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This study hypothesizes that the application of low-dose nonthermal biocompatible dielectric barrier discharge plasma (DBD-NBP) to human gingival fibroblasts (HGFs) will inhibit colony formation but not cell death and induce matrix metalloproteinase (MMP) expression, extracellular matrix (ECM) degradation, and subsequent cell migration, which can result in enhanced wound healing. HGFs treated with plasma for 3 min migrate to each other across the gap faster than those in the control and 5-min treatment groups on days 1 and 3. The plasma-treated HGFs show significantly high expression levels of the cell cycle arrest-related p21 gene and enhanced MMP activity. Focal adhesion kinase (FAK) mediated attenuation of wound healing or actin cytoskeleton rearrangement, and plasma-mediated reversal of this attenuation support the migratory effect of DBD-NBP. Further, this work performs computer simulations to investigate the effect of oxidation on the stability and conformation of the catalytic kinase domain (KD) of FAK. It is found that the oxidation of highly reactive amino acids (AAs) Cys427, Met442, Cys559, Met571, Met617, and Met643 changes the conformation and increases the structural flexibility of the FAK protein and thus modulates its function and activity. Low-dose DBD-NBP-induces host cell cycle arrest, ECM breakdown, and subsequent migration, thus contributing to the enhanced wound healing process.

Formation of an electrolyte complex using the electrostatic interactions between a polyanionic polymer and a cationic drug is a simple and efficient method of preparing a colloidal drug carrier system. Dextran sulfate, with a negatively charged sulfate group, was reacted in an acetate buffer solution of pH 3 with positively charged 1° amine, 2° amine, 3° amine, piperazine, and piperidine structures from 24 small-molecule drugs. The electrolyte complex was formed from 15 drugs, 63% of those tested. The tendency to form the electrolyte complex was in the order of piperazine and piperidine >3° amine >>2° amine. The drugs with the 1° amine structure failed to form an electrolyte complex. The mean particle sizes were in the range of 50-740 nm, and most of them showed a submicron colloidal dispersion of

Background The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues. Methods Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups. Results We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression. Conclusions This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies.

Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor and the development of leptomeningeal dissemination (LM seeding) through the cerebrospinal fluid (CSF) circulation is a major cause of treatment failure. We have previously established the MB LM seeding mouse model. In this study, we aimed to determine molecules that can target seeding (metastatic) cells by analyzing their specific genetic and functional characteristics. Methods: Seeding and non-seeding cells were isolated and cultured, respectively, and microarray analysis was carried out. Proliferation and wound-healing assays were performed through the HCS system, and viability, migration and adhesion assays were accomplished. In addition, the therapeutic effect of the selected inhibitor was analyzed by region of interest (ROI) analysis of bioluminescence in vivo. Results: The gene expression and functional characteristics of the successfully obtained seed cells and non-seed cells were compared and analyzed. Differentially expressed genes (DEGs) analysis indicated that heat shock protein 70 (Hsp70) was in the highest rank in seeding cells, and pathway enrichment analysis revealed that the metabolism was the main pathway enriched in seeding cells. Proliferation of seeding cells was slower than that of non-seeding cells, but there was no significant difference in viability. Notably, the wound-healing of seeding cells was delayed, but the adhesion ability on collagen was higher. Among the six HSP70 inhibitors, VER155008 was efficiently sensitive to seeding cells, and suppression of expression of MRP proteins along with HSP70 was also confirmed. In addition, it was observed that the treatment of VER155008 reduced seeding through the spinal cord in vivo. Conclusion: Our study suggests that VER15008 can be a promising treatment option, targeting LM seeding of MB. Citation Format: Seung Ah Choi, Saehim Ha, Hee-Young Lee, Joo Whan Kim, Jin Chul Paeng, Ji Hoon Phi. Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2468.

Childhood cancers are rare and clinically diverse. They are typically associated with few driver mutational events than adult cancers, constituting potential targets for patient-specific precision therapy approaches. Here, we evaluated the feasibility of using a patient-derived tumor cell (PDC) based drug screening system and integrated multi-omics data to achieve precision oncology for pediatric patients. We established a PDC library derived from a few passage-cultured tumor cells from surgically resected tumor specimens and conducted chemical screening, which composed of various target agents of major oncogenic pathways (e.g. receptor tyrosine kinase inhibitor, proteasome inhibitor and histone deacetylase etc.). Next Generation Sequencing was performed to characterize the genomic and transcriptomic traits of tumors. Overall, success of establishing PDCs of pediatric cancers was high (80.4%) and comparable to adult cancers. The amount of obtained tissue was an important factor for the success of PDC establishment; the estimated optimal weight for PDC establishment was small (1.14g) and it is noteworthy that a small amount of tumor sample is sufficient to identify the potential hit(s) of parental tumors. The platform provided therapeutic options to pediatric tumors regardless of actionable targets. Our PDC approach identified several potential gene-drug associations, including anti-PI3K/Akt agents for neuroblastomas and anti-SHH agents for sarcomas with EWSR1 fusion. Given that a considerable proportion of pediatric tumors still lack actionable targets with matched treatment options, PDC-based drug screening profiles can be an optimal therapeutic strategy for these cases. Collectively, our analysis confirmed the feasibility of PDC-based in vitro drug screening systems to guide the therapeutic strategy for pediatric patients. This approach will accelerate the preclinical research for pediatric tumors to understand their pathophysiology and investigate the potential therapeutic strategies to fulfill the future precision oncology. Citation Format: Gi Ju Lee, Seung-Won Choi, Seung Ah Choi, Hee-Jin Cho, Robyn Gartrell, Ji Won Lee, Joo Whan Kim, Nam-Gu Her, Raul Rabadan, Ki Woong Sung, Do-Hyun Nam, Seung-Ki Kim. Proof of principle for pharmacogenomic-guided precision oncology for pediatric malignancy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4486.

This study explores how social media act as a tool to communicate with the government and the world through the research of the role of social media and the processes by which people can be mobilized to engage in protests. Focusing primarily on Facebook and Instagram as Social Networking Sites (SNS), the study uses survey data collected through Typeform online survey (N=100). Findings indicate that the frequency of SNS has been strongly correlated with protest activities. SNS promoted on-site news consumption and political speech, which in turn facilitated protest participation. Despite the prevalence of incidental exposure to news on SNS, the exposure did not give rise to more political action, such as the voicing of political opinions on SNS.

Background/aim Both pediatric glioblastoma (pGB) and adult glioblastoma (aGB) are clinically devastating, and are known to have different molecular pathogenesis. Here, we focused on the role of ZEB2 in pGB and aGB. Materials and methods Following transfection with ZEB2 siRNA into pGB cells (KNS42) and aGB cells (U87 and U373), cell proliferation, migration and invasion, and cell cycle progression were evaluated. Results Targeted inhibition of ZEB2 induced up-regulation of E-cadherin expression and down-regulation of vimentin expression. Furthermore, it reduced invasion and migration of both pGB and aGB cells. Interestingly, in pGB cells, but not in aGB cells, silencing of ZEB2 reduced cell proliferation and viability, and affected the cell cycle progression of tumor cells. Conclusion Inhibition of ZEB2 altered the mesenchymal features and reduced the migration and invasive ability of both pGB and aGB cells. ZEB2 effects were different in pGB and aGB cells regarding proliferation and cell cycle progression, suggesting that different underlying molecular mechanisms drive progression in these two types of tumors.

Purpose Molecular subgrouping of medulloblastoma has become important due to its impact on risk group stratification. Immunohistochemistry (IHC) has been widely used but it has innate limitations. The NanoString assay has been proposed as an alternative method. This study aims to present the characteristics of medulloblastoma subgrouped by the NanoString assay and to compare the subgrouping results with the IHC method. Methods Pediatric patients with histological diagnosis of medulloblastoma who underwent surgery from 2007 to 2021 were included. Clinical characteristics, pathological findings were reviewed. Molecular subgrouping was performed by IHC and by NanoString nCounter Elements TagSets assay. Test for concordance between two methods was made. Results Among a total of 101 patients analyzed, subgrouping using the NanoString assay resulted in 14 (13.8%) WNT, 20 (19.8%) SHH, 18 (17.8%) Group 3, and 39 (38.6%) Group 4 subgroup cases. Survival analysis revealed the following from best to worse prognosis: WNT, Group 4, SHH, and Group 3. In SHH subgroup the large cell/anaplastic histology was present in 30% of cases. Seventy-one cases were analyzed for concordance between NanoString and IHC. Cohen’s kappa value indicated moderate agreement but identification of Groups 3 and 4 with IHC using NPR3 and KCNA1 markers exhibited poor results. Conclusions The NanoString assay of Korean medulloblastoma patients revealed a more aggressive clinical course in the SHH subgroup which may be explained by a higher proportion of large cell/anaplastic histology being present in this subgroup. IHC did not distinguish Group 3 or 4 accurately. The NanoString assay may represent a good alternative method for practical use in the clinical field.

Pelvic organ prolapse (POP) is a chronic disorder that affects quality of life in women. Several POP treatments may be accompanied by abrasion, constant infection, and severe pain. Therefore, new treatment methods and improvements in current treatments for POP are required. Non-thermal atmospheric-pressure plasma is a rising biomedical therapy that generates a mixed cocktail of reactive species by different mechanisms. In this study, we applied a cylinder-type dielectric barrier discharge plasma device to create a plasma-treated liquid (PTL). The PTL was added to primary cultured human uterosacral ligament fibroblast (hUSLF) cells from POP patients at each stage. Surprisingly, treatment with diluted PTL increased hUSLF cell viability but decreased ovarian cancer cell viability. PTL also decreased cell apoptosis in hUSLF cells but increased it in SKOV3 cells. Our results suggest that PTL protects hUSLF cells from cell apoptosis by controlling the p53 pathway and improves cell viability, implying that PTL is a promising application for POP therapy.

PurposeAtypical teratoid/rhabdoid tumor (AT/RT) is arising typically in young children and is associated with a dismal prognosis which there is currently no curative chemotherapeutic regimen. Based on previous studies showing high histone deacetylase 1 (HDAC1) expression in AT/RT, the HDAC1 inhibitor CI-994 was used as a novel treatment strategy in this study. We assessed the anticancer effects of CI-994 and conventional drugs (etoposide, cisplatin or 4-HC) in AT/RT cells.MethodsAT/RT patient-derived primary cultured cells and cell lines were prepared. HDAC1 was estimated by real-time quantitative polymerase chain reaction (RT-qPCR). The interaction of the drugs was analyzed using isobologram analysis. Cell viability, apoptosis, HDAC enzyme activity and western blot assays were carried out.ResultsHDAC1 was overexpressed in AT/RT compared to medulloblastoma. The combination index (CI) of CI-994 with etoposide revealed a synergistic effect in all AT/RT cells, but no synergistic effect was observed between CI-994 and cisplatin or 4-HC. CI-994 effectively reduced not only Class I HDAC gene expression but also HDAC enzyme activity. The combination treatment of CI-994 with etoposide significantly increased apoptosis compared to the single treatment. The enhanced effect of apoptosis by this combination treatment is related to a signaling pathway which decreases topoisomerase (Topo) II and increases histone H3 acetylation (Ac-H3).ConclusionWe demonstrate that the combination treatment of CI-994 with etoposide exerts a synergistic anticancer effect against AT/RT by significantly inducing apoptosis through Topo II and Ac-H3 regulation.Clinical RelevanceThis combination treatment might be considered a viable therapeutic strategy for AT/RT patients.

Background Using a pathway-focused approach, we aimed to provide a subgroup-specific basis for finding novel therapeutic strategies and further refinement of the risk stratification in pediatric medulloblastoma. Method Based on genome-wide Cox regression and Gene Set Enrichment Analysis, we investigated prognosis-related signaling pathways and core genes in pediatric medulloblastoma subgroups using 530 patient data from Medulloblastoma Advanced Genomic International Consortium (MAGIC) project. We further examined the relationship between expression of the prognostic core genes and frequent chromosome aberrations using broad range copy number change data. Results In SHH subgroup, relatively high expression of the core genes involved in p53, PLK1, FOXM1, and Aurora B signaling pathways are associated with poor prognosis, and their average expression synergistically increases with co-occurrence of losses of 17p, 14q, or 10q, or gain of 17q. In Group 3, in addition to high MYC expression, relatively elevated expression of PDGFRA, IGF1R, and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK pathways are related to poor survival outcome, and their average expression is increased with the presence of isochromosome 17q [i(17q)] and synergistically down-regulated with simultaneous losses of 16p, 8q, or 4q. In Group 4, up-regulation of the genes encoding various immune receptors and those involved in NOTCH, NF-κB, PI3K/AKT, or RHOA signaling pathways are associated with worse prognosis. Additionally, the expressions of Notch genes correlate with those of the prognostic immune receptors. Besides the Group 4 patients with previously known prognostic aberration, loss of chromosome 11, those with loss of 8q but without i(17q) show excellent survival outcomes and low average expression of the prognostic core genes whereas those harboring 10q loss, 1q gain, or 12q gain accompanied by i(17q) show bad outcomes. Finally, several metabolic pathways known to be reprogrammed in cancer cells are detected as prognostic pathways including glutamate metabolism in SHH subgroup, pentose phosphate pathway and TCA cycle in Group 3, and folate-mediated one carbon-metabolism in Group 4. Conclusions The results underscore several subgroup-specific pathways for potential therapeutic interventions: SHH-GLI-FOXM1 pathway in SHH subgroup, receptor tyrosine kinases and their downstream pathways in Group 3, and immune and inflammatory pathways in Group 4. Electronic supplementary material The online version of this article (10.1186/s12885-019-5742-x) contains supplementary material, which is available to authorized users.

OBJECTIVEEndothelial colony-forming cells (ECFCs) isolated from pediatric patients with moyamoya disease (MMD) have demonstrated decreased numbers and defective functioning in in vitro experiments. However, the function of ECFCs has not been evaluated using in vivo animal models. In this study, the authors compared normal and MMD ECFCs using a chronic cerebral hypoperfusion (CCH) rat model.METHODSA CCH rat model was made via ligation of the bilateral common carotid arteries (2-vessel occlusion [2-VO]). The rats were divided into three experimental groups: vehicle-treated (n = 8), normal ECFC-treated (n = 8), and MMD ECFC-treated (n = 8). ECFCs were injected into the cisterna magna. A laser Doppler flowmeter was used to evaluate cerebral blood flow, and a radial arm maze test was used to examine cognitive function. Neuropathological examinations of the hippocampus and agranular cortex were performed using hematoxylin and eosin and Luxol fast blue staining in addition to immunofluorescence with CD31, von Willebrand factor, NeuN, myelin basic protein, glial fibrillary acidic protein, and cleaved caspase-3 antibodies.RESULTSThe normal ECFC-treated group exhibited improvement in the restoration of cerebral perfusion and in behavior compared with the vehicle-treated and MMD ECFC-treated groups at the 12-week follow-up after the 2-VO surgery. The normal ECFC-treated group showed a greater amount of neovasculogenesis and neurogenesis, with less apoptosis, than the other groups.CONCLUSIONSThese results support the impaired functional recovery of MMD ECFCs compared with normal ECFCs in a CCH rat model. This in vivo study suggests the functional role of ECFCs in the pathogenesis of MMD.

The velocity dependence on the magnetic friction and the magnetic field dependence on the terminal velocity of the magnets moving on the conductor plane were investigated. A mechanical friction effect was eliminated by attaching the magnet to a cart which moves almost frictionless on the plane. From the relation between the terminal velocity and acceleration of the cart, the magnetic friction acting on the cart was found to be linearly dependent on the velocity. The magnetic field dependence on the terminal velocity was also investigated under the various magnetic fields and fixed acceleration. The terminal velocity of the moving cart decreases linearly with respect to the increasing relative magnetic field intensity., {"references":["Fodor, Petru S, and Peppard, Tara. \"Lenz's law demonstration using an ultrasonic position sensor.\" Physics Teacher, vol. 50, no. 6, 2012, pp. 344-346, https://doi.org/10.1119/1.4745685.","Ivanova, Dragia T. \"Another way to demonstrate Lenz's law.\" Physics Teacher, vol. 38, no. 1, 2000, p. 48, https://doi.org/10.1119/1.880423","PASCO, \"2.2 m Aluminum Dynamics Track.\" https://www.pasco.com/products/lab-apparatus/mechanics/dynamics-systems/me-9779. Accessed 23 July 2020.","PASCO, \"PASPORT Motion Sensor.\" https://www.pasco.com/products/sensors/pasport/ps-2103. Accessed 23 July 2020.","Rossing, Thomas D. \"Eddy currents and magnetic friction.\" Physics Teacher, vol. 35, no. 3, 1997, p. 133, https://doi.org/10.1119/1.2344619.","Walker, J, Halliday, D, and Resnick, R. Principles of Physics. John Wiley & Sons, Inc., 2014."]}

A 450-uW 8-bit PLL-based frequency-to-digital converter (PFDC) for digital sensors with 1k-to-1MHz input frequency range is proposed in a 65nm CMOS technology. In the proposed PFDC, the coarse frequency detector (CFD) detects the rough frequency range of input signal which is from the digital sensor used in the IoT application, and the output frequency of VCO and dividing ratio of PLL are digitally controlled by the output of CFD. Because the sampling clock used in the fine frequency detector (FFD) is adaptively controlled by the frequency of input clock. Also, the PFDC immunes against to the environmental noise with a help of digital operation. The proposed PFDC occupies $0.103mm^{2}$ and the power consumption with the highest input frequency which makes the highest sampling clock frequency is 450-uW with 1-V supply voltage.

Atypical teratoid/rhabdoid tumor (AT/RT) is the most malignant tumor of the central nervous system that generally occurs in young children. Despite the use of intensive multimodal therapy for AT/RT, the prognosis is still poor. The brain tumor initiating cells in AT/RT cells has been suggested as one of the challenges in AT/RT treatment. These cells have high expression of aldehyde dehydrogenase (ALDH). We investigated the combination effect of the ALDH inhibitor, disulfiram and cisplatin in the treatment of AT/RT cells. Isobologram analysis revealed that the combination therapy synergistically increases AT/RT cell death. The enzyme activity of ALDH AT/RT cells was effectively reduced by the combination therapy. We proposed that the synergistic augmentation occurs, at least partially through an increase in cleaved Poly (ADP-ribose) polymerase (PARP)-dependent apoptosis mediated by activating transcription factor 3 (ATF3). In the AT/RT mouse model, the combination therapy decreased tumor volume and prolonged survival. Immunofluorescence assay in mouse brain tissues were consistent with the expression of ATF3 and cleaved PARP. Our study demonstrates enhanced anti-cancer effect of combination therapy of disulfiram and cisplatin. This combination might provide a viable therapeutic strategy for AT/RT patients.

Despite great advances in understanding of molecular pathogenesis and achievement of a high cure rate in medulloblastoma, recurrent medulloblastomas are still dismal. Additionally, misidentification of secondary malignancies due to histological ambiguity leads to misdiagnosis and eventually to inappropriate treatment. Nevertheless, the genomic characteristics of recurrent medulloblastomas are poorly understood, largely due to a lack of matched primary and recurrent tumor tissues. We performed a genomic analysis of recurrent tumors from 17 pediatric medulloblastoma patients. Whole transcriptome sequencing revealed that a subset of recurrent tumors initially diagnosed as locally recurrent medulloblastomas are secondary glioblastomas after radiotherapy, showing high similarity to the non-G-CIMP proneural subtype of glioblastoma. Further analysis, including whole exome sequencing, revealed missense mutations or complex gene fusion events in PDGFRA with augmented expression in the secondary glioblastomas after radiotherapy, implicating PDGFRA as a putative driver in the development of secondary glioblastomas after treatment exposure. This result provides insight into the possible application of PDGFRA-targeted therapy in these second malignancies. Furthermore, genomic alterations of TP53 including 17p loss or germline/somatic mutations were also found in most of the secondary glioblastomas after radiotherapy, indicating a crucial role of TP53 alteration in the process. On the other hand, analysis of recurrent medulloblastomas revealed that the most prevalent alterations are the loss of 17p region including TP53 and gain of 7q region containing EZH2 which already exist in primary tumors. The 7q gain events are frequently accompanied by high expression levels of EZH2 in both primary and recurrent medulloblastomas, which provides a clue to a new therapeutic target to prevent recurrence. Considering the fact that it is often challenging to differentiate between recurrent medulloblastomas and secondary glioblastomas after radiotherapy, our findings have major clinical implications both for correct diagnosis and for potential therapeutic interventions in these devastating diseases.

// Ji Hoon Phi 1, 2, 3, * , Seung Ah Choi 1, 2, * , Pil Ae Kwak 1, 2 , Ji Yeoun Lee 1, 3, 4 , Kyu-Chang Wang 1, 3 , Do Won Hwang 5 and Seung-Ki Kim 1, 2, 3 1 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul, Korea 2 Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Korea 3 Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea 4 Department of Anatomy, Seoul National University Hospital, Seoul, Korea 5 Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Seung-Ki Kim, email: nsthomas@snu.ac.kr Do Won Hwang, email: hdw6592@hanmail.net Keywords: medulloblastoma, leptomeningeal seeding, histone deacetylase inhibitor, anti-cancer therapy, bioluminescence imaging Received: February 28, 2017 Accepted: April 25, 2017 Published: May 24, 2017 ABSTRACT Leptomeningeal seeding is a strong negative prognostic factor for medulloblastoma (MB). The mechanism of leptomeningeal seeding is unclear but may involve epigenetic regulation. In this study, we evaluated the feasibility of a histone deacetylase (HDAC) inhibitor, panobinostat, in the suppression of MB leptomeningeal seeding. Panobinostat decreased the cell viability and proliferation, inducing cell cycle arrest and apoptosis in MB cell lines. The migration and adhesion capabilities were significantly decreased. Panobinostat effectively down-regulated protein expression of CCND1 and ID3 which has been associated with leptomeningeal seeding of MB. After panobinostat treatment, neurophil-like cellular processes developed and expression of synaptophysin and NeuroD1 was increased, indicating neuronal differentiation. In MB leptomeningeal seeding in vivo model, the panobinostat-treated group showed significantly decreased spinal leptomeningeal seeding and a survival benefit. The findings demonstrate that panobinostat suppresses MB leptomeningeal seeding through the down-regulation of ID3 and the induction of neuronal differentiation. An HDAC inhibitor might be a potent treatment option for the treatment of MB patients with leptomeningeal seeding.

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

Background Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets. Methods Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines. Results WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNA-Seq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells. Conclusions We propose that NPM1 is a novel therapeutic target for AT/RTs. Electronic supplementary material The online version of this article (10.1186/s12885-019-6044-z) contains supplementary material, which is available to authorized users.

Background Olfactory dysfunction is frequently experienced by patients with allergic rhinitis. It is thought to result from structural and functional changes occurring in the olfactory mucosa caused by inflammation. However, the current understanding of the pathophysiology of olfactory dysfunction in allergic rhinitis remains unclear. Objective To investigate the mechanism by which the olfactory neural cells are damaged in allergic rhinitis. Methods Olfactory sphere cells (OSCs) were established after dissociation and serial cultures of cells from the mouse olfactory mucosa. Viability and proliferation of OSCs were compared between control and allergic rhinitis mice models, and olfactory stem cell markers were analysed in vivo. To elucidate which cytokines have an inhibitory effect on OSCs, viability and apoptotic markers of OSCs were investigated. Results Olfactory sphere cells were successfully isolated from the olfactory mucosa of mice, and these cells expressed markers of neural stem cells. To investigate the neural differentiation, we performed the immunocytochemical staining and found significantly elevated expressions of Tuji1, GFAP and O4 on OSCs. On the comparison of the characteristics of OSCs between control and allergic rhinitis model, we detected significantly fewer neurospheres, reduced clonogenic capacity and decreased expression of olfactory neural stem cell markers in allergic rhinitis model. When OSCs were treated with several major allergic cytokines were treated on OSCs, only TNF-α showed an inhibitory effect on OSCs. Interestingly, IL-5 had an inhibitory effect on the viability of OSCs in combination with TNF-α, whereas IL-5 alone does not have an effect. Moreover, TNF-α combined with IL-5 significantly increased the apoptotic expression, compared with TNF-α or IL-5 alone. Additionally, allergic rhinitis mice models showed the increased apoptotic expression. Conclusion and clinical relevance Allergic rhinitis mice models showed lower expression of OSCs, and TNF-α combined with IL-5 had an apoptotic effect on OSCs. Therefore, these cytokines may be therapeutic targets for olfactory dysfunction in patients with allergic rhinitis.

BACKGROUND Diagnosis of leptomeningeal metastasis (LM) in medulloblastoma is made by positive findings in either MRI or CSF cytology. We studied if CSF metabolomics profile can differentiate the discordant results between MRI and CSF cytology and reflect the sampling time related to treatment. MATERIALS AND METHODS We prospectively collected 83 CSF samples from 45 medulloblastoma patients. A total of 6,527 low-mass ions (LMIs) were detected using liquid chromatography tandem mass spectrometry (LC-MS/MS). Discriminative low-mass ions (LMIs) between four different MRI and cytology results groups were evaluated and representative LMIs were identified. RESULTS CSF cytology and MRI finding were both positive for LM in 8 samples and both negative for 47 samples. Tests were cytology (-) and MRI (+) in 20 samples, whereas cytology (+) and MRI (-) status were in the remaining 8 samples. The diagnostic accuracy by area under the curve (AUC) was 0.722 for cytology and 0.888 for MRI each. Based on the exclusiveness of LMI between groups, we verified 27 discriminative LMIs in MRI (+)/ cytology (+), 9 LMIs in MRI (+)/ cytology (-), and 12 LMIs in MRI (-) and cytology (+) group, separately. Metabolic pathways involved in MRI (+)/ cytology (+) group were linoleic acid, phenylalanine, TCA cycle, retinol, arginine-ornithine, nicotinate-nicotinamide, etc. Low-mass-ion discriminant equation (LOME), which could differentiate both different MRI and cytology results and the sampling time or presence of LM-related symptoms was found. CONCLUSION Non-targeted MSanalysis CSF metabolite in medulloblastomas revealed significantly different profiles, and these results suggest LMI profiles might have a higher sensitivity for LM diagnosis than either MRI or cytology.