perform a three dimensional Particle-In-Cell study of a model Cassini spacecraft immersed in plasma representative of Saturn's ionosphere. The simulations reveal complex interaction features such as electron wings and a highly structured wake containing spacecraft-scale vortices. The results show how a large negative ion concentration combined with a large negative to positive ion mass ratio is able to drive the spacecraft to the observed positive potentials. Despite the high electron depletions, the electron properties are found as a significant controlling factor for the spacecraft potential together with the magnetic field orientation which induces a potential gradient directed across Cassini's asymmetric body. This study reveals the global spacecraft interaction experienced by Cassini during the Grand Finale and how this is influenced by the unexpected negative ion and dust populations., 16 pages, 7 figures, 1 table, Monthly Notices of the Royal Astronomical Society Main Journal: Accepted 2021 March 8. Received 2021 March 5; in original form 2021 January 22

TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90–100%) were associated with favorable prognosis (p TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio = 0.421, p = 0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio = 0.648, p = 0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.

Spacecraft-plasma interactions are studied with self-consistent numerical simulations of magnetized plasmas, where electrons are strongly magnetized whereas ions are weakly magnetized. It is found that for a spacecraft in such a magnetized plasma corresponding to a low Earth orbit, electrons can be reflected from a negatively charged spacecraft and then guided by geomagnetic field lines. The reflected electrons can leave a sharp trail like wings if the spacecraft size is greater than an average electron gyroradius of the environment. Such an electron wing-like structure is associated with propagating Langmuir waves. This results in nontrivial asymmetric electrostatic potentials close to the spacecraft and even farther than the Debye screening distance. The convective electric field also gives rise to a differential potential of the spacecraft with respect to the plasma, resulting in yet another asymmetry in the plasma dynamics and the potential distribution around the spacecraft. These asymmetries in the plasma dynamics can significantly influence in-situ measurements of space plasma. The results show a good qualitative agreement with actual measurements by a satellite in the polar regions.

We carry out a series of self-consistent electron hybrid code simulations for the dependence of chorus generation process on the temperature anisotropy and density of energetic electrons in the Earth's inner magnetosphere. We use the same magnetic field gradient in the simulation system and different temperature anisotropy AT for the initial distribution of energetic electrons at the magnetic equator. We conduct 6 sets of simulations for different AT from 4 to 9, changing the initial number density N-h of energetic electrons at the equator in each set of simulations. By analyzing the spectra obtained in the simulation results, we identify chorus elements with rising tones in the results for higher Nh but no distinct chorus in smaller Nh. We compare the simulation results with estimations of the threshold and optimum amplitude proposed by the nonlinear wave growth theory. We find that the chorus generation processes reproduced in the simulation results are consistently explained by the theoretical estimates. We also compare the simulation results with linear growth rates for all simulation runs. We find clear disagreement between the spectral characteristics of reproduced chorus and the predictions by the linear theory. The present study clarifies that the spectra of chorus are essentially different from those predicted by the linear theory and are determined fully by nonlinear processes of wave-particle interactions in the chorus generation region.

We report a case of a 24-year-old woman who presented with an uncomfortable feeling in her right foot with a 6-month history of slight weakness in her right hand. Neuroimaging demonstrated irregular shaped lesions in the left thalamus and basal ganglia in addition to spotty lesions in the contralateral thalamus. The MRI showed high-intensity signals on T2-weighted, fluid-attenuated inversion recovery, and diffusion-weighted images. The lesions demonstrated low-intensity signaling on T1-weighted images and were slightly enhanced with gadolinium. Other examinations including positron emission tomography, MR spectroscopy, and laboratory tests did not reveal any specific information regarding the lesions. The biopsied specimens, from the left basal ganglia, revealed proliferation of dysplastic neuronal cells without any neoplastic glial elements; thus, gangliocytoma (WHO grade I) was the most likely diagnosis. The patient was further observed based on this diagnosis of suspicious gangliocytoma, and the follow-up MRI, performed a year after the biopsy, revealed that the disease was stable. To our knowledge, gangliocytoma in the thalamus and basal ganglia have not been reported. Additionally, the findings of the magnetic resonance imaging (MRI) in this case were unique and different from those previously reported in cases of gangliocytoma. The authors report this unique case and discuss the radiological, pathological, and genetic findings.

Introduction: The standard therapy for malignant brain tumors includes surgery and combination therapy with radiation and chemotherapy, but to provide individualized treatment based on the biological and molecular genetic background of the tumor, integrate genetic information with various functional data are required. In this study, we present an overview of our integrated approaches for translational research and clinical management. Methods: In glioma, pre-and intra-operative clinical information, including intraoperative genetic diagnosis, and intraoperative rapid immunohistochemistry is obtained, then a multidisciplinary treatment approach is started based on these integrated data. Specimens collected intraoperatively are cryopreserved for future analysis, and primary cultured cells are routinely collected. The cultured cells are transplanted into the brain of immunodeficient mice to establish patient-derived xenograft model (PDX). Genetic screening, such as IDH, TERT, BRAF, H3F3A mutation and MGMT methylation analysis are routinely assessed within a few days after surgery and used as information for integrated diagnosis. In case of PDX establishment or recurrence, we perform whole exon sequencing or comprehensive genomic assessment to identify genetic abnormalities. If genomic alterations for possible molecular targeted therapy are identified, we assess drug sensitivity test in vitro and in vivo, which are utilized for research to develop optimal molecular targeted therapy. The results, such as the therapeutic effects of molecular targeted drugs, are used for clinical applications. Results: Since the platform was established, we have treated a total of 286 patients, including 189 gliomas and 37 central nervous system lymphomas based on the integrated information. We are currently collecting clinical data to examine if this integrated approach could provide clinical benefit.Conclusion: The translational research system for malignant brain tumors plays an important role in the promotion of clinical and basic research.

The BRAFV600E mutation results in the constitutive activation of downstream mitogen activated protein kinase (MAPK) pathway that promotes tumor growth. Recently, molecular targeted therapy using BRAF/MEK inhibitor has been reported for BRAFV600E mutant high-grade glioma, but the therapeutic effect is limited by the emergence of drug resistance. Herein, we established paired BRAFV600E mutant glioblastoma (GBM) patient-derived xenograft (PDX) models, which were derived from tumors at prior to and recurrence after molecular targeted therapy. These PDX models were found to extensively recapitulate the histology, genetic abnormalities, and even the clinical course of the patients. Furthermore, BRAF/MEK inhibitor gradually caused resistance in cell lines derived from specimens that initially responded to molecular targeted therapy. In this study, genomic and epigenomic changes had little effect on the resistance mechanism. On the other hand, we found that hyperactivation of the MAPK pathway through c-Raf and the AKT/mTOR pathway primarily caused resistance to molecular targeted therapy in BRAFV600E mutant GBM. Through a high throughput drug screening, we find that HSP90 inhibitor with BRAF/MEK inhibitor coordinately deactivates MAPK pathway and AKT/mTOR pathway, and mediates potent toxicity in vitro and in vivo in refractory and acquired resistant models. These findings support that this therapeutic approach can overcome the limitation of current molecular targeted therapy in BRAFV600E mutant GBM.

Central nervous system lymphoma (CNSL), including primary and secondary CNSL, has a poor prognosis despite standard intensive chemotherapy. Since the majority of CNSL tumors are highly dependent on NF-κB signaling pathway for survival, Bruton’s kinase inhibitors, which target upstream in the NF-κB pathway, have demonstrated favorable clinical response in PCNSL patients. However, early recurrence is frequently observed. Therefore, novel therapeutic strategies are required in this progressive CNS disease. To understand the underlying tumor biology and explore a novel therapeutic strategy of CNSL, we previously established a panel of patient-derived xenograft (PDX) models, from both immunocompetent and Epstein-Barr virus (EBV)-positive CNSL patients. We confirmed that these PDX models highly recapitulated the phenotypic and genetic features of patient tumors. Using 19 PDX models, including 17 originally established PDXs, we found that NF-κB pathway related genomic alterations and AKT/mTOR signaling did not correlate with sensitivity to BTK inhibitors. We also found that RelA/p65 dephosphorylation as a biomarker of CNSL cells, which are responding to ibrutinib. Through high-throughput and NF-κB pathway-targeted drug screenings, we discovered that proteasome inhibitors suppressed cell viability across all CNSL models. The therapeutic effect, observed at a lower nanomolar range, was mediated by inhibition of the canonical NF-κB and AKT/mTOR pathways and was reversed by silencing of MYD88/CD79B in immunocompetent CNSL or LMP1 in EBV-positive CNSL. The second-generation proteasome inhibitor marizomib prolonged overall survival in CNSL orthotopic xenograft models through simultaneous suppression of RelA/p65 and AKT/mTOR signaling. Proteasome inhibition deregulated Mcl-1 and mediated caspase-dependent apoptosis, which was further enhanced by Bcl-2 family inhibition. Our results demonstrate the potential of proteasome inhibition as a novel therapeutic strategy in patients with immunocompetent and EBV-positive CNSL.

The double-probe technique, commonly used for electric field measurements in magnetospheric plasmas, is susceptible to environmental perturbations caused by spacecraft–plasma interac- tions. To better model the interactions, we have extended the existing particle-in-cell simu-lation technique so that it accepts very small spacecraft structures, such as thin wire booms, by incorporating an accurate potential field solution calculated based on the boundary element method. This immersed boundary element approach is effective for quantifying the impact of geometrically small, but electrically large spacecraft elements on the formation of sheaths or wakes. The developed model is applied to the wake environment near a Cluster satellite for three distinctive plasma conditions: the solar wind, the tail lobe, and just outside the plasma-pause. The simulations predict the magnitudes and waveforms of wake-derived spurious elec-tric fields, and these are in good agreement with in-situ observations. The results also reveal the detailed structure of potential around the double probes. It shows that any probes hardly experience a negative wake potential in their orbit, and instead, they experience an unbalanced drop rate of a large potential hill that is created by the spacecraft and boom bodies. As a by-product of the simulations, we also found a photoelectron short-circuiting effect that is anal-gous to the well-known short-circuiting effect due to the booms of a double-probe instrument. The effect is sustained by asymmetric photoelectron distributions that cancel out the external electric field.

INTRODUCTION Alkylating agents, including Temozolomide (TMZ) and CCNU (ACNU) have been widely accepted as a standard treatment in malignant gliomas. Several studies also demonstrated that BCNU wafer placement extended survival in glioblastoma patients. However, little study demonstrated gene-specific efficacy of BCNU local therapy in malignant gliomas. Herein, we investigated BCNU sensitivity for patient-derived primary cultured glioma cells. MATERIALS AND METHODS From January 2017 to July 2019, 58 gliomas (grade III, IV) were tested genomic analysis and ATP-based cell viability after BCNU treatment. IDH1/2 mutation and TERT promoter mutation status was determined by Sanger sequencing. MGMT methylation status were evaluated by methylation specific PCR. RESULTS Of 58 cases,10 cases (17.2%) and 32 (55.2%) cases harbored IDH1/2 mutation and TERT mutation (C228T, C250T), respectively. Among them, co-mutation was identified in 5/58 cases (8.6%). MGMT was methylated in 17/58 cases (29.3%). Interestingly, the presence of TERT promoter mutation was positively correlated with BCNU sensitivity, particularly in IDH1/2 wild-type tumors (p CONCLUSION Although sample size is small, our results imply TERT promoter mutations might be a predictive molecular marker for BCNU sensitivity in malignant gliomas. Since TERT mutations are located at two hot spot loci (C228T and C250T), vast majority of TERT promoter mutations can be evaluated during surgery, which may contribute tailored therapeutic strategy in malignant gliomas.

TERT promoter mutation is associated with 1p/19q codeletion and favorable prognosis in IDH-mutated gliomas. Prognostic and diagnostic significance of TERT promoter mutation is well-recognized in IDH-wildtype glioblastomas, but not in IDH-mutated gliomas. We investigated prognostic efficacy of TERT mutation in a cohort of 560 Japanese IDH-mutated adult gliomas. The molecular status of IDH, TERT and 1p/19q and patient clinical data including Karnofsky performance status (KPS) were collected in all cases. TERT mutations and 1p/19q codeletions were found in 303 and 285 cases, respectively. The patient cohort was divided into four groups by a combination of the 1p/19q and TERT status. The characteristics of 1p/19q intact-TERT mutated group (Astro-TERT group, n=24) were compared with those of 1p/19q intact-TERT wild (Astro-group, n=251) or 1p/19q codeleted-TERT mutated (Oligo-group, n=279) cases. Astro-TERT group with any grade showed intermediate overall survival between the Oligo-group and Astro-group although the survival differences were not statistically significant (median overall survival (OS) not reached (NR) versus NR, and 106 months, respectively. p >0.05). We further conducted subgroup analysis by adjusting KPS and WHO grade as Cox regression analysis for survival indicated the unfavorable survival impact of KPS < 90 and WHO grade IV. In the subgroup with favorable KPS (90–100) and grade II-III (n=438), The OS of Astro-TERT group (median NR) was significantly longer survival than that of Astro-group (median 120.2 months, p=0.032), and was comparable with that of the Oligo-group (median NR, p >0.05). On the other hand, OS of none of the molecular groups significantly differ in poorer KPS subgroups (p >0.05). In grade IV tumors, the OS of the Astro-TERT group (NR) was comparable with that of Astro-group (29 months, p=0.19) rather than Oligo-group (NR, p=0.051). Thus, TERT promoter status provides a valuable prognostic information for IDH-mutated grade II-III gliomas in the current molecular diagnostic system.

In this study, we have introduced the Code-to-Code Adapter (CoToCoA) library to couple the magnetohydrodynamic (MHD) simulation and the Electron Hybrid (EH) simulation of planetary magnetospheres. CoToCoA has been developed newly to connect the different codes easily. The concept of CoToCoA is that we do not add modifications to each code as possible without data transfer functions, and we do not need to know the referred code without data format. With CoToCoA, we have been developing the cross-reference simulation of macro (MHD) and micro (EH) scales in the magnetosphere. Then, we have evaluated the performance of cross-reference simulation using CoToCoA on the massively parallel computer system.

BACKGROUND Activation of telomerase plays a critical role in tumor development. Somatic alterations in the promoter of the telomerase reverse transcriptase (TERT) gene are a major mechanism of upregulating telomerase. Several mechanisms have been associated with TERT abnormalities, including TERT promoter mutations or methylation. Mutations in the TERT promoter have been observed in a subset of brain tumors, especially in adult gliomas. In pituitary adenomas (PAs), however, TERT abnormalities are not fully understood. The present study aimed to investigate not only mutational but also methylation status changes in the TERT promoter in PAs and to analyze their correlations with clinical variables. MATERIAL AND METHODS We retrospectively studied 70 PAs consisting of 53 primary and 17 recurrent samples. Clinical data, including age at surgery, sex, tumor size, tumor subtype, resection rate, presence or absence of postoperative irradiation, and progression-free survival (PFS), were obtained from medical records. First, we investigated TERT promoter hotspot mutations via Sanger sequencing. Next, we quantified the methylation status of the TERT promoter using methylation-sensitive high-resolution melting analysis (MS-HRM). Finally, we investigated TERT mRNA expression levels using real-time quantitative PCR. Fisher’s exact test was applied to evaluate the statistical significance between TERT promoter methylation status and tumor recurrence. PFS was calculated using Kaplan-Meier estimates and compared between methylated with ummethylated PAs with the log-rank test. The correlation between TERT promoter methylation status and mRNA levels was analyzed with the Mann-Whitney U-test. PFS was analyzed using multivariate analysis with the Cox proportional hazards model and included the following variables: age, sex, tumor size, tumor subtype, resection rate, radiation therapy, and methylation status. RESULTS TERT promoter hotspot mutations were not observed in any PA sample. Nineteen percent of PAs exhibitedTERT promoter methylation, which was significantly predominant in recurrent PA samples. PFS was significantly shorter in the methylated cases than in the unmethylated cases. Higher TERT expression levels were correlated with methylation status. CONCLUSION We found that TERT promoter methylation upregulated TERT expression and was associated with shorter PFS in PAs. Our results suggest thatTERT promoter methylation may be a potential biomarker for predicting tumor recurrence in PAs.

Effects of booms of a sounding rocket on rocket charging and on the local plasma conditions are studied with numerical and analytical models accounting for flowing, ionospheric plasmas. Simulations are carried out with a first principles self-consistent Particle-In-Cell numerical code. It is shown that the booms can affect the charging of the payload and disturb the local plasma to a high degree. The boom-to-plasma potential, which varies with the position due to the convective electric field, can lead to significantly different currents, in particular electron currents, to the booms on either side of the rocket. The analytical models for the collected currents considered in this study show good agreement with the simulations. The potential difference between the plasma and the rocket can electrostatically focus the ions to create regions of enhanced ion density downstream of the rocket and can lead to an asymmetric wake. It is shown that ion focusing can be asymmetric between the booms due to the potential gradient. These effects can have implications for instrument placements and data analysis.Effects of booms of a sounding rocket on rocket charging and on the local plasma conditions are studied with numerical and analytical models accounting for flowing, ionospheric plasmas. Simulations are carried out with a first principles self-consistent Particle-In-Cell numerical code. It is shown that the booms can affect the charging of the payload and disturb the local plasma to a high degree. The boom-to-plasma potential, which varies with the position due to the convective electric field, can lead to significantly different currents, in particular electron currents, to the booms on either side of the rocket. The analytical models for the collected currents considered in this study show good agreement with the simulations. The potential difference between the plasma and the rocket can electrostatically focus the ions to create regions of enhanced ion density downstream of the rocket and can lead to an asymmetric wake. It is shown that ion focusing can be asymmetric between the booms due to the potenti...

Epithelioid glioblastoma (E-GBM) predominantly arises at younger age and promotes dismal prognosis. Because of its rare etiology, pathological and genetical characterization of E-GBM remains elusive. Herein, we report 2 patient-derived E-GBM xenograft (PDX) models from young adult patients (YMG62 and YMG89) with BRAFV600E and TERT promoter mutation. The YMG62 patient received dabrafenib with trametinib, while YMG89 patient received dabrafenib monotherapy after recurrence with Stupp regimen. These molecular target therapies were initially responded, but gradually became resistant (YMG62R and YMG89R) and resulted in lethal. Treatment resistant cells were collected from CSF. These primary cells were propagated at multiple passage in vitro. Paired PDX models were established from initial and recurrent cells. All PDX tumors were preferentially disseminated and negative expression of GFAP, which were recapitulated to the patient characteristics. BRAF and MEK inhibitor moderately suppressed cell viability of YMG62 and YMG89 in vitro. However, BRAF and MEK inhibitor became resistant at recurrence in vitro. Western blotting indicated retained phospho-MEK expression after BRAF/MEK inhibitor treatment in recurrent cells, which implies crucial role of MEK activation for tumor maintenance in BRAFV600E mutant E-GBM. Together, paired E-GBM PDX models with/without molecular target therapy recapitulate patient characteristics, which may contribute to elucidate tumor biology and establish novel therapeutic target in E-GBM.

Epithelioid glioblastoma (E-GBM) arises at younger age, commonly disseminates to cerebrospinal fluid, and results in dismal prognosis. About half of E-GBM harbors BRAF V600E mutation, thus BRAF/MEK inhibitors are expected to be specifically sensitive to E-GBM like other BRAF V600E mutant carcinomas. However, therapeutic effect is limited by the emergence of drug resistance. To overcome this issue, it is crucial to elucidate the treatment resistance mechanisms by clinically representative models. Herein, we establish 2 paired E-GBM patient-derived xenograft (PDX) models from young adult patients (YMG62 and YMG89) with BRAF V600E, TERT promoter mutations and CDKN2A homozygous deletions. The YMG62 patient received dabrafenib with trametinib, while YMG89 patient received dabrafenib monotherapy after recurrence with standard treatment. The YMG62 patient was refractory to combination therapy. The YMG89 patient was initially responded to dabrafenib, but gradually became resistant and the 2 patients died due to CNS dissemination. Paired PDX models were established from tumors prior and after molecular target therapy. All PDXs were formed as CNS dissemination model, which were recapitulated to the patient characteristics. BRAF/MEK inhibitors strongly suppressed cell viability in primary tumor (YMG89P). However, BRAF/MEK inhibitors became resistant in recurrent tumor (YMG89R). YMG62 paired PDXs were resistant to molecular target therapy. Western blotting indicated retained MAPK signaling pathway and/or increased AKT phosphorylation after BRAF/MEK inhibitors treatment in refractory and recurrent cells, which indicates crucial role of re-activation in the MAPK signaling pathway and/or PI3 kinase pathway for tumor maintenance in BRAF V600E mutant E-GBM. We have done high throughput drug screening to identify compounds to overcome resistant to molecular target therapy. Our established E-GBM paired PDX models recapitulate patient characteristics, which may uncover treatment resistant mechanism and novel therapeutic target in E-GBM.

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified recurrent genetic alterations in Primary central nervous system lymphoma (PCNSL). However, lack of clinically representative PCNSL models has diminished our understanding of the pathogenic mechanisms of those genetic events. Here, we established 14 patient-derived orthotopic xenografts (PDOXs). Comprehensive analysis showed that PDOXs faithfully retained the phenotypic, metabolic, and genetic features with 100 % concordance of MYD88 and CD79B mutations present in immuno-competent PCNSL patients. Notably, orthotopic xenograft formation was consistently dependent on deregulated signaling through the RelA/p65-hexokinase 2 (HK-2) axis. MYD88/CD79B mutations and Pin1 activation, or LMP1 and Pin1 activation, converge on the RelA/p65-HK-2 signaling in immunocompetent and EBV-positive PCNSL, respectively. Genetic and pharmacological inhibition of this key signaling axis potently suppressed PCNSL tumor growth in vitro and in vivo. Additionally, our models further offer a platform for predicting clinical chemotherapeutics efficacy. Therefore, our models provide critical insights into pathogenic mechanisms and therapeutic discovery in PCNSL.

Recent genomic analyses have identified highly recurrent genetic alterations in PCNSL. However, due to the lack of clinically representative PCNSL preclinical models, the pathogenic mechanisms of these alterations remains largely unknown. Here, we established the largest panel of 12 clinically relevant PCNSL patient-derived orthotopic xenografts retained the histopathologic phenotype, lymphoma expression subtype, copy number alterations and 90% of the non-synonymous mutations of primary tumors, with 100% concordance of MYD88 and CD79B mutations, which are highly recurrent in PCNSL. Patient tumor regression with high-dose methotrexate correlated with in vitro sensitivity to methotrexate in corresponding PCNSL models. By knocking down canonical NF-kB pathway genes, we found that successful orthotopic xenograft formation was dependent on NF-kB canonical pathway activation induced by MYD88 mutation or overexpression of EBV-related LMP1. Metabolically, PCNSL xenografts phenocopied the high 18F-fluorodeoxyglucose uptake observed in patients and demonstrated glycolytic dependence, revealing new potential therapeutic strategies in PCNSL. Collectively, we found NF-kB canonical pathway activation as a crucial driver of PCNSL xenograft progression and found that NF-kB canonical pathway induced an addiction to glycolysis, revealing a novel potential therapeutic strategy. Our PCNSL xenograft panel represents a valuable and reproducible preclinical tool that has the potential to help decipher how genetic and/or epigenetic alterations contributes to lymphomagenesis and tumor maintenance and enhance the development of novel therapeutic strategies in PCNSL.

Epithelioid glioblastoma (E-GBM) predominantly arises at younger age and promotes dismal prognosis. Because of its rare etiology, pathological and genetical characterization of E-GBM remains elusive. Herein, we report unique patient-derived E-GBM xenograft (PDX) models from 3 E-GBM patients (2 BRAFV600E mutant and 1 BRAFV600E wild-type). Two BRAF mutant E-GBM cells (YMG62 and YMG89) were originated from adolescent and young adult patients and harbored TERT promoter mutation and CDKN2A homozygous deletion, while 1 BRAFV600E E-GBM cell (YMG64) was from elderly patient and had TERT wild-type. YMG62 and YMG89 could be propagated at multiple passage in vitro, while YMG64 could not be maintained. PDX models were established from YMG62, YMG89, and YMG64. All PDX tumors were preferentially disseminated and negative expression of GFAP, which were recapitulated to the patient characteristics. BRAF and MEK inhibitor mildly suppressed cell viability in vitro. Collectively, E-GBM PDX models recapitulate patient characteristics, which may be helpful to elucidate tumor biology and establish novel therapeutic target in E-GBM.

According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AII(IDHmut)), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII(IDHmut)), and WHO grade IV glioblastoma, IDH-mutant (GBM(IDHmut)). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII(IDHmut) and AAIII(IDHmut) have lost their significance. In contrast, GBM(IDHmut) still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.

Alterations in the promoter of the telomerase reverse transcriptase (TERT) gene are a major mechanism of upregulating telomerase, which plays a crucial role in tumor development. Mutations in the TERT promoter have been observed in a subset of brain tumors, including adult gliomas and high-grade meningiomas. In pituitary adenomas (PAs), however, abnormalities in TERT are not fully understood. The present study aimed to investigate not only mutational but also methylation changes in the TERT promoter in PAs and to analyze their correlations with clinical variables. We retrospectively studied 70 PAs consisting of 53 primary and 17 recurrent samples. Clinical data, including age at surgery, sex, largest tumor dimension, tumor subtype, resection rate, and progression-free survival (PFS), were obtained from medical records. We investigated TERT promoter hotspot mutations via Sanger sequencing and quantified the methylation status of the TERT promoter using methylation-sensitive high-resolution melting analysis (MS-HRM). Additionally, we investigated TERT mRNA expression using real-time quantitative PCR. TERT promoter hotspot mutations were not observed in any PA sample, while 16% of PAs exhibited TERT promoter methylation. PAs with methylated TERT promoters were significantly more likely to show disease progression, shorter PFS, and higher TERT expression levels compared to those with unmethylated promoters. This is the first study showing that TERT promoter methylation is associated with disease progression and shorter PFS as well as upregulated TERT expression in PAs. Our results suggest that TERT promoter methylation may be a potential biomarker for predicting tumor recurrence in PAs.

We study the electric and dust environment near a complex surface structure on the moon: a vertical hole. In order to model an electric field structure near the surface, we performed the particle-in-cell simulations. The simulations provide electric field and plasma current density profiles in three-dimensional space above the complex lunar surface topography. Subsequently, we applied the obtained electric field and plasma current density data to the test-particle simulation on the dynamics of submicronsized charged dust grains. We focus on an effect of a stochastic charging process of such small dust grains. Because of their small surface areas, the dusts will get/lose one elementary charge infrequently. The preliminary simulation results show an evidence of dust mobilization across the sunlight–shadow interface formed inside the lunar hole.We study the electric and dust environment near a complex surface structure on the moon: a vertical hole. In order to model an electric field structure near the surface, we performed the particle-in-cell simulations. The simulations provide electric field and plasma current density profiles in three-dimensional space above the complex lunar surface topography. Subsequently, we applied the obtained electric field and plasma current density data to the test-particle simulation on the dynamics of submicronsized charged dust grains. We focus on an effect of a stochastic charging process of such small dust grains. Because of their small surface areas, the dusts will get/lose one elementary charge infrequently. The preliminary simulation results show an evidence of dust mobilization across the sunlight–shadow interface formed inside the lunar hole.