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Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042). [ABSTRACT FROM AUTHOR]

Chordoma is a rare, but aggressive bone tumor with a high recurrence rate that primarily arises at the cranial and caudal ends of the axial skeleton. Systemic chemotherapies are not effective against the tumor, and outside of surgical resection and radiation, no approved options are available. Prognosis depends on the extent of surgical resection, with the more the better, and adjuvant radiotherapy. Herein is presented the first-ever case of a recurrent chordoma patient that responded to the combination of one dose of an experimental TGF-beta trap carrying oncolytic adenovirus, known as AdAPT-001, followed by immune checkpoint inhibitor therapy, despite prior progression on an anti-PD-1. This case report highlights the potential of AdAPT-001 as a treatment modality in combination with checkpoint inhibition for recurrent chordoma. [ABSTRACT FROM AUTHOR]

Chronic suppurative otitis media (CSOM) denotes a chronic inflammation of the middle ear and mastoid mucosa in which the tympanic membrane is not intact and discharge is present (Verhoeff et al. in Int J Pediatr Otorhinolaryngol 70:1-12, 2006). The risk factors for the development of CSOM have not been clearly established in the available literature. Risk factors of COM include low socioeconomic status, malnutrition, high number of children in the household, family history, and passive exposure to smoking (Lasisi et al. in Int J Pediatr Otorhinolaryngol 71:1549–1554, 2007). The effects of various host and environmental factors have not been well defined. There are very few studies to assess the risk factors and disease burden in the community. The study aims to estimate the disease burden of CSOM in the state of Sikkim which would help in effective treatment and control of the disease. This study which is the first of its kind in Sikkim would help us in identification of risk factors which could be present in the Sikkimese population and this could be attributed to ethnic as well as unique geographical factors of this place. Observational study where all Sikkimese patients reporting to ENT with ENT complaints were included after taking consent, The information was noted in a specific questionnaire and all patient were subjected to Otoscopic examination. Analyses using SPSS 17.00. A total of 497 subjects had participated in the study and all the relevant data has been categorized and tabulated according to the requirements of the study. [ABSTRACT FROM AUTHOR]

In sporadic amyotrophic lateral sclerosis (sALS), IL-17A- and granzyme-positive cytotoxic T lymphocytes (CTL), IL-17A-positive mast cells, and inflammatory macrophages invade the brain and spinal cord. In some patients, the disease starts following a trauma or a severe infection. We examined cytokines and cytokine regulators over the disease course and found that, since the early stages, peripheral blood mononuclear cells (PBMC) exhibit increased expression of inflammatory cytokines IL-12A, IFN-γ, and TNF-α, as well as granzymes and the transcription factors STAT3 and STAT4. In later stages, PBMCs upregulated the autoimmunity-associated cytokines IL-23A and IL-17B, and the chemokines CXCL9 and CXCL10, which attract CTL and monocytes into the central nervous system. The inflammation is fueled by the downregulation of IL-10, TGFβ, and the inhibitory T-cell co-receptors CTLA4, LAG3, and PD-1, and, in vitro, by stimulation with the ligand PD-L1. We investigated in two sALS patients the regulation of the macrophage transcriptome by dimethyl fumarate (DMF), a drug approved against multiple sclerosis and psoriasis, and the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway inhibitor H-151. Both DMF and H-151 downregulated the expression of granzymes and the pro-inflammatory cytokines IL-1β, IL-6, IL-15, IL-23A, and IFN-γ, and induced a pro-resolution macrophage phenotype. The eicosanoid epoxyeicosatrienoic acids (EET) from arachidonic acid was anti-inflammatory in synergy with DMF. H-151 and DMF are thus candidate drugs targeting the inflammation and autoimmunity in sALS via modulation of the NFκB and cGAS/STING pathways. [ABSTRACT FROM AUTHOR]

To determine the spectrum of Tuberculous Infection in Patients suffering from HIV/AIDS and its correlation with CD-4 cell counts. A retrospective analysis of data of all the patient suffering from HIV/AIDS who are registered in the Sikkim State AIDS control society register during the past 7 years to look for tuberculosis as a opportunistic infection and its correlation with CD4 cell counts. Out of 268 patient registered, 51 were suffering with tuberculosis as co-infection, Amongst which cervical tuberculosis was common. There was significantly relation with CD4 cells count. Tuberculosis is one of the commonest opportunistic infection and chances of developing tuberculosis increases with decrease CD4 cell count. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation is a predisposing factor to numerous degenerative diseases including cancer, heart failure and Alzheimer's disease. Infla-Kine is a natural supplement comprised of a proprietary blend of Lactobacillus fermentum extract, burdock seed (arctigenin), zinc, alpha lipoic acid, papaya enzyme and an enhanced absorption bio-curcumin complex (BCM-95®).Methods: Infla-Kine was administered twice daily to 24 health volunteers for 4 weeks. Quantitative RT-PCR was used to assess mRNA transcripts of IL-1b, IL8, IL-6, NF-κB, and TNF-α from peripheral blood mononuclear cells (PBMC). C reactive protein (CRP) was measured from serum. Additionally, quality of life questionnaires were employed to assess general feeling of well-being. Assessments were made before treatment and at conclusion of treatment (4 weeks).Results: As compared to pre-treatment, after 4 weeks, a statistically significant reduction of IL8, IL-6, NF-κB, and TNF-α transcripts was observed in PBMC. Furthermore, reduction of IL-1b transcript and serum CRP was observed but did not reach statistical significance. Quality of life improvements were most prevalent in muscle and joint pains.Conclusions: Overall, our data demonstrate that twice daily administration of Infla-Kine for 4 weeks reduces inflammatory markers and quality of life in healthy volunteers. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is a highly aggressive astrocytoma with a dismal prognosis. Since 1976, only three chemotherapeutic agents have been approved for the treatment of GBM. Tumor-treating fields (TTFields) therapy, delivered via a noninvasive device, is a new therapy approved for use in patients with recurrent GBM and in combination with temozolomide for the treatment of newly diagnosed GBM. Objectives: This article reviews the mechanism of action and findings from preclinical and clinical studies supporting the use of TTFields for patients with newly diagnosed and recurrent GBM. Methods: This article provides an overview of published lite rature on the efficacy and safety of treating GBM with TTFields. Findings: For the first time in more than a decade, patients with GBM have a noninvasive treatment option that has been shown to increase progression-free survival and overall survival with minimal adverse events. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is a highly aggressive astrocytoma with a dismal prognosis. Since 1976, only three chemotherapeutic agents have been approved for the treatment of GBM. Tumor-treating fields (TTFields) therapy, delivered via a noninvasive device, is a new therapy approved for use in patients with recurrent GBM and in combination with temozolomide for the treatment of newly diagnosed GBM. Objectives: This article reviews the mechanism of action and findings from preclinical and clinical studies supporting the use of TTFields for patients with newly diagnosed and recurrent GBM. Methods: This article provides an overview of published literature on the efficacy and safety of treating GBM with TTFields. Findings: For the first time in more than a decade, patients with GBM have a noninvasive treatment option that has been shown to increase progression-free survival and overall survival with minimal adverse events. [ABSTRACT FROM AUTHOR]

Abstract: With 5.9 billion reported users, mobile phones constitute a new, ubiquitous and rapidly growing exposure worldwide. Mobile phones are two-way microwave radios that also emit low levels of electromagnetic radiation. Inconsistent results have been published on potential risks of brain tumors tied with mobile phone use as a result of important methodological differences in study design and statistical power. Some studies have examined mobile phone users for periods of time that are too short to detect an increased risk of brain cancer, while others have misclassified exposures by placing those with exposures to microwave radiation from cordless phones in the control group, or failing to attribute such exposures in the cases. In 2011, the World Health Organization, International Agency for Research on Cancer (IARC) advised that electromagnetic radiation from mobile phone and other wireless devices constitutes a “possible human carcinogen,” 2B. Recent analyses not considered in the IARC review that take into account these methodological shortcomings from a number of authors find that brain tumor risk is significantly elevated for those who have used mobile phones for at least a decade. Studies carried out in Sweden indicate that those who begin using either cordless or mobile phones regularly before age 20 have greater than a fourfold increased risk of ipsilateral glioma. Given that treatment for a single case of brain cancer can cost between $100,000 for radiation therapy alone and up to $1 million depending on drug costs, resources to address this illness are already in short supply and not universally available in either developing or developed countries. Significant additional shortages in oncology services are expected at the current growth of cancer. No other environmental carcinogen has produced evidence of an increased risk in just one decade. Empirical data have shown a difference in the dielectric properties of tissues as a function of age, mostly due to the higher water content in children's tissues. High resolution computerized models based on human imaging data suggest that children are indeed more susceptible to the effects of EMF exposure at microwave frequencies. If the increased brain cancer risk found in young users in these recent studies does apply at the global level, the gap between supply and demand for oncology services will continue to widen. Many nations, phone manufacturers, and expert groups, advise prevention in light of these concerns by taking the simple precaution of “distance” to minimize exposures to the brain and body. We note than brain cancer is the proverbial “tip of the iceberg”; the rest of the body is also showing effects other than cancers. [Copyright &y& Elsevier]

Recent, studies have shown that Tcf7l2, an important transcription factor in Wnt pathway, plays critical roles in oligodendrocyte development. In this article we report a study showing that Tcf7l2 is under tight regulation during myelin formation. We have found that during early development, Tcf7l2 mRNA appears much earlier than the protein, suggesting a regulation at the translational level. We induced demyelination in a mouse model by a dietary toxin, where remyelination followed after a few weeks, and found that Tcf7l2 protein was expressed specifically during the active remyelination phase. Similarly, in human patients with demyelination diseases, Tcf7l2 protein expression was specifically promoted in regions undergoing active remyelination. During remyelination, Tcf7l2 was only expressed in non-dividing oligodendrocyte precursors and was associated with modest levels of nuclear beta-catenin. We also documented that Tcf7l2 could form protein complex with Olig2, but not with Olig1. Our data showed that during myelin formation, Tcf7l2/beta-catenin is regulated temporally, spatially, and also at levels of expression. These data suggest a key role for Tcf7l2 in myelination/remyelination processes via a tightly controlled activation of Wnt/beta-catenin pathway and the interaction with Olig2. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer that is characterized by the paradoxical features of intense apoptosis resistance yet a marked propensity to undergo necrosis. BcI2L12 (for Bc12-Like12) is a nuclear and cytoplasmic oncoprotein that is universally overexpressed in primary GBM and functions to block postmitochondrial apoptosis signaling by neutralizing effector caspase-3 and caspase-7 maturation. This postmitochondrial block in apoptosis engenders the alternate cell fate of cellular necrosis, thus providing a molecular explanation for GBM's classical features. Whereas BcI2L12-mediated neutralization of caspase-7 maturation involves physical interaction, the mechanism governing BcI2L12-mediated inhibition of caspase-3 activity is not known. The nuclear localization of BcI2L12 prompted expression profile studies of primary astrocytes engineered to overexpress Bcl2L12. The BcI2L12 transcriptome revealed a striking induction of the small heat shock protein α-basic-crystallin (αB-crystallin/HspBS), a link reinforced by robust αB-crystallin expres- sion in BcI2L12-expressing orthotopic glioma and strong coexpression of αB-crystallin and BcI2L12 proteins in human primary GBMs. On the functional level, enforced αB-crystallin or Bcl2L12 expression enhances orthotopic tumor growth. Conversely, RNAi-mediated knock-down of αB-crystallin in Bcl2L12-expressing astrocytes and glioma cell lines with high endogenous αB-crystallin showed enhanced apoptosis, yet decreased necrotic cell death with associated increased caspase-3 but not caspase-7 activation. Mirroring this specific effect on effector caspase-3 activation, αB-crystallin selectively binds pro-caspase-3 and its cleavage intermediates in vitro and in vivo. Thus, αB-crystallin is a BcI2L12-induced oncoprotein that enables BcI2L12 to block the activation of both effector caspases via distinct mechanisms, thereby contributing to GBM pathogenesis and its hallmark biological properties. [ABSTRACT FROM AUTHOR]

The article presents an overview of malignant gliomas, which account for approximately 70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the U.S. each year. A discussion of low survival rates which are seen with patients with malignant gliomas, and of progress which has been made in understanding them and effectively treating them, is presented. The accurate diagnosis and management of brain tumors in adults is discussed. Research which is being conducted into the management of gliomas is examined.

In the adult central nervous system, two distinct populations of glial cells expressing the chondroitin sulfate proteoglycan NG2 have been described: bipolar progenitor cells and more differentiated "synantocytes." These cells have diverse neurological functions, including critical roles in synaptic transmission, repair, and regeneration. Despite their potential importance, the genetic factors that regulate NG2 cell development are poorly understood, and the relationship of synantocytes to the oligodendroglial lineage. In particular, remains controversial. Here, we show that >90% of embryonic and adult NG2 cells express Olig2, a basic helix-loop-helix transcription factor required for oligodendrocyte lineage specification. Analysis of mice lacking Olig function demonstrates a failure of NG2 cell development at embryonic and perinatal stages that can be rescued by addition of a transgene containing the human OLIG2 locus. These findings show a general requirement for Olig function in NG2 cell development and highlight further roles for Olig transcription factors in neural progenitor cells. [ABSTRACT FROM AUTHOR]

We characterized inflammatory infiltrates in archival brain biopsy and autopsy samples from 26 HIV+ and 20 HIV- patients with progressive multifocal leukoencephalopathy (PML). The predominant inflammatory cells were CD8+ T lymphocytes. We defined CD8+ T cell distribution with regard to JCV-infected glial cells, PML lesions and the extent of demyelination. In most samples from either HIV+ and HIV- patients, we found positive correlations between the parenchymal CD8+ T cells and JCV-infected glial cells and conversely, negative correlations between the perivascular CD8+ T cells and JCV-infected glial cells in the surrounding brain. Most of these correlations remained significant after accounting for the degree of demyelination and location of the cells relative to lesions. Moreover, high numbers of CD8+ T cells were found within and at the border of active PML lesions. These results suggest that CD8+ T cells are primarily associated with JCV-infected glial cells in most PML cases and that an active ongoing recruitment of CD8+ T cells and possibly viral antigen-specific retention could occur. These observations are discussed in the context of the recent evidence of PML in multiple sclerosis and Crohn's patients treated with natalizumab, underscoring the role of CD8+ T lymphocytes in continued immunosurveillance of the CNS. [ABSTRACT FROM AUTHOR]

In this issue of Neuron, Jackson et al. show that adult neural stem cells (B cells) express PDGF receptors. Functional analysis of PDGF signaling in these neural progenitors resonates in provocative ways with an older body of literature on PDGF autocrine loops in malignant glioma and with more recent observations on the bHLH transcription factor Olig2. [Copyright &y& Elsevier]

Glioblastoma (GBM) is the most common primary malignant cancer of the central nervous system. Insufficient oxygenation (hypoxia) has been linked to GBM invasion and aggression, leading to poor patient outcomes. Hypoxia induces gene expression for cellular adaptations. However, GBM is characterized by high intertumoral (molecular subtypes) and intratumoral heterogeneity (cell states), and it is not well understood to what extent hypoxia triggers patient-specific gene responses and cellular diversity in GBM. Here, we surveyed eight patient-derived GBM stem cell lines for invasion phenotypes in 3D culture, which identified two GBM lines showing increased invasiveness in response to hypoxia. RNA-seq analysis of the two patient GBM lines revealed a set of shared hypoxia response genes concerning glucose metabolism, angiogenesis, and autophagy, but also a large set of patient-specific hypoxia-induced genes featuring cell migration and anti-inflammation, highlighting intertumoral diversity of hypoxia responses in GBM. We further applied the Shared GBM Hypoxia gene signature to single cell RNA-seq datasets of glioma patients, which showed that hypoxic cells displayed a shift towards mesenchymal-like (MES) and astrocyte-like (AC) states. Interestingly, in response to hypoxia, tumor cells in IDH-mutant gliomas displayed a strong shift to the AC state, whereas tumor cells in IDH-wildtype gliomas mainly shifted to the MES state. This distinct hypoxia response of IDH-mutant gliomas may contribute to its more favorable prognosis. Our transcriptomic studies provide a basis for future approaches to better understand the diversity of hypoxic niches in gliomas. [ABSTRACT FROM AUTHOR]

Insulin resistance is the decreased effectiveness of insulin receptor function during signaling of glucose uptake. Insulin receptors are regulated by endocytosis, a process that removes receptors from the cell surface to be marked for degradation or for re-use. Our goal was to discover insulin-resistance-related genes that play key roles in endocytosis which could serve as potential biological targets to enhance insulin sensitivity. The gene mutations related to insulin resistance were elucidated from ClinVar. These were used as the seed set. Using the GeneFriends program, the genes associated with this set were elucidated and used as an enriched set for the next step. The enriched gene set network was visualized by Cytoscape. After that, using the VisANT program, the most significant cluster of genes was identified. With the help of the DAVID program, the most important KEGG pathway corresponding to the gene cluster and insulin resistance was found. Eleven genes part of the KEGG endocytosis pathway were identified. Finally, using the ChEA3 program, seven transcription factors managing these genes were defined. Thirty-two genes of pathogenic significance in insulin resistance were elucidated, and then co-expression data for these genes were utilized. These genes were organized into clusters, one of which was singled out for its high node count of 58 genes and low p -value (p = 4.117 × 10−7). DAVID Pathways, a functional annotation tool, helped identify a set of 11 genes from a single cluster associated with the endocytosis pathway related to insulin resistance. These genes (AMPH , BIN1 , CBL , DNM1 , DNM2 , DNM3 , ITCH , SH3GL1 , SH3GL2 , SH3GL3 , and SH3KBP1) are all involved in either clathrin-mediated endocytosis of the insulin receptor (IR) or clathrin-independent endocytosis of insulin-resistance-related G protein-coupled receptors (GPCR). They represent prime therapeutic targets to improve insulin sensitivity through modulation of transmembrane cell signaling. Using the ChEA3 database, we also found seven transcription factors (REST, MYPOP, CAMTA2, MYT1L, ZBTB18, NKX6–2, and CXXC5) that control the expression of these 11 genes. Inhibiting these key transcription factors would be another strategy to downregulate endocytosis. We believe that delaying removal of insulin receptors from the cell surface would prolong signaling of glucose uptake and counteract the symptoms of insulin resistance. • Insulin resistance-related genes include a significant number of insulin receptor (IR) endocytosis genes. • Mutations of the insulin receptor (IR) endocytosis-related genes are enriched in the insulin-resistant patients. • Coexpression analysis made it possible to elucidate the cluster of endocytosis pathway genes affected in insulin resistance. • Analysis of endocytosis-related genes elucidated the set of transcription factors—possible targets for diabetes therapy. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) is a fungal metabolite found in animal feeds and human foods. It is one of the most toxic and carcinogenic of aflatoxins and is classified as a Group 1 carcinogen. Dietary exposure to AFB1 and infection with chronic Hepatitis B Virus (HBV) make up two of the major risk factors for hepatocellular carcinoma (HCC). These two major risk factors raise the probability of synergism between the two agents. This review proposes some collaborative molecular mechanisms underlying the interaction between AFB1 and HBV in accelerating or magnifying the effects of HCC. The HBx viral protein is one of the main viral proteins of HBV and has many carcinogenic qualities that are involved with HCC. AFB1, when metabolized by CYP450, becomes AFB1-exo-8,9-epoxide (AFBO), an extremely toxic compound that can form adducts in DNA sequences and induce mutations. With possible synergisms that exist between HBV and AFB1 in mind, it is best to treat both agents simultaneously to reduce the risk by HCC. • Aflatoxin B1 and Hepatitis B Virus interact accelerating hepatocellular carcinoma. • Hepatitis B viral protein HBx and demethylase ALKBH5 are activated by aflatoxin B1. • The stability of HBx may be due to removal m6A modification by demethylase ALKBH5. • ER stress caused by both AFB1 and viral protein HBsAg lead to hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Advancing personalized medicine in brain cancer relies on innovative strategies, with mRNA vaccines emerging as a promising avenue. While the initial use of mRNA vaccines was in oncology, their stunning success in COVID-19 resulted in widespread attention, both positive and negative. Regardless of politically biased opinions, which relate more to the antigenic source than form of delivery, we feel it is important to objectively review this modality as relates to brain cancer. This class of vaccines trigger robust immune responses through MHC-I and MHC-II pathways, in both prophylactic and therapeutic settings. The mRNA platform offers advantages of rapid development, high potency, cost-effectiveness, and safety. This review provides an overview of mRNA vaccine delivery technologies, tumor antigen identification, combination therapies, and recent therapeutic outcomes, with a particular focus on brain cancer. Combinatorial approaches are vital to maximizing mRNA cancer vaccine efficacy, with ongoing clinical trials exploring combinations with adjuvants and checkpoint inhibitors and even adoptive cell therapy. Efficient delivery, neoantigen identification, preclinical studies, and clinical trial results are highlighted, underscoring mRNA vaccines' potential in advancing personalized medicine for brain cancer. Synergistic combinatorial therapies play a crucial role, emphasizing the need for continued research and collaboration in this area. [ABSTRACT FROM AUTHOR]

Advancing personalized medicine in brain cancer relies on innovative strategies, with mRNA vaccines emerging as a promising avenue. While the initial use of mRNA vaccines was in oncology, their stunning success in COVID-19 resulted in widespread attention, both positive and negative. Regardless of politically biased opinions, which relate more to the antigenic source than form of delivery, we feel it is important to objectively review this modality as relates to brain cancer. This class of vaccines trigger robust immune responses through MHC-I and MHC-II pathways, in both prophylactic and therapeutic settings. The mRNA platform offers advantages of rapid development, high potency, cost-effectiveness, and safety. This review provides an overview of mRNA vaccine delivery technologies, tumor antigen identification, combination therapies, and recent therapeutic outcomes, with a particular focus on brain cancer. Combinatorial approaches are vital to maximizing mRNA cancer vaccine efficacy, with ongoing clinical trials exploring combinations with adjuvants and checkpoint inhibitors and even adoptive cell therapy. Efficient delivery, neoantigen identification, preclinical studies, and clinical trial results are highlighted, underscoring mRNA vaccines' potential in advancing personalized medicine for brain cancer. Synergistic combinatorial therapies play a crucial role, emphasizing the need for continued research and collaboration in this area. [ABSTRACT FROM AUTHOR]

TGFβ functions as a tumor suppressor in some contexts and a tumor promoter in others. In a recent issue of Cancer Cell, shed light on an epigenetic mechanism that underlies this schizophrenic behavior in malignant glioma. Their findings highlight a stem cell/cancer link…and a potential blind spot in large-scale cancer genome sequencing projects. [Copyright &y& Elsevier]

The presence of missing values in a time-series dataset is a very common and well-known problem. Various statistical and machine learning methods have been developed to overcome this problem, with the aim of filling in the missing values in the data. However, the performances of these methods vary widely, showing a high dependence on the type of data and correlations within the data. In our study, we performed some of the well-known imputation methods, such as expectation maximization, k-nearest neighbor, iterative imputer, random forest, and simple imputer, to impute missing data obtained from smart, wearable health trackers. In this manuscript, we proposed the use of data binning for imputation. We showed that the use of data binned around the missing time interval provides a better imputation than the use of a whole dataset. Imputation was performed for 15 min and 1 h of continuous missing data. We used a dataset with different bin sizes, such as 15 min, 30 min, 45 min, and 1 h, and we carried out evaluations using root mean square error (RMSE) values. We observed that the expectation maximization algorithm worked best for the use of binned data. This was followed by the simple imputer, iterative imputer, and k-nearest neighbor, whereas the random forest method had no effect on data binning during imputation. Moreover, the smallest bin sizes of 15 min and 1 h were observed to provide the lowest RMSE values for the majority of the time frames during the imputation of 15 min and 1 h of missing data, respectively. Although applicable to digital health data, we think that this method will also find applicability in other domains. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most lethal form of brain tumor with a recurrence rate of almost 90% and a survival time of only 15 months post-diagnosis. It is a highly heterogeneous, aggressive, and extensively studied tumor. Multiple studies have proposed therapeutic approaches to mitigate or improve the survival for patients with glioblastoma. In this article, we review the loss of the 5′-methylthioadenosine phosphorylase (MTAP) gene as a potential therapeutic approach for treating glioblastoma. MTAP encodes a metabolic enzyme required for the metabolism of polyamines and purines leading to DNA synthesis. Multiple studies have explored the loss of this gene and have shown its relevance as a therapeutic approach to glioblastoma tumor mitigation; however, other studies show that the loss of MTAP does not have a major impact on the course of the disease. This article reviews the contrasting findings of MTAP loss with regard to mitigating the effects of glioblastoma, and also focuses on multiple aspects of MTAP loss in glioblastoma by providing insights into the known findings and some of the unexplored areas of this field where new approaches can be imagined for novel glioblastoma therapeutics. [ABSTRACT FROM AUTHOR]

Background: Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival. Methods: Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration. Results: Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%. Conclusions: AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted. Trial registration: NCT, NCT03400917, Registered 10 January 2018, [ABSTRACT FROM AUTHOR]

Background: Distinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention.Objective: We investigated diagnostic categorization using an FDA-cleared quantitative electroencephalographic/event-related potential (qEEG/ERP)-based cognitive testing system (eVox ® by Evoke Neuroscience) combined with an automated volumetric magnetic resonance imaging (vMRI) tool (Neuroreader ® by Brainreader).Methods: Patients who self-presented with memory complaints were assigned to a diagnostic category by dementia specialists based on clinical history, neurologic exam, neuropsychological testing, and laboratory results. In addition, qEEG/ERP (n = 161) and quantitative vMRI (n = 111) data were obtained. A multinomial logistic regression model was used to determine significant predictors of cognitive diagnostic category (SCD, MCI, or dementia) using all available qEEG/ERP features and MRI volumes as the independent variables and controlling for demographic variables. Area under the Receiver Operating Characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the prediction models.Results: The qEEG/ERP measures of Reaction Time, Commission Errors, and P300b Amplitude were significant predictors (AUC = 0.79) of cognitive category. Diagnostic accuracy increased when volumetric MRI measures, specifically left temporal lobe volume, were added to the model (AUC = 0.87).Conclusion: This study demonstrates the potential of a primarily physiological diagnostic model for differentiating SCD, MCI, and dementia using qEEG/ERP-based cognitive testing, especially when combined with volumetric brain MRI. The accessibility of qEEG/ERP and vMRI means that these tools can be used as adjuncts to clinical assessments to help increase the diagnostic certainty of SCD, MCI, and dementia. [ABSTRACT FROM AUTHOR]

The increasing usage of smart wearable devices has made an impact not only on the lifestyle of the users, but also on biological research and personalized healthcare services. These devices, which carry different types of sensors, have emerged as personalized digital diagnostic tools. Data from such devices have enabled the prediction and detection of various physiological as well as psychological conditions and diseases. In this review, we have focused on the diagnostic applications of wrist-worn wearables to detect multiple diseases such as cardiovascular diseases, neurological disorders, fatty liver diseases, and metabolic disorders, including diabetes, sleep quality, and psychological illnesses. The fruitful usage of wearables requires fast and insightful data analysis, which is feasible through machine learning. In this review, we have also discussed various machine-learning applications and outcomes for wearable data analyses. Finally, we have discussed the current challenges with wearable usage and data, and the future perspectives of wearable devices as diagnostic tools for research and personalized healthcare domains. [ABSTRACT FROM AUTHOR]

Combining dendritic cell vaccination with the adjuvant effect of a strain of dengue virus may be a way to overcome known tumor immune evasion mechanisms. Dengue is unique among viruses as primary infections carry lower mortality than the common cold, but secondary infections carry significant risk of hypovolemic shock. While current immuno-therapies rely on a single axis of attack, this approach combines physiological (hyperthermic reduction of tumor perfusion), immunological (activation of effector cells of the adaptive and innate immune system), and apoptosis-inducing pathways (sTRAIL) to destroy tumor cells. The premise of using multiple mechanisms of action in synergy with a decline in the ability of the tumor cells to employ resistance methods suggests the potential of this combination approach in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: There is a great interest in targeting and selective ablation of populations of circulating cells for research or therapeutic purposes. Red blood cells (RBCs) are readily available and fully biocompatible long-circulating intravascular carriers (natural life is 120days) that are amenable to chemical modifications, drug loading and reinjection. Here we demonstrate that using our previously described lipophilic ligand painting strategy, red blood cells (RBCs) could be in one step converted into targeted entities that selectively seek and bind various cells in vitro and in vivo. In vitro, RBCs modified with lipophilic anti-EpCAM or anti-CD45 antibodies efficiently bound to cancer cells and leukocytes, forming characteristic rosettes. In vivo, intravenously injected RBCs painted with anti-CD45 antibody immediately associated with CD45 positive cells in blood, forming RBC-leukocyte rosettes. Moreover, anti-CD45-modified RBCs, but not the same amount of anti-CD45 antibody or anti-CD45-lipid conjugate (1–2μg/mouse), depleted over 50% of CD45+ leukocytes from circulation, with main clearance organs of leukocytes being liver and spleen with no visible deposition in kidneys and lungs. Anti-CD20 (Rituximab)-painted RBCs efficiently (over 90%) depleted CD19+/CD20+/CD45+ human lymphoma cells in mantle cell lymphoma (MCL) JeKo-1 model, while the same amount of rituximab–lipid (2μg/mouse) was much less efficient in lymphoma cell depletion. Treatment of MCL mice with rituximab-modified RBCs carrying only 2μg of the antibody resulted in a significant prolongation of survival as compared to the same amount of antibody–lipid control. Lipophilic ligand-painted RBCs is a novel tool that can be utilized for targeting blood borne cells for experimental immunology and drug delivery applications. [Copyright &y& Elsevier]

Background: Due to the difficult geographic terrain with lack of roads and transport, the Sikkim State in India finds difficulties in contending the respiratory diseases especially during the rainy seasons. Findings: A case-control study was conducted for two months at the Central Referral Hospital of East Sikkim involving 110 individuals in the age group of 10 years and above. Due to feasibility constraints, 55 cases and 55 controls were selected by applying the non-probability sampling method with age and sex matching. The collected data were tabulated and analyzed by using the SPSS (Statistical Package for Social Sciences) version 10.0 for windows. Findings were expressed in terms of proportion, Chi Square Test and Multiple Logistic Regression Analysis. Here, p-value <0.05 was considered as statistically significant. This study revealed that the presence of overcrowding, chronic exposure to allergens, smoking habits, chronic respiratory illnesses within last 5 years, family history of chronic respiratory illnesses and mental illnesses were independently associated with respiratory diseases. Conclusion: This study should be replicated in other parts of Sikkim to obtain more confirmatory evidence on determinants of respiratory diseases. [ABSTRACT FROM AUTHOR]

In neurosurgery, an exact delineation of functional areas is of great interest to spare important regions to ensure the best possible outcome for the patient (i.e., maximum removal while maintaining the highest possible quality of life). Preoperative imaging is routinely performed, including the visualization of not only structural but also functional information. During surgery, however, brain shift can occur, leading to an offset between the previously defined and the real position. Real-time imaging during the procedure is therefore desired to obtain this information while performing surgery. In this study 15 patients suffering from glioblastoma multiforme were included. These patients underwent structural and perfusion imaging using arterial spin labeling during the procedure. The latter has been used for gathering information about tumor residual perfusion. However, special postprocessing of this data allows for additional mapping of resting state networks and is intended to be used to gather deeper insights to aid the surgeon in planning the procedure. The data of each patient could be successfully postprocessed and used to map different resting state networks alongside the default mode network. On the basis of this study, it is feasible to use the information obtained from perfusion imaging to visualize not only vascular signal but also functional activation of resting state networks without acquiring any additional data besides the already available information. This may help guide the neurosurgeon in real time to adjust the surgical plan. [ABSTRACT FROM AUTHOR]

WT2725 is a Wilms' tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56–81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309–648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6–19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development. Trial registration: NCT01621542. [ABSTRACT FROM AUTHOR]

Purpose: To retrospectively assess the utility of F fluorodeoxyglucose (FDG) positron emission tomography (PET) images of standardized uptake values corrected for blood glucose (SUV), and to compare this to various quantitative methods to identify the presence or absence of high grade malignancy. Methods: A retrospective review in 42 patients, found 81 central nervous system (CNS) lesions. Fifty one were malignant and 30 were benign or post treatment changes based on pathology ( n = 32) and on clinical outcome ( n = 49). Dynamic FDG PET scans were processed to generate parametric images of SUV, SUV, glucose metabolic rate (GMR), and lesion to cerebellum ratios (SUV), and contralateral white matter ratios (SUV). The SUV was calculated from $$ {{{\mathrm{SU}{{\mathrm{V}}_{\max }}*\mathrm{BG}}} \left/ {{\left[ {100\,\mathrm{mg}/\mathrm{dl}} \right]}} \right.} $$, where SUV is the maximum SUV and BG is the blood glucose level (mg/dL). Results: Using a malignant threshold for SUV of 4.5 and GMR of 13.0 μmole/min/100 g, the accuracies were similar for the SUV (80 %) and GMR (81 %) and were higher than the conventional SUV (73 %). The area under the receiver operating characteristic (ROC) curve for the SUV (0.8661) was better than that for the SUV (0.7955) ( p < 0.02) and was similar to those of the GMR (0.8694), SUV (0.8278), and SUV (0.8559). Conclusion: These results suggest that the SUV may assist in the interpretation of FDG PET brain images in patients with CNS lesions. The SUV method avoids the complexity of kinetic modeling and the definition of a reference region. [ABSTRACT FROM AUTHOR]

Summary: High-grade gliomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority of these tumors. Resistance to genotoxic modalities in p53-positive gliomas is generally attributed to attenuation of p53 functions by mutations of other components within the p53 signaling axis, such as p14Arf , MDM2, and ATM, but this explanation is not entirely satisfactory. We show here that the central nervous system (CNS)-restricted transcription factor Olig2 affects a key posttranslational modification of p53 in both normal and malignant neural progenitors and thereby antagonizes the interaction of p53 with promoter elements of multiple target genes. In the absence of Olig2 function, even attenuated levels of p53 are adequate for biological responses to genotoxic damage. [ABSTRACT FROM AUTHOR]

Multiple receptor tyrosine kinases (RTKs), including PDGFR, have been validated as therapeutic targets in glioblastoma multiforme (GBM), yet inhibitors of RTKs have had limited clinical success. As various antiapoptotic mechanisms render GBM cells resistant to chemo- and radiotherapy, we hypothesized that these antiapoptotic mechanisms also confer resistance to RTK inhibition. We found that in vitro inhibition of PDGFR in human GBM cells initiated the intrinsic pathway of apoptosis, as evidenced by mitochondrial outer membrane permeabilization, but downstream caspase activation was blocked by inhibitor of apoptosis proteins (IAPs). Consistent with this, inhibition of PDGFR combined with small molecule inactivation of IAPs induced apoptosis in human GBM cells in vitro and had synergistic antitumor effects in orthotopic mouse models of GBM and in primary human GBM neurospheres. These results demonstrate that concomitant inhibition of IAPs can overcome resistance to RTK inhibitors in human malignant GBM cells, and suggest that blockade of IAPs has the potential to improve treatment outcomes in patients with GBM. [ABSTRACT FROM AUTHOR]

Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for "physiological" modulation of multiple proteins whose expression is deregulated in cancer. [ABSTRACT FROM AUTHOR]

The WNT (Wingless/Integrated) signaling pathway is implicated in various stages of glioblastoma, which is an aggressive brain tumor for which therapeutic options are limited. WNT has been recognized as a hallmark of therapeutic challenge due to its context-dependent role and critical function in healthy tissue homeostasis. In this review, we deeply scrutinize the WNT signaling pathway and its involvement in the genesis of glioblastoma as well as its acquired therapy resistance. We also provide an analysis of the WNT pathway in terms of its therapeutic importance in addition to an overview of the current targeted therapies under clinical investigation. [ABSTRACT FROM AUTHOR]

High‐grade astrocytomas are malignant and aggressive, with limited treatment options. Treatment is geared not only toward increasing patient's overall survival but also in delaying or preventing neurological disability, a cause of significant morbidity. Increasingly, targeted and customized treatment approaches, especially for recurrent disease, are being explored. Here we present a successful outcome in a young patient with rapidly progressive disease who responded to targeted treatment based on genetic sequencing and circulating tumor DNA markers, given the inaccessibility of the tissue to biopsy. Molecular testing on tissue, serum or CSF may be helpful in identifying unique targets in these complex patients. [ABSTRACT FROM AUTHOR]

Background: Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level.Methods: Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS.Results: Potentially meaningful associations (p<0.1, Fisher's exact test (FET)) were found for 14 of these tests in GS vs. GB. A novel finding was higher levels of proteins mediating immuno-evasion (PD-1, PD-L1) in GS. All of the differences we observed have been associated with epithelial-to-mesenchymal transition (EMT) in other tumor types. Many of the changes we saw in GS are novel in the setting of glial tumors, including copy number amplification in LYL1 and mutations in PTPN11.Conclusions: GS shows certain characteristics of EMT, by contrast with GB. Treatments targeting immuno-evasion may be of greater therapeutic value in GS relative to GB. [ABSTRACT FROM AUTHOR]

Modified, non-neurovirulent herpes simplex viruses (HSV) have shown promise for the treatment of brain tumors, including intracranial melanoma. In this report, we show that HSV-1716, an HSV-1 mutant lacking both copies of the gene coding-infected cell protein 34.5 (ICP 34.5), can effectively treat experimental subcutaneous human melanoma in mice. In vitro, HSV-1716 replicated in all 26 human melanoma cell lines tested, efficiently lysing the cells. Therapeutic infection of subcutaneous human melanoma nodules with HSV-.171.6 led to viral replication that was restricted to tumor cells by immunohistochemistry. Moreover, HSV-1716 treatment significantly inhibited progression of preformed subcutaneous human melanoma nodules in SCID mice and caused complete regression of some tumors. This work expands the potential scope of HSV-1-based cancer therapy. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) and Squamous cell carcinoma (SCC), in combination, are referred to as Nonmelanoma skin cancers (NMSCs). NMSC has not been extensively studied in the population of the North eastern India as it has been done in the rest of India. This study was performed to understand the pattern of NMSCs in head and neck region in Sikkimese population. The present study is a retrospective analysis of NMSC of head and neck region that presented to the Department of ENT, Sikkim Manipal Institute of Medical sciences (SMIMS), a tertiary care center in Gangtok, Sikkim from July 2009 to July 2012. They were reviewed according to age, gender, site of involvement and histological types. Of the thirty-seven cases of NMSC analyzed during the 3 year study period, 24 cases were SCC and 13 cases were BCC. The most common age group for SCC was 40-50 years and BCC was 61-70 years. The most common site for both SCC and BCC was the upper lip. For SCC, the most common histologically type was well-differentiated and for BCC, it was the solid type. NMSCs comprise a small but significant proportion of all skin cancer patients in the world. SCC is the commonest variety unlike in western countries. The importance of understanding the risk factors as well as studying the frequency of histopathological patterns can help in the overall prognostic outlook for patients and also in planning an effective management. [ABSTRACT FROM AUTHOR]

2 B Search Terms b : T-cell lymphoma, CNS lymphoma, temozolomide, MGMT References 1 Shiels MS, Pfeiffer RM, Besson C, et al. Primary Central Nervous System Lymphoma (PCSNL) accounts for 2% of all primary brain tumors with increasing incidence in the immunocompetent elderly population [[1]]. At this point we lack information on the frequency or significance of MGMT methylation in peripheral T-cell lymphomas and PCNS-TCL, though some innovative studies have started to explore this in CNS diffuse large B-cell lymphomas [[15]]. Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group breast cancer radiotherapy patterns of practice in europe view project primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. [Extracted from the article]

Purpose: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response.Methods and Materials: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume.Results: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01).Conclusions: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response. [ABSTRACT FROM AUTHOR]

To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into "responder" and "non-responder". By RNASeq analysis we found that the non-responder phenotype is significantly linked with the expression of UPR genes, and in particular ERN1 (IRE1) and ATF4. We also identified two additional genes selectively overexpressed among non-responders, IGFBP3 and IGFBP5. CRISPR-mediated deletion of the ERN1, IGFBP3, IGFBP5 signature genes in the U251 human GBM cell line increased responsiveness to 12ADT. Remarkably, >65% of GBM cases in The Cancer Genome Atlas express the non-responder (ERN1, IGFBP3, IGFBP5) gene signature. Thus, elevated levels of IRE1α and IGFBPs predict a poor response to drugs inducing unresolvable UPR and possibly other forms of chemotherapy helping in a better stratification GBM patients. [ABSTRACT FROM AUTHOR]

Abnormal regulation of β-catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, β-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel β-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of β-catenin. C2 selectively inhibits β-catenin, lowers its cellular load and significantly reduces viability of β-catenin-driven cancer cells. Through direct binding to β-catenin, C2 renders the target inactive that eventually activates proteasome system for its removal. Here we report a novel pharmacologic approach for selective inhibition of β-catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of β-catenin. [ABSTRACT FROM AUTHOR]

Parasellar meningiomas involving the cavernous sinus and Meckel's cave pose a management challenge because of invasion around neurovascular structures and the pituitary gland. The management options range from aggressive resection to focused radiotherapy alone. We present a strategy for these tumors that includes endonasal bony decompression, partial tumor removal, and stereotactic radiotherapy (SRT) in select cases. The tumor location, previous treatments, cranial neuropathies, pituitary dysfunction, tumor control rates, use of stereotactic radiosurgery, SRT, and complications were retrospectively evaluated. Twenty patients (age range, 43–81 years; 65% women; 90% with World Health Organization grade I; median follow-up, 57 months; 14 without previous debulking and RT; 6 with previous debulking and RT) underwent endonasal bony decompression and partial tumor removal. The most common tumor locations were cavernous sinus (95%), Meckel's cave (95%), sella (75%), petroclival (60%), and optic canal/orbit (30%). Three patients with large meningiomas underwent staged transcranial and endonasal debulking. Of the 14 patients without previous debulking and RT, 11 had undergone postoperative SRT, with tumor shrinkage in 3 (27%). At the last follow-up examination, for these 14 patients and the 6 patients who had undergone previous surgery and RT, tumor control was 100% and 33% (P < 0.001) and the cranial neuropathies had improved in 57% and 33%, respectively. Major complications occurred in 2 patients: a permanent sixth cranial nerve palsy and cerebrospinal fluid leakage requiring reoperation. Endonasal bony decompression and selective tumor removal, followed by SRT, appears to be a reasonable treatment option for most previously untreated parasellar meningiomas. For patients who have undergone previous debulking and RT, new targeted treatment strategies are needed. [ABSTRACT FROM AUTHOR]

Antibody drug conjugates (ADCs) represent a promising and an efficient strategy for targeted cancer therapy. Comprised of a monoclonal antibody, a cytotoxic drug, and a linker, ADCs offer tumor selectively, reduced toxicity, and improved stability in systemic circulation. Recent approvals of two ADCs have led to a resurgence in ADC research, with more than 60 ADCs under various stages of clinical development. The therapeutic success of future ADCs is dependent on adherence to key requirements of their design and careful selection of the target antigen on cancer cells. Here we review the main components in the design of antibody drug conjugates, improvements made, and lessons learned over two decades of research, as well as the future of third generation ADCs. [ABSTRACT FROM AUTHOR]

Purpose: We present a patient with adrenal Cushing’s syndrome causing steroid myopathy. The purpose of the case report is to illustrate the clinical usefulness of quantitative muscle ultrasonography for the assessment of glucocorticoid-induced changes in muscle mass (MM) and structure. Methods: Assessments of physical performance, muscle strength, MM (i.e., total body skeletal MM, appendicular skeletal MM, and thickness of lower limb muscles), and muscle structure (i.e., echo intensity of lower limb muscles) were performed in the patient both in the active phase of the disease (preoperatively) and 6 months after surgical intervention (postoperatively). Results: Muscle strength, physical performance, and MM were low both preoperatively and postoperatively. We also found preoperatively an increased echo intensity that normalized postoperatively. Conclusions: Clinical implications of these findings are double-fold. First, although the muscle structure can recover quickly in steroid myopathy patients, the recovery of MM may take months to years. Second, we show that muscle echo intensity can be useful to track the progression of steroid myopathy overtime and may help to indicate early response to therapeutic interventions. Further prospective studies are needed to confirm the value of muscle echo intensity in patients with endogenous or exogenous Cushing’s syndrome presenting with steroid myopathy. [ABSTRACT FROM AUTHOR]