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Nuclear data, describing neutron reaction probabilities (cross sections) and decay behaviour, are critical to the design and operation of fusion experiments and future fusion power plants. Equally vital, are the inventory codes that use the data to predict neutron-induced activation and transmutation of materials, which will define the radiological hazards that must be managed during reactor operation and decommissioning. Transmutation, including gas production, combined with the neutron-induced displacement damage, will also cause the properties of materials to degrade, for example through swelling and embrittlement, eventually limiting the lifetime of components. Thus validated and accurate nuclear data and inventory codes are essential. For data validation there are decay heat measurements performed at FNS in Japan more than 20 years ago. The experiments produced an invaluable database for benchmarking of nuclear data libraries; the latest versions of several international libraries perform well against this data during tests with the FISPACT-II inventory code, although there is still scope for improvement. A recent attempt to provide fusion-relevant validation based on γ -spectroscopy data from neutron-irradiated material samples tests produced predictions for short-lived (several hours or less) radionuclides. The detailed analysis performed for molybdenum demonstrates how these data could eventually provide a new benchmark, and also illustrates the potential benefits of further experiments targeting the longer-lived radionuclides relevant to maintenance and decommissioning timescales. There are also some successful tests of transmutation predictions with FISPACT-II. These direct validations of inventory simulations are critical for lifetime predictions and future experiments should learn lessons from the examples described for tungsten, which demonstrate the importance of an accurate description of the neutron spectrum in experiments. More novel experimental techniques are needed to measure helium production in materials such as Fe and C, but the need to validate the nuclear data evaluations used by simulations should motivate future experimental efforts.

Abstract Objective High self‐efficacy is associated with improved self‐care and reduced symptoms in cancer patients but has not been fully interrogated in adults with central nervous system (CNS) cancers. We aimed to identify the relationship between self‐efficacy levels in managing emotions (SEMEM) and social interactions (SEMSI) by examining sample characteristics and symptom burden. Methods Sample characteristics and patient‐reported outcome (PRO) measures addressing self‐efficacy (PROMIS SEMEM & SEMSI) and symptom burden (MDASI BT or SP) were collected in a novel web‐based study of 158 adult patients diagnosed with rare CNS tumors. Results The sample was predominantly female (73%), diagnosed with an ependymoma (66%), and had a median age of 45 (19–75). Low SEMEM was associated with a longer duration of symptoms before surgery (r = −0.26) and female gender (92%) among brain tumor (BT) participants and in spinal cord tumors (SCT), those with lower education (r = 0.29). Reporting low SEMSI was associated with being married (42%), lower education (r = 0.22), and a prolonged time with symptoms before surgery (r = 0.29) in those with BTs, with no associations identified in SCT. More severe mood‐related interference (including mood, enjoyment of life, and relationship with others) was associated with lower SEMEM among both locations (r = −0.61 brain, r = −0.28 spine) and SEMSI in BT participants (r = −0.54). Conclusions Low self‐efficacy was linked to a prolonged time between symptom onset and initial surgery, education, gender, and marital status and was associated with higher mood‐related interference. Understanding characteristics associated with low self‐efficacy underscores a need for future studies to tailor interventions that enhance self‐efficacy.

Abstract Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving the onset of sleep disturbances after cranial radiation remains unclear but may result from treatment-induced injury to neural circuits controlling sleep behavior, both circadian and homeostatic. Here, we develop a mouse model of cranial radiation-induced hypersomnolence which recapitulates the human experience. Additionally, we used the model to explore the impact of radiation on the brain. We demonstrated that the DNA damage response following radiation varies across the brain, with homeostatic sleep and cognitive regions expressing higher levels of γH2AX, a marker of DNA damage, than the circadian suprachiasmatic nucleus (SCN). These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes. Moreover, in our mouse model, MRI identified structural effects in cognitive and homeostatic sleep regions two-months post-treatment. While the findings are preliminary, they suggest that homeostatic sleep and cognitive circuits are vulnerable to radiation and these findings may be relevant to optimizing treatment plans for patients.

Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C‐tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine‐deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine‐free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine‐related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

Abstract Comprising approximately 8% of our genome, Human Endogenous RetroViruses (HERVs) represent a class of germline retroviral infections that are regulated through epigenetic modifications. In cancer cells, which often have epigenetic dysregulation, HERVs have been implicated as potential oncogenic drivers. However, their role in gliomas is not known. Given the link between HERV expression in cancer cell lines and the distinct epigenetic dysregulation in gliomas, we utilized a tailored bioinformatic pipeline to characterize and validate the glioma retrotranscriptome and correlate HERV expression with locus-specific epigenetic modifications. We identified robust overexpression of multiple HERVs in our cell lines, including a retroviral transcript, HML-6, at 19q13.43b in glioblastoma cells. HERV expression inversely correlated with loci-specific DNA methylation. HML-6 contains an intact open reading frame encoding a small envelope protein, ERVK3-1. Increased expression of ERVK3-1 in GBM patients is associated with a poor prognosis independent of IDH-mutational status. Our results suggest that not only is HML-6 uniquely overexpressed in highly invasive cell lines and tissue samples, but also its gene product, ERVK3-1, may be associated with reduced survival in GBM patients. These results may have implications for both the tumor biology of GBM and the role of ERVK3-1 as a potential therapeutic target.

Abstract Background Compared to normal cells, cancer cells exhibit a higher level of oxidative stress, which primes key cellular and metabolic pathways and thereby increases their resilience under oxidative stress. This higher level of oxidative stress also can be exploited to kill tumor cells while leaving normal cells intact. In this study we have found that isovalerylspiramycin I (ISP I), a novel macrolide antibiotic, suppresses cancer cell growth and tumor metastases by targeting the nucleolar protein selenoprotein H (SELH), which plays critical roles in keeping redox homeostasis and genome stability in cancer cells. Methods We developed ISP I through genetic recombination and tested the antitumor effects using primary and metastatic cancer models. The drug target was identified using the drug affinity responsive target stability (DARTS) and mass spectrum assays. The effects of ISP I were assessed for reactive oxygen species (ROS) generation, DNA damage, R-loop formation and its impact on the JNK2/TIF-IA/RNA polymerase I (POLI) transcription pathway. Results ISP I suppresses cancer cell growth and tumor metastases by targeting SELH. Suppression of SELH induces accumulation of ROS and cancer cell-specific genomic instability. The accumulation of ROS in the nucleolus triggers nucleolar stress and blocks ribosomal RNA transcription via the JNK2/TIF-IA/POLI pathway, causing cell cycle arrest and apoptosis in cancer cells. Conclusions We demonstrated that ISP I links cancer cell vulnerability to oxidative stress and RNA biogenesis by targeting SELH. This suggests a potential new cancer treatment paradigm, in which the primary therapeutic agent has minimal side-effects and hence may be useful for long-term cancer chemoprevention.

Astrocytomas are the most common subtype of brain tumors and no curative treatment exist. Longitudinal assessment of patients, usually via Magnetic Resonance Imaging (MRI), is crucial since tumor progression may occur earlier than clinical progression. MRI usually provides a means for monitoring the disease, but it only informs about the structural changes of the tumor, while molecular changes can occur as a treatment response without any MRI-visible change. Radiotherapy (RT) is routinely performed following surgery as part of the standard of care in astrocytomas, that can also include chemotherapy involving temozolomide. Monitoring the response to RT is a key factor for the management of patients. Herein, we provide plasma and tissue metabolic biomarkers of treatment response in a mouse model of astrocytoma that was subjected to radiotherapy. Plasma metabolic profiles acquired over time by Liquid Chromatography Mass Spectrometry (LC/MS) were subjected to multivariate empirical Bayes time-series analysis (MEBA) and Receiver Operating Characteristic (ROC) assessment including Random Forest as the classification strategy. These analyses revealed a variation of the plasma metabolome in those mice that underwent radiotherapy compared to controls; specifically, fumarate was the best discriminatory feature. Additionally, Nuclear Magnetic Resonance (NMR)-based 13C-tracing experiments were performed at end-point utilizing [U-13C]-Glutamine to investigate its fate in the tumor and contralateral tissues. Irradiated mice displayed lower levels of glycolytic metabolites (e.g. phosphoenolpyruvate) in tumor tissue, and a higher flux of glutamine towards succinate was observed in the radiation cohort. The plasma biomarkers provided herein could be validated in the clinic, thereby improving the assessment of brain tumor patients throughout radiotherapy. Moreover, the metabolic rewiring associated to radiotherapy in tumor tissue could lead to potential metabolic imaging approaches for monitoring treatment using blood draws.

Most tumors, including brain tumors, are sporadic. However, a small subset of CNS tumors are associated with hereditary cancer conditions like Lynch Syndrome (LS). Here, we present a case of an oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and LS with a germline pathogenic PMS2 mutation. To our knowledge, this has only been reported in a few cases in the literature. While the family history is less typical of LS, previous studies have indicated the absence of a significant family history in patient cohorts with PMS2 mutations due to its low penetrance. Notably, only a handful of studies have worked on characterizing PMS2 mutations in LS, and even fewer have looked at these mutations in the context of brain tumor development. This report aims to add to the limited literature on germline PMS2 mutations and oligodendrogliomas. It highlights the importance of genetic testing in neuro-oncology.

Cancer stem cells are thought to be the main drivers of tumorigenesis for malignancies such as glioblastoma (GBM). They are maintained through a close relationship with the tumor vasculature. Previous literature has well-characterized the components and signaling pathways for maintenance of this stem cell niche, but details on how the niche initially forms are limited. This review discusses development of the nonmalignant neural and hematopoietic stem cell niches in order to draw important parallels to the malignant environment. We then discuss what is known about the cancer stem cell niche, its relationship with angiogenesis, and provide a hypothesis for its development in GBM. A better understanding of the mechanisms of development of the tumor stem cell niche may provide new insights to potentially therapeutically exploit.

Abstract Age plays a critical role in disease development and tolerance to cancer treatment, often leading to an increased risk of developing negative symptoms including sleep disturbances. Circadian rhythms and sleep become disrupted as organisms age. In this study, we explored the behavioral alterations in sleep, circadian rhythms, and masking using a novel video system and interrogate the long-term impact of age-based changes in the non-image forming visual pathway on brain anatomy. We demonstrated the feasibility and utility of the novel system and establish that older mice have disruptions in sleep, circadian rhythms, and masking behaviors that were associated with major negative volume alterations in the non-imaging forming visual system, critical for the induction and rhythmic expression of sleep. These results provide important insights into a mechanism, showing brain atrophy is linked to age in distinct non-image forming visual regions, which may predispose older individuals to developing circadian and sleep dysfunction when further challenged by disease or treatment.

The understanding of altered lipid metabolism by isocitrate dehydrogenase 1 (IDH1) mutations in gliomas at a compartment-specific level is limited. Here, the authors use Raman spectroscopy to monitor organelle-specific metabolic changes and report that IDH1 mutations induce phospholipid imbalances which lead to ER and Golgi dilation.

Abstract Background Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1 mut ) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG). Methods We have employed a combination of 13C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1 mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity. Results We report the adaptability of IDH1 mut cells’ metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1 mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition. Conclusions Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 mut gliomas.

Abstract We report a novel group of clinically aggressive spinal cord ependymomas characterized by Grade III histology, MYCN amplification, an absence of NF2 alterations or other recurrent pathogenic mutations, and a unique methylation classifier profile. Seven cases were found to have MYCN amplification in the course of routine mutational profiling of 552 patients with central nervous system tumors between December 2016 and July of 2019 and an eighth patient was identified from an unrelated set of cases. Methylation array analysis revealed that none of the 8 cases clustered with any of the nine previously described ependymoma methylation subgroups, and 7 of 8 formed their own tight unique cluster. Histologically all cases showed grade III features, and all demonstrated aggressive clinical behavior. These findings are presented in the context of data from three other studies describing similar cases. Therefore, a combined total of 27 MYCN amplified spinal cord ependymoma cases have now been reported in the literature, warranting their consideration as a distinctive subtype of spinal cord ependymoma (SP-EPN-MYCN) with their unique molecular characteristics and aggressive clinical behavior.

The isocitrate dehydrogenase (IDH1/2) mutations are frequent genetic abnormalities in the majority of WHO grade II/III glioma and secondary GBM. IDH1-mutated (IDH1Mut) glioma exhibits distinctive patterns in cancer biology and metabolism. In the present study, we showed that bone morphogenetic proteins (BMP4) are significantly upregulated in IDH1Mut glioma. Further, we demonstrated that cancer-associated BMP4 is secreted to tumor microenvironment, which enhances the tumor migration and invasion through an autocrine manner. Mechanistically, BMP4 activates its receptor and concomitant SMAD1/5/8 signaling, which potentiates Wnt/β-catenin signaling by enhancing Frizzled receptor expression. LDN-193189, a selective BMP receptor inhibitor, prolonged the overall survival of mice bearing IDH1-mutated intracranial xenografts by limiting BMP/catenin signaling. These findings demonstrate the pivotal role of BMP4 on tumor aggressiveness in IDH1Mut gliomas, suggesting a possible therapeutic strategy for this type of malignancy.

Glioblastoma cells are known to be able to adapt easily to different environments. The authors study the dynamic adaptation of glioblastoma cells to the heterogenous brain tumor microenvironment, showing that tumor cells demonstrate varying plasticity of their transcriptomic profiles and an ability to survive new stimuli, in part, by propagating stochastic perturbations over their gene-regulatory network.

Background: Leptomeningeal metastasis (LM) creates symptoms related to both the disease within the nervous system and treatment toxicities. Biologic processes, such as inflammation and behavioral processes, such as the meaning ascribed to illness (Meaning of Illness: MoI), can impact physical and psychosocial symptoms. The aim of this study was to understand the relationships among MoI, physical and psychosocial symptoms, and inflammation in patients with LM. Methods: Thirty enrolled participants completed the MD Anderson Symptom Inventory-Brain Tumor with spine experimental symptoms added. Meaning of illness, quality of life (QoL), and depression were captured by validated instruments. Interleukin (IL)-6 and tumor necrosis factor (TNF)-α in serum and cerebrospinal fluid (CSF) were measured by ELISA. Correlations were performed to assess relationships among the variables. Results: Participants were primarily white (73%), female (63%). Median age was 54 years (34–83). Breast (50%) and lung (20%) were most common diagnosis. Higher MoI scores were associated with better QoL (p

Glioblastoma (GBM) is an aggressive brain malignancy with a dismal prognosis. With emerging evidence to disprove brain-immune privilege, there has been much interest in examining immunotherapy strategies to treat central nervous system (CNS) cancers. Unfortunately, the limited success of clinical studies investigating immunotherapy regimens, has led to questions about the suitability of immunotherapy for these cancers. Inadequate inherent populations of tumor infiltrating lymphocytes (TILs) and limited trafficking of systemic, circulating T cells into the CNS likely contribute to the poor response to immunotherapy. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier (BBB) permeable small molecule inhibitor of EZH2, to reverse GBM immune evasion by epigenetic suppression of T cell chemotaxis. We also evaluated the in vivo efficacy of this drug in combination with anti-PD-1 treatment on tumor growth, survival and T cell infiltration in syngeneic mouse models. GSK126 reversed H3K27me3 in murine and human GBM cell lines. When combined with anti-PD-1 treatment, a significant increase in activated T cell infiltration into the tumor was observed. This resulted in decreased tumor growth and enhanced survival both in sub-cutaneous and intracranial tumors of immunocompetent, syngeneic murine models of GBM. Additionally, a significant increase in CXCR3+ T cells was also seen in the draining lymph nodes, suggesting their readiness to migrate to the tumor. Closer examination of the mechanism of action of GSK126 revealed its ability to promote the expression of IFN-γ driven chemokines CXCL9 and CXCL10 from the tumor cells, that work to traffic T cells without directly affecting T maturation and/or proliferation. The loss of survival benefit either with single agent or combination in immunocompromised SCID mice, suggest that the therapeutic efficacy of GSK126 in GBM is primarily driven by lymphocytes. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor.

The use of immunotherapies for the treatment of brain tumors is a topic that has garnered considerable excitement in recent years. Discoveries such as the presence of a glymphatic system and immune surveillance in the central nervous system (CNS) have shattered the theory of immune privilege and opened up the possibility of treating CNS malignancies with immunotherapies. However, despite many immunotherapy clinical trials aimed at treating glioblastoma (GBM), very few have demonstrated a significant survival benefit. Several factors for this have been identified, one of which is that GBMs are immunologically “cold,” implying that the cancer does not induce a strong T cell response. It is postulated that this is why clinical trials using an immune checkpoint inhibitor alone have not demonstrated efficacy. While it is well established that anti-cancer T cell responses can be facilitated by the presentation of tumor-specific antigens to the immune system, treatment-related death of GBM cells and subsequent release of molecules have not been shown to be sufficient to evoke an anti-tumor immune response effective enough to have a significant impact. To overcome this limitation, vaccines can be used to introduce exogenous antigens at higher concentrations to the immune system to induce strong tumor antigen-specific T cell responses. In this review, we will describe vaccination strategies that are under investigation to treat GBM; categorizing them based on their target antigens, form of antigens, vehicles used, and pairing with specific adjuvants. We will review the concept of vaccine therapy in combination with immune checkpoint inhibitors, as it is hypothesized that this approach may be more effective in overcoming the immunosuppressive milieu of GBM. Clinical trial design and the need for incorporating robust immune monitoring into future studies will also be discussed here. We believe that the integration of evolving technologies of vaccine development, delivery, and immune monitoring will further enhance the role of these therapies and will likely remain an important area of investigation for future treatment strategies for GBM patients.

Abstract Background Identifying symptoms experienced throughout the disease trajectory is pivotal to understanding management of patient symptoms. Patient interviews to solicit input from those who have experienced these symptoms is one method to capture this perspective to validate symptoms included in patient reported outcomes (PRO) measures. Methods A thematic approach was used to identify themes within qualitative interviews. The MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) was completed by glioma patients. Descriptive statistics was used for analysis of the MDASI-BT. Results Thematic saturation was reached with 23 participants, with a median age of 53 (23–62), on treatment (57%) and diagnosed with a glioblastoma (48%). Patients endorsed 20 out of the 22 MDASI-BT symptoms (symptoms not reported: dry mouth, shortness of breath) during the interviews and with completion of the instrument (seizures and vomiting were not endorsed). Fatigue (55%), seizures (50%), and pain (50%) were common symptoms described by the sample. During treatment, more symptoms were identified with fatigue, hair loss, and nausea more problematic. Aside from itching and swelling (endorsed by 2 patients each), all other symptoms not included in the MDASI-BT instrument were endorsed by only one patient. Conclusions Completion of the MDASI-BT, found patients reported on average 6.8 symptoms with 14% of reported symptoms (mean = 3) rated as moderate to severe. The findings demonstrate how applicable the MDASI-BT is in capturing significant symptoms experienced and how important it is to utilize throughout ones’ care to manage symptoms effectively.

Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.

Glioma is the most common primary malignant brain tumor with a poor prognosis. Immune checkpoint inhibitors have been of great interest in investigation of glioma treatments. Here, we report single-cell transcriptomic analyses of two tumor areas from an oligodendroglioma taken from a patient who had multiple tumor recurrences, following several chemotherapies and radiation treatments. The patient subsequently received nivolumab and was considered have disease progression based on conventional diagnostic imaging after two cycles of treatment. He underwent a debulking surgical resection and pathological diagnosis was recurrent disease. During the surgery, tumor tissues were also collected from the enhancing and non-enhancing areas for a scRNAseq analysis to investigate the tumor microenvironment of these radiographically divergent areas. The scRNAseq analysis reveals a plethora of immune cells, suggesting that the increased mass observed on MRI may be partially a result of immune cell infiltration. The patient continued to receive immunotherapy after a short course of palliative radiation and remained free of disease progression for at least 12 months after the last surgery, suggesting a sustained response to immunotherapy. The scRNAseq analysis indicated that the radiological progression was in large part due to immune cell infiltrate and continued immunotherapy led to a positive clinical outcome in a patient who would have otherwise been admitted to hospice care with halting of immunotherapy. Our study demonstrates the potential of scRNAseq analyses in understanding the tumor microenvironment, which may assist the clinical decision-making process for challenging glioma cases following immunotherapy.

Glioblastoma remains a challenging disease to treat, despite well-established standard-of-care treatments, with a median survival consistently of less than 2 years. In this review, we delineate the unique disease-specific challenges for immunotherapies, both brain-related and non-brain-related, which will need to be adequately overcome for the development of effective treatments. We also review current immunotherapy treatments, with a focus on clinical applications, and propose future directions for the field of GBM immunotherapy.

Abstract Background Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment. Methods Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry. Results Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice. Conclusions Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response.

Protein phosphatase 2A (PP2A) has been proposed as a target for cancer immunotherapy. Here the authors show that pharmacological inhibition of PP2A with a clinically-relevant inhibitor enhances response to immune checkpoint blockade in pre-clinical models of cancer, resulting in long lasting immunity.

Abstract Background Immune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to the challenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs. Case presentation We reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination. Conclusions A high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques. Trial registration ClinicalTrials.gov NCT02311920. Registered 8 December 2014.

Background: A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. Methods: Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype). Results: Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5% of IDH-wildtype gliomas (p = 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R = −0.46, p = 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. The Antigen Processing and Presentation (APP) score correlated with immune score and was surprisingly higher in NHMP versus HMP samples in IDH-wildtype gliomas, but higher in HMP versus NHMP in IDH-mutant gliomas. Conclusion: TMB was inversely correlated with immune score in IDH-wildtype gliomas and showed no correlation in IDH-mutant tumors. APP was correlated with immune score and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a larger glioma cohort are warranted.

Human endogenous retroviruses (HERVs), which are critical to normal embryologic development and downregulated during normal maturation, have been implicated in a variety of cancers. Abnormal persistent production of HERVs has been suggested to play a role in oncogenesis and to confer stem cell properties to cells. We recently demonstrated that the most recently incorporated HERV element (HERV-K HML-2) has been associated with the pathogenesis of the embryonal atypical teratoid rhabdoid tumor (AT/RT), shifting our understanding of embryonal tumor development. HML-2 expression is vital for proper human development and its expression is suppressed via methylation or chromatin remodeling as cells differentiate. We previously found that dysfunctional chromatin remodeling due to loss of SMARCB1 expression induces HML-2 envelope (env) expression, impairing cellular differentiation and migration, and facilitating tumor growth in AT/RT. Epigenetic dysregulation in other embryonal tumors with concomitant expression of stem-cell markers may facilitate HML-2 expression. Future studies could utilize HML-2 as potential diagnostic criteria, use its expression as a treatment biomarker, and investigate the efficacy of therapies targeting cells with high HML-2 expression.

Improvements in Radio-Isotope IDentification (RIID) algorithms have seen a resurgence in interest with the increased accessibility of machine learning models. Convolutional Neural Network (CNN)-based models have been developed to identify arbitrary mixtures of unstable nuclides from gamma spectra. In service of this, methods for the simulation and pre-processing of training data were also developed. The implementation of 1D multi-class, multi-label CNNs demonstrated good generalisation to real spectra with poor statistics and significant gain shifts. It is also shown that even basic CNN architectures prove reliable for RIID under the challenging conditions of heavy shielding and close source geometries, and may be extended to generalised solutions for pragmatic RIID.

Circadian clock genes have been linked to clinical outcomes in cancer, including gliomas. However, these studies have not accounted for established markers that predict the prognosis, including mutations in Isocitrate Dehydrogenase (IDH), which characterize the majority of lower-grade gliomas and secondary high-grade gliomas. To demonstrate the connection between circadian clock genes and glioma outcomes while accounting for the IDH mutational status, we analyzed multiple publicly available gene expression datasets. The unsupervised clustering of 13 clock gene transcriptomic signatures from The Cancer Genome Atlas showed distinct molecular subtypes representing different disease states and showed the differential prognosis of these groups by a Kaplan–Meier analysis. Further analyses of these groups showed that a low period (PER) gene expression was associated with the negative prognosis and enrichment of the immune signaling pathways. These findings prompted the exploration of the relationship between the microenvironment and clock genes in additional datasets. Circadian clock gene expression was found to be differentially expressed across the anatomical tumor location and cell type. Thus, the circadian clock expression is a potential predictive biomarker in glioma, and further mechanistic studies to elucidate the connections between the circadian clock and microenvironment are warranted.

Glioblastoma is the most common and aggressive primary malignant brain tumor, and more than two-thirds of patients with glioblastoma die within two years of diagnosis. The challenges of treating this disease mainly include genetic and microenvironmental features that often render the tumor resistant to treatments. Despite extensive research efforts, only a small number of drugs tested in clinical trials have become therapies for patients. Targeting cyclin-dependent kinase 9 (CDK9) is an emerging therapeutic approach that has the potential to overcome the challenges in glioblastoma management. Here, we discuss how CDK9 inhibition can impact transcription, metabolism, DNA damage repair, epigenetics, and the immune response to facilitate an anti-tumor response. Moreover, we discuss small-molecule inhibitors of CDK9 in clinical trials and future perspectives on the use of CDK9 inhibitors in treating patients with glioblastoma.

W-Cr-Y smart alloys are potential material candidates for plasma facing components due to their protective behaviour during the loss-of-coolant accident (LOCA), while maintaining beneficial properties of W during the normal operation of the fusion power plant. During plasma exposure, the lighter alloying elements are preferentially sputtered at the surface, but in case of a LOCA, the plasma quenches and sputtering stops and diffusion of the alloying elements to the surface becomes intensive. The diffusion of Cr to the surface due to alloying elements (Y, Ti) yields a protective oxide layer stopping the sublimation of WO3. The phase stability and short-range ordering of ternary alloys in W-Cr-Y(Ti) systems has been investigated, using combination of Density Functional Theory (DFT) and Cluster Expansion (CE) methods with Monte-Carlo (MC) simulations. It has been found out from the DFT calculations, that all pairs in the W-Cr-Y system have positive values of the enthalpy of mixing, while most of the Cr-Ti and Ti-W binary structures have negative enthalpies of mixing. The shift in the short-range order as a function of temperature between Cr and W has been predicted as a result of Y addition in W-Cr-Y alloys compared to W70Cr30, by around 400 K towards lower temperatures. A strong tendency towards clustering of Y has been observed even at elevated temperatures (1800 K). The decrease of the order–disorder transition temperature (ODTT) as a result of the Y addition has been observed, while the addition of Ti has not shown any significant changes in the ordering of W-Cr-Ti alloys compared to W-Cr alloy. Our MC simulations showed that for the W70Cr29Y1 alloy the enthalpy of mixing (Hmix) value is positive in the whole analysed temperature range. Free energy of mixing above 1000 K has been calculated from the first nearest neighbours approximation for W70Cr29Y1 and W70Cr29Ti1 alloys. The results of the present investigations provide an insight enabling for optimizing chemical composition of materials for future plasma facing components.