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Mismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options. The authors examined 13 mismatch repair-deficient (MMRD)-associated primary brain tumors to determine molecular characteristics and biological behavior. MMRD occurred after chemotherapy and radiotherapy in two cases. The genetic profile of MMRD glioblastoma was different from that of conventional glioblastoma. Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R + microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders.

The past two decades has seen new methodological debates on the identification of production function. Olley and Pakes (J Polit Econ 101(6):1149–1164, 1996), Levinsohn and Petrin (Rev Econ Stud 70(2):317–340, 2003), and Ackerberg et al. (Econometrica 83(6):2411–2451, 2015) introduced nonparametric approaches to control for the unobserved productivity in the estimation of production function, which requires the availability of panel data. There has been an another body of the literature that argued that models that are typically estimated on the basis of panel data can also be identified with repeated cross-sections under certain conditions (Verbeek and Vella, 2005). The objective of this paper is two-fold. First, built on the insight of Verbeek and Vella (2005), this paper proposes a new approach to estimate the nonparametric control function based on repeated cross-sections. This is important because in many studies there is a lack of panel data where agents are followed over time, while repeated cross-sections may be available. Second, using cross-sections of Korean ginseng farms over 2006 to 2013, we apply our method to examine the evolution of farm-level productivity over time and across major production regions. Comparing our method with the pooled OLS regressions, the results show that the materials input coefficients are underestimated in the OLS regressions, which is consistent with the data where farms in the large ginseng production regions use relatively less materials than those in the other regions.

Background Epigenetic regulations frequently appear in Glioblastoma (GBM) and are highly associated with metabolic alterations. Especially, Histone deacetylases (HDACs) correlates with the regulation of tumorigenesis and cell metabolism in GBM progression, and HDAC inhibitors report to have therapeutic efficacy in GBM and other neurological diseases; however, GBM prevention and therapy by HDAC inhibition lacks a mechanism in the focus of metabolic reprogramming. Methods HDAC2 highly express in GBM and is analyzed in TCGA/GEPIA databases. Therefore, HDAC2 knockdown affects GBM cell death. Analysis of RNA sequencing and qRT-PCR reveals that miR-3189 increases and GLUT3 decreases by HDAC2 knockdown. GBM tumorigenesis also examines by using in vivo orthotopic xenograft tumor models. The metabolism change in HDAC2 knockdown GBM cells measures by glucose uptake, lactate production, and OCR/ECAR analysis, indicating that HDAC2 knockdown induces GBM cell death by inhibiting GLUT3. Results Notably, GLUT3 was suppressed by increasing miR-3189, demonstrating that miR-3189-mediated GLUT3 inhibition shows an anti-tumorigenic effect and cell death by regulating glucose metabolism in HDAC2 knockdown GBM. Conclusions Our findings will demonstrate the central role of HDAC2 in GBM tumorigenesis through the reprogramming of glucose metabolism by controlling miR-3189-inhibited GLUT3 expression, providing a potential new therapeutic strategy for GBM treatment.

We present a back-to-back (BTB) structured, dual-mode ultrasonic device that incorporates a single-element 5.3 MHz transducer for high-intensity focused ultrasound (HIFU) treatment and a single-element 20.0 MHz transducer for high-resolution ultrasound imaging. Ultrasound image-guided surgical systems have been developed for lesion monitoring to ensure that ultrasonic treatment is correctly administered at the right locations. In this study, we developed a dual-element transducer composed of two elements that share the same housing but work independently with a BTB structure, enabling a mode change between therapy and imaging via 180-degree mechanical rotation. The optic fibers were embedded in the HIFU focal region of ex vivo chicken breasts and the temperature change was measured. Images were obtained in vivo mice before and after treatment and compared to identify the treated region. We successfully acquired B-mode and C-scan images that display the hyperechoic region indicating coagulation necrosis in the HIFU-treated volume up to a depth of 10 mm. The compact BTB dual-mode ultrasonic transducer may be used for subcutaneous thermal ablation and monitoring, minimally invasive surgery, and other clinical applications, all with ultrasound only.

Epithelial-mesenchymal transition (EMT) is a major cellular process in which epithelial cells lose cell polarity and cell-cell adhesion and become motility and invasiveness by transforming into mesenchymal cells. Catechol is one of the natural compounds present in fruits and vegetables and has various pharmacological and physiological activities including anti-carcinogenic effects. However, the effects of catechol on EMT has not been reported. Epidermal growth factor (EGF) is one of the growth factors and is known to play a role in inducing EMT. The present study showed that catechol suppressed not only the morphological changes to the mesenchymal phenotype of epithelial HCC cells, but also the reduction of E-cadherin and the increment of Vimentin, which are typical hallmark of EMT. In addition, catechol suppressed EMT-related steps such as migration, invasion, anoikis resistance acquisition, and stem cell-like characterization through the EGFR-AKT-ERK signaling pathway during liver cancer metastasis. Therefore, these results suggest that catechol may be able to regulate the early metastasis of liver cancer in vitro .

Proper management and treatment of end-of-life fluorescent lamps with a toxic metal of mercury has attracted critical concern in the solid waste community. In this study, material flow analysis (MFA) and substance flow of mercury were performed on the lamps by life cycle in South Korea. It was found that, in 2020, approximately 2957 tons (or 27.9 million units) of end-of-life fluorescent lamps from households were collected and recycled by the recycling facilities in South Korea. Approximately 278 kg of mercury was recovered from the lamps and treated at the hazardous incineration facilities. Based on the results of dynamic flow analysis, the amount of fluorescent lamps to be retried is expected to continually decrease to be about 14.2 million units, which is estimated to be 23 kg of mercury. However, continued collection efforts on end-of-life fluorescent lamps owing to increasing demands for light-emitting diode lamps should be made from the perspectives of proper treatment of mercury as well as resource recovery. More detailed studies on other mercury-containing lamps (e.g., metal halogen lamps, high-pressure mercury lamps, and high-pressure sodium lamps) are warranted to determine mercury flows in waste streams for proper collection and treatment upon disposal.

Since β-lactam antibiotics are widely used, emergence of bacteria with resistance to them poses a significant threat to society. In particular, acquisition of genes encoding β-lactamase, an enzyme that degrades β-lactam antibiotics, has been a major contributing factor in the emergence of bacteria that are resistant to β-lactam antibiotics. However, relatively few genetic targets for killing these resistant bacteria have been identified to date. Here, we used a systematic approach called transposon-sequencing (Tn-Seq), to screen the genome for host genetic factors that, when mutated, affect resistance to ampicillin, one of the β-lactam antibiotics, in a strain carrying a plasmid that encodes β-lactamase. This approach enabled not just the isolation of genes previously known to affect β-lactam resistance, but the additional loci , , and . Individual mutations in these genes modestly but consistently affected antibiotic resistance. We have identified that these genes are not only implicated in β-lactam resistance by itself but also play a crucial role in conditions associated with the expression of β-lactamase. and appear to contribute to β-lactam resistance by regulating membrane integrity. Notably, the overexpression of the uncharacterized membrane-associated protein, , has been shown to significantly enhance β-lactam resistance. We applied the genes identified from the screening into Typhimurium and strains, both critical human pathogens with antibiotic resistance, and observed their significant impact on β-lactam resistance. Therefore, these genes can potentially be utilized as therapeutic targets to control the survival of β-lactamase-producing bacteria.

A variety of airborne pathogens can induce inflammatory responses in airway epithelial cells, which is a crucial component of host defence. However, excessive inflammatory responses and chronic inflammation also contribute to different diseases of the respiratory system. We hypothesized that the activation of protein kinase C (PKC) is one of the essential mechanisms of inflammatory response in airway epithelial cells. In the present study, we stimulated human bronchial lung epithelial (BEAS-2B) cells with the phorbol ester Phorbol 12, 13-dibutyrate (PDBu), and examined gene expression profile using microarrays. Microarray analysis suggests that PKC activation induced dramatic changes in gene expression related to multiple cellular functions. The top two interaction networks generated from these changes were centered on NFκB and TNF-α, which are two commonly known pathways for cell death and inflammation. Subsequent tests confirmed the decrease in cell viability and an increase in the production of various cytokines. Interestingly, each of the increased cytokines was differentially regulated at mRNA and/or protein levels by different sub-classes of PKC isozymes. We conclude that pathological cell death and cytokine production in airway epithelial cells in various situations may be mediated through PKC related signaling pathways. These findings suggest that PKCs can be new targets for treatment of lung diseases.

Aluminium hydroxide is a well-known adjuvant used in vaccines. Although it can enhance an adaptive immune response to a co-administered antigen, it causes adverse effects, including macrophagic myofasciitis (MMF), subcutaneous pseudolymphoma, and drug hypersensitivity. The object of this study is to demonstrate pediatric cases of aluminium hydroxide-induced diseases focusing on its rarity, under-recognition, and distinctive pathology. Seven child patients with biopsy-proven MMF were retrieved from the Seoul National University Hospital (SNUH) pathology archives from 2015 to 2019. The medical records and immunisation history were reviewed, and a full pathological muscle examination was carried out. The mean age was 1.7 years (8.9–40 months), who had records of vaccination against hepatitis B, hepatitis A, and tetanus toxoid on the quadriceps muscle. The chief complaints were muscle weakness (n = 6), delayed motor milestones (n = 6), instability, dysarthria, and involuntary movement (n = 1), swallowing difficulty (n = 1), high myopia (n = 1), and palpable subcutaneous nodules with skin papules (n = 1). Muscle biopsy showed MMF (n = 6) and pseudolymphoma (n = 1) with pathognomic basophilic large macrophage infiltration, which had distinctive spiculated inclusions on electron microscopy. The intracytoplasmic aluminium was positive for PAS and Morin stains. Distinctive pathology and ultrastructure suggested an association with aluminium hydroxide-containing vaccines. To avoid misdiagnosis and mistreatment, we must further investigate this uncommon condition, and pharmaceutical companies should attempt to formulate better adjuvants that do not cause such adverse effects.