A mouse model of Salmonella typhi infection.

Salmonella spp. are gram-negative flagellated bacteria that can cause food- and waterborne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. Typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. Typhimurium, S. Typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice, but not in humans, and remarkably, we find that tlr11(-/-) mice are efficiently infected with orally administered S. Typhi. We also find that tlr11(-/-) mice can be immunized against S. Typhi. Therefore, tlr11(-/-) mice represent a small-animal model for the study of the immune response to S. Typhi and for the development of vaccines against this important human pathogen.

The role of charge recombination to triplet excitons in organic solar cells.

The use of non-fullerene acceptors (NFAs) in organic solar cells has led to power conversion efficiencies as high as 18%1. However, organic solar cells are still less efficient than inorganic solar cells, which typically have power conversion efficiencies of more than 20%2. A key reason for this difference is that organic solar cells have low open-circuit voltages relative to their optical bandgaps3, owing to non-radiative recombination4. For organic solar cells to compete with inorganic solar cells in terms of efficiency, non-radiative loss pathways must be identified and suppressed. Here we show that in most organic solar cells that use NFAs, the majority of charge recombination under open-circuit conditions proceeds via the formation of non-emissive NFA triplet excitons; in the benchmark PM6:Y6 blend5, this fraction reaches 90%, reducing the open-circuit voltage by 60 mV. We prevent recombination via this non-radiative channel by engineering substantial hybridization between the NFA triplet excitons and the spin-triplet charge-transfer excitons. Modelling suggests that the rate of back charge transfer from spin-triplet charge-transfer excitons to molecular triplet excitons may be reduced by an order of magnitude, enabling re-dissociation of the spin-triplet charge-transfer exciton. We demonstrate NFA systems in which the formation of triplet excitons is suppressed. This work thus provides a design pathway for organic solar cells with power conversion efficiencies of 20% or more.

Investigation of Planckian behavior in a high-conductivity oxide: PdCrO2.

The layered delafossite metal PdCrO[Formula: see text] is a natural heterostructure of highly conductive Pd layers Kondo coupled to localized spins in the adjacent Mott insulating CrO[Formula: see text] layers. At high temperatures, T, it has a T-linear resistivity which is not seen in the isostructural but nonmagnetic PdCoO[Formula: see text]. The strength of the Kondo coupling is known, as-grown crystals are extremely high purity and the Fermi surface is both very simple and experimentally known. It is therefore an ideal material platform in which to investigate "Planckian metal" physics. We do this by means of controlled introduction of point disorder, measurement of the thermal conductivity and Lorenz ratio, and studying the sources of its high-temperature entropy. The T-linear resistivity is seen to be due mainly to elastic scattering and to arise from a sum of several scattering mechanisms. Remarkably, this sum leads to a scattering rate within 10[Formula: see text] of the Planckian value of k[Formula: see text]T/[Formula: see text].

Meta-analysis of the human upper respiratory tract microbiome reveals robust taxonomic associations with health and disease.

BACKGROUND: The human upper respiratory tract (URT) microbiome, like the gut microbiome, varies across individuals and between health and disease states. However, study-to-study heterogeneity in reported case-control results has made the identification of consistent and generalizable URT-disease associations difficult. RESULTS: In order to address this issue, we assembled 26 independent 16S rRNA gene amplicon sequencing data sets from case-control URT studies, with approximately 2-3 studies per respiratory condition and ten distinct conditions covering common chronic and acute respiratory diseases. We leveraged the healthy control data across studies to investigate URT associations with age, sex, and geographic location, in order to isolate these associations from health and disease states. CONCLUSIONS: We found several robust genus-level associations, across multiple independent studies, with either health or disease status. We identified disease associations specific to a particular respiratory condition and associations general to all conditions. Ultimately, we reveal robust associations between the URT microbiome, health, and disease, which hold across multiple studies and can help guide follow-up work on potential URT microbiome diagnostics and therapeutics.

Thin Film Composite Membranes as a New Category of Alkaline Water Electrolysis Membranes.

Alkaline water electrolysis (AWE) is considered a promising technology for green hydrogen (H2 ) production. Conventional diaphragm-type porous membranes have a high risk of explosion owing to their high gas crossover, while nonporous anion exchange membranes lack mechanical and thermochemical stability, limiting their practical application. Herein, a thin film composite (TFC) membrane is proposed as a new category of AWE membranes. The TFC membrane consists of an ultrathin quaternary ammonium (QA) selective layer formed via Menshutkin reaction-based interfacial polymerization on a porous polyethylene (PE) support. The dense, alkaline-stable, and highly anion-conductive QA layer prevents gas crossover while promoting anion transport. The PE support reinforces the mechanical and thermochemical properties, while its highly porous and thin structure reduces mass transport resistance across the TFC membrane. Consequently, the TFC membrane exhibits unprecedentedly high AWE performance (1.16 A cm-2 at 1.8 V) using nonprecious group metal electrodes with a potassium hydroxide (25 wt%) aqueous solution at 80 °C, significantly outperforming commercial and other lab-made AWE membranes. Moreover, the TFC membrane demonstrates remarkably low gas crossover, long-term stability, and stack cell operability, thereby ensuring its commercial viability for green H2 production. This strategy provides an advanced material platform for energy and environmental applications.

Viral detection from negative mumps cases with respiratory symptoms in Gwangju, South Korea in 2021.

Mumps is the second-most reported infectious disease in South Korea; however, due to the low pathogen confirmation rate in laboratory diagnoses, we proposed a method for reevaluating the high incidence rate via the laboratory verification of other viral diseases. In 2021, 63 cases of pharyngeal or cheek mucosal swabs of suspected mumps cases in Gwangju, South Korea, were assessed for causative pathogens using massive simultaneous pathogen testing. More than one respiratory virus was detected in 60 cases (95.2%), 44 (73.3%) of which were codetected. Human rhinovirus was detected in 47 cases, followed by human herpesvirus (HHV)6 in 30; HHV4 (17), human bocavirus (17), HHV5 (10), and human parainfluenza virus 3 (6) were also detected. Our findings suggest the need for further investigations on the pathogenesis of diseases mimicking mumps, which are considered to aid with appropriate public health responses, treatment, and the prevention of infectious disease outbreaks.

Improving mammography interpretation for both novice and experienced readers: a comparative study of two commercial artificial intelligence software.

OBJECTIVES: To evaluate the improvement of mammography interpretation for novice and experienced radiologists assisted by two commercial AI software. METHODS: We compared the performance of two AI software (AI-1 and AI-2) in two experienced and two novice readers for 200 mammographic examinations (80 cancer cases). Two reading sessions were conducted within 4 weeks. The readers rated the likelihood of malignancy (range, 1-7) and the percentage probability of malignancy (range, 0-100%), with and without AI assistance. Differences in AUROC, sensitivity, and specificity were analyzed. RESULTS: Mean AUROC increased in both novice (0.86 to 0.90 with AI-1 [p = 0.005]; 0.91 with AI-2 [p < 0.001]) and experienced readers (0.87 to 0.92 with AI-1 [p < 0.001]; 0.90 with AI-2 [p = 0.004]). Sensitivities increased from 81.3 to 88.8% with AI-1 (p = 0.027) and to 91.3% with AI-2 (p = 0.005) in novice readers, and from 81.9 to 90.6% with AI-1 (p = 0.001) and to 87.5% with AI-2 (p = 0.016) in experienced readers. Specificity did not decrease significantly in both novice (p > 0.999, both) and experienced readers (p > 0.999 with AI-1 and 0.282 with AI-2). There was no significant difference in the performance change depending on the type of AI software (p > 0.999). CONCLUSION: Commercial AI software improved the diagnostic performance of both novice and experienced readers. The type of AI software used did not significantly impact performance changes. Further validation with a larger number of cases and readers is needed. CLINICAL RELEVANCE STATEMENT: Commercial AI software effectively aided mammography interpretation irrespective of the experience level of human readers. KEY POINTS: • Mammography interpretation remains challenging and is subject to a wide range of interobserver variability. • In this multi-reader study, two commercial AI software improved the sensitivity of mammography interpretation by both novice and experienced readers. The type of AI software used did not significantly impact performance changes. • Commercial AI software may effectively support mammography interpretation irrespective of the experience level of human readers.

General self-efficacy differentially moderates depressive symptoms in adults with epilepsy depending on seizure severity.

PURPOSE: We evaluated whether the relationship between general self-efficacy and depressive symptoms in patients with epilepsy differed depending on age, sex, and seizure status. METHODS: This multicenter, cross-sectional study was conducted on 299 adults with epilepsy, using the Beck Depression Inventory (BDI) and the General Self-efficacy Scale (GSES). We performed stepwise linear regression analysis and analysis of covariance with interaction terms. RESULTS: The stepwise linear regression analysis showed that BDI scores were negatively correlated with GSES scores and positively correlated with age ≥ 40 years, unemployed status, recurrence of generalized or focal to bilateral tonic-clonic seizures (GTCS or FBTCS), and antiseizure medication polytherapy. The final model explained 38.9% of the variance in BDI scores. The analysis of covariance revealed that the moderating effect of GSES scores on BDI scores was less in subjects who had seizure freedom for at least 1 year than in those who did not. In contrast, the moderating effect of GSES scores on BDI scores was greater in subjects who had an age ≥ 40 years and those who experienced GTCS or FBTCS during the previous year than in those who did not. The negative relationship between GSES and BDI scores tended to be stronger in men than in women, but it did not reach statistical significance (p = 0.098). All models were adjusted by significant factors in the linear regression analysis of BDI scores. CONCLUSIONS: The negative relationship between general self-efficacy and depressive symptoms may be stronger in older patients and patients with poorer seizure outcomes.

Radiotherapy in recurrent ovarian cancer: updated results of involved-field radiation therapy.

OBJECTIVE: This study aimed to update the possible clinical benefits of radiation therapy in recurrent ovarian cancer. METHODS: The medical records of 495 patients with recurrent ovarian cancer after initially undergoing maximal cytoreductive surgery and adjuvant platinum-based chemotherapy based on the pathologic stage between January 2010 and December 2020 were analyzed: 309 and 186 patients were treated without and with involved-field radiation therapy, respectively. Involved-field radiation therapy is defined as radiation therapy only to the areas of the body involved by tumor. The prescribed doses were ≥45 Gy (equivalent dose in 2 Gy/fraction). Overall survival was compared between patients treated with and without involved-field radiation therapy. The favorable group was defined as patients who satisfied at least four of the following factors: good performance, no ascites, normal CA-125, platinum-sensitive tumor, and nodal recurrence. RESULTS: The median age of the patients was 56 years (range 49-63) and median time to recurrence was 11.1 months (range 6.1-15.5). 217 patients (43.8%) were treated at a single site. Radiation therapy, performance status, CA-125, platinum sensitivity, residual disease, and ascites were all significant prognostic factors. The 3-year overall survival of all patients, patients treated without radiation therapy, and patients treated with radiation therapy was 54.0%, 44.8%, and 69.3%, respectively. Radiation therapy was associated with higher overall survival rates in the unfavorable and favorable patient groups. Patient characteristics showed higher rates of normal CA-125, lymph node metastasis only, lower platinum sensitivity, and higher rates of ascites in the radiation therapy group. After propensity score matching, the radiation therapy group showed superior overall survival to the non-radiation therapy group. Normal CA-125, good performance status, and platinum sensitivity were associated with a good prognosis in patients treated with radiation therapy. CONCLUSION: Our study showed that higher overall survival was observed in patients treated with radiation therapy in recurrent ovarian cancer.

Investigation of pharmacokinetic properties of a PEGylated bilirubin nanoparticle in male Sprague-Dawley rats using liquid chromatography-quadrupole time-of-flight mass spectrometry.

Polyethylene glycol (PEG) was introduced into synthetic bilirubin 3α and a PEGylated bilirubin 3α nanoparticle (BX-001N, Brixelle®) was developed for the first time.An in vitro microsomal stability study, in vivo PK studies with intravenous bolus (IV) and subcutaneous injection (SC), and a semi-mass balance study of BX-001N were investigated to evaluate its pharmacokinetic (PK) properties in male Sprague-Dawley (SD) rats using developed liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-qTOF/MS).Following IV administration at 10 or 30 mg/kg, BX-001N showed very low clearance (0.33-0.67 mL/min/kg) with predominant distribution in the vascular system (Vd = 51.73-83.02 mL/kg). BX-001N was also very stable in vitro liver microsomal stability study.Following SC administration at 10 or 30 mg/kg, the bioavailability of BX-001N in plasma at 10 mg/kg was around 43% and showed the less dose-proportionality at 30 mg/kg dose.BX-001N was mainly excreted via the urinary pathway (86.59-92.99% of total amount of parent drug in excreta; urine and feces) not via the biliary one.

Chemical hazard of robotic hull in-water cleaning discharge on coastal embryonic fish.

In-water cleaning (IWC) involves the removal of biofilms and foulants from the hull of a ship using brush or water jet. During IWC, several factors associated with the harmful chemical contaminants release to the marine environment, which can create "hotspots" of chemical contamination in coastal areas. To elucidate the potential toxic effects of IWC discharge, we investigated developmental toxicity in embryonic flounder, which are sensitive life stage to chemical exposure. Zinc and copper were the dominant metals, while zinc pyrithione was the most abundant biocide associated with IWC discharge in two remotely operated IWC. Discharge from IWC carried by both remotely operated vehicles (ROVs) produced developmental malformations including pericardial edema, spinal curvature, and tail-fin defects. In an analyses of differential gene expression profiles (fold-change of genes with a cutoff < 0.05) as assessed by high-throughput RNA sequencing, genes associated with muscle development were commonly and significantly changed. The gene ontology (GO) of embryos exposed to IWC discharge from ROV A activities highly enriched muscle and heart development, while cell signaling and transport were evident in embryos exposed to IWC discharge of ROV B. We analyzed the gene network by significant GO terms. In the network, TTN, MYOM1, CASP3, and CDH2 genes appeared to be key regulators of the toxic effects on muscle development. In embryos exposed to ROV B discharge, HSPG2, VEGFA, and TNF genes related to the nervous system pathway were affected. These results shed light on the potential impacts of muscle and nervous system development in non-target coastal organisms exposed to contaminants found in IWC discharge.

DDC-Promoter-Driven Chemogenetic Activation of SNpc Dopaminergic Neurons Alleviates Parkinsonian Motor Symptoms.

Parkinson's disease (PD) is a neurodegenerative disorder with typical motor symptoms. Recent studies have suggested that excessive GABA from reactive astrocytes tonically inhibits dopaminergic neurons and reduces the expression of tyrosine hydroxylase (TH), the key dopamine-synthesizing enzyme, in the substantia nigra pars compacta (SNpc). However, the expression of DOPA decarboxylase (DDC), another dopamine-synthesizing enzyme, is relatively spared, raising a possibility that the live but non-functional TH-negative/DDC-positive neurons could be the therapeutic target for rescuing PD motor symptoms. However, due to the absence of a validated DDC-specific promoter, manipulating DDC-positive neuronal activity has not been tested as a therapeutic strategy for PD. Here, we developed an AAV vector expressing mCherry under rat DDC promoter (AAV-rDDC-mCherry) and validated the specificity in the rat SNpc. Modifying this vector, we expressed hM3Dq (Gq-DREADD) under DDC promoter in the SNpc and ex vivo electrophysiologically validated the functionality. In the A53T-mutated alpha-synuclein overexpression model of PD, the chemogenetic activation of DDC-positive neurons in the SNpc significantly alleviated the parkinsonian motor symptoms and rescued the nigrostriatal TH expression. Altogether, our DDC-promoter will allow dopaminergic neuron-specific gene delivery in rodents. Furthermore, we propose that the activation of dormant dopaminergic neurons could be a potential therapeutic strategy for PD.

Consumer testing away from a sensory facility: Application of home-use test and no-contact home-use test.

COVID-19 pandemic-related restrictions for approximately three years have heavily influenced sensory evaluations. People have become accustomed to working remotely and communicating online. This has led to opportunities in sensory testing paired with logistics systems and information technologies, resulting in a wide application of the home-use test (HUT), wherein panelists evaluate samples from their homes or other off-site locations. This study aimed to compare three sensory evaluation conditions: a central location test (CLT, n = 104), a HUT (n = 120), and a no-contact HUT (N-HUT, n = 111). We recruited participants via the local community website, delivered samples using a delivery service, and conducted sensory testing using a smartphone for the N-HUT. Participants were requested to report the acceptance ratings, sensory profiles, and emotion responses to four coffee samples. Some differences in the acceptance ratings might be due to the different attitudes participating in the evaluation. In the sensory profiling of the samples, multi-factor analysis (MFA) revealed highly similar sensory characteristics across the three types of tests. All RV coefficients (RVs) among the test conditions were above 0.93. The emotion responses to coffee samples were similar among test conditions based on the MFA with RV values greater than 0.84. In conclusion, we found that N-HUT produced similar results regarding the descriptions of sensory profiles and emotions, indicating that N-HUT is a suitable test method for collecting sensory data and overcoming CLT and HUT's regional limitations. Modern logistics systems and information technologies make it possible to conduct nationwide sensory evaluations without in-person contact or participant attendance at sensory testing facilities.

Development and Modification of a Culturally Tailored Education Program to Prevent Breast Cancer in Korean Immigrant Women in New York City.

Breast cancer (BC) is the most common cancer in Korean American (KA) women. In view of its high prevalence in these women, their low screening rates, and the cultural influence of BC risk factors in their lifestyles, we developed a community-based culturally tailored BC prevention program, the Korean Breast Cancer Risk Reduction Program (KBCRRP). Guided by the PRECEDE-PROCEDE and health belief models, the KBCRRP was developed to achieve four goals: (1) healthy weight, (2) physically active lifestyle, (3) healthy diet, and (4) BC screening and adherence. KBCRRP combines effective multicomponent strategies for BC screening and a group-based lifestyle intervention incorporating traditional Korean health beliefs and is tailored for BC risk reduction. In this paper, we provide an overview of the program, the process of program development, implementation, and evaluation, and modification during the COVID-19 pandemic. The initial program involved 8 weeks of in-person group education sessions led by interdisciplinary healthcare professionals and 16 weeks of follow-up involving smartphone applications, phone calls, and text messaging from trained lifestyle coaches. Participants received opportunities to obtain free mammography during the program. After feasibility testing, the program was modified by incorporating participants' feedback. During the COVID-19 pandemic, we provided the program using the Zoom video platform. Participants' recruitment and retention during the pandemic was successful, reflecting the fact that virtual delivery of group-based education was a feasible and acceptable alternative to in-person sessions. Collaboration with community organizations serving the target population is the key to developing and sustaining a successful community-based educational program.

Evaluation of In Vivo Prepared Albumin-Drug Conjugate Using Immunoprecipitation Linked LC-MS Assay and Its Application to Mouse Pharmacokinetic Study.

There have been many attempts in pharmaceutical industries and academia to improve the pharmacokinetic characteristics of anti-tumor small-molecule drugs by conjugating them with large molecules, such as monoclonal antibodies, called ADCs. In this context, albumin, one of the most abundant proteins in the blood, has also been proposed as a large molecule to be conjugated with anti-cancer small-molecule drugs. The half-life of albumin is 3 weeks in humans, and its distribution to tumors is higher than in normal tissues. However, few studies have been conducted for the in vivo prepared albumin-drug conjugates, possibly due to the lack of robust bioanalytical methods, which are critical for evaluating the ADME/PK properties of in vivo prepared albumin-drug conjugates. In this study, we developed a bioanalytical method of the albumin-conjugated MAC glucuronide phenol linked SN-38 ((2S,3S,4S,5R,6S)-6-(4-(((((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano [3',4':6,7] indolizino [1,2-b] quinolin-9-yl)oxy)methyl)(2 (methylsulfonyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylpropanamido)acetamido)phenoxy)-3,4,5-trihydroxytetra-hydro-2H-pyran-2-carboxylic acid) as a proof-of-concept. This method is based on immunoprecipitation using magnetic beads and the quantification of albumin-conjugated drug concentration using LC-qTOF/MS in mouse plasma. Finally, the developed method was applied to the in vivo intravenous (IV) mouse pharmacokinetic study of MAC glucuronide phenol-linked SN-38.

Hedonic plasticity of vegan burger patty in implicit or explicit reference frame conditions.

BACKGROUND: The vegan food market is one of the fastest growing markets worldwide for ethical, environmental, and health reasons. However, vegan food is still relatively unfamiliar to Korean consumers. Their liking for vegan burger patties is in the early phase of development; thus, it is necessary to place the patties in an appropriate context or 'frame'. RESULTS: We investigated consumer (n = 269) liking for vegan patty under different frame conditions. The implicit frame condition was manipulated by evaluating a target sample along with four other vegan or meat samples. Consumers were further divided into two explicit groups that were exposed to or not exposed to a video clip on ethical food consumption before evaluating the samples. A control group evaluated the target sample only. The results showed that the implicit frame formed during the sample evaluation had a stronger influence than the explicit frame created by the video clip. Perceived familiarity with the target vegan patty drastically decreased when evaluated with other meat samples and negatively influenced the liking for it. CONCLUSION: The findings show that the type of samples evaluated sequentially together with the target vegan burger patty within the same session had a greater effect on the target sample than the information provided explicitly. To introduce the target vegan burger patty effectively to consumers who are relatively new to the vegan food product category such as Koreans, it is suggested that the product should be positioned under the category of vegan foods rather than the category of conventional burger patties. © 2022 Society of Chemical Industry.

Mutation spectrum and genotype-phenotype correlations in 157 Korean CADASIL patients: a multicenter study.

CADASIL is an inherited disease caused by mutations in the NOTCH3 gene. We aimed to investigate the mutation and clinical spectrum, and genotype-phenotype correlations of Korean CADASIL patients. Samples from 492 clinically suspicious patients were collected from four hospitals. Sanger sequencing was performed to screen exons 2 to 25 of the NOTCH3 gene and variants of unknown significance (VUS) were analyzed using the ACMG guidelines. The medical records and MRI data were received from each hospital, for comprehensive analysis of genotype-phenotype correlations. Previously reported NOTCH3 variants were most commonly detected in exon 11 whereas exon 4 was the most common in European studies. The variants were detected equally between the EGFr domains 1-6 and 7-34, which was different from EGFr 1-6 predominant European studies. The average age-of-onset of patients with EGFr 1-6 variants were 4.81 ± 1.95 years younger than patients with EGFr 7-34 variants. Overall, it took Korean patients 51.2 ± 10 years longer to develop CADASIL in comparison to European patients. The most common mutation was p.R544C, which was associated with a later onset of stroke and a significant time-to-event curve difference. We verified four atypical phenotypes of p.R544C that had been reported in previous studies. Eight novel variants in 15 patients were detected but remained a VUS based on the ACMG criteria. This study reported a different EGFr distribution of Korean patients in comparison to European patients and its correlation with a later age-of-onset. An association between a later onset of stroke/TIA and p.R544C was observed.

Identifying serum miRNA biomarkers for radiation exposure in hematopoietic humanized NSG-SGM3 mice.

BACKGROUND: Humans are commonly exposed to ionizing radiation. The conventional approach for estimating radiation exposure is to integrate physical and clinical measurements for optimizing the dose calculation. However, these methods have several limitations. The present study attempted to identify candidate microRNA (miRNA) biomarkers for radiation exposure in a hematopoietic humanized NSGS (hu-NSGS) mouse model. METHODS: We grafted human CD34+ hematopoietic stem cells into NSG-SGM3 (NSGS) mice. The hu-NSGS mice underwent total body irradiation at doses of 2, 3, and 4 Gy. Tissues from the spleen, thymus, and lymph nodes of hu-NSGS mice were prepared to analyze levels of CD45+ and CD3+ T cells and CD 20+ B cells using flow cytometry and immunohistochemistry. Serum miRNAs were profiled using a digital multiplexed NanoString n-Counter. RESULTS: The expression of 45 miRNAs was upregulated/downregulated hu-NSGS mice. The miRNAs hsa-mir-188-5p, hsa-let-7a-5p, hsa-mir-612, hsa-mir-671-5p, and hsa-mir-675-5p were highly radiation-responsive in irradiated hu-NSGS mice. When compared with control mice, radiation-exposed mice exhibited significant upregulated of hsa-let-7a-5p expression and significant downregulation of hsa-mir-188-5p expression. CONCLUSIONS: Single miRNAs or combinations of hsa-mir-188-5p, hsa-let-7a-5p, hsa-mir-675-5p, hsa-mir-612, and hsa-mir-671-5p can be used as biomarkers for predicting the impact of radiation exposure. The current findings suggest the usefulness of hu-NSGS models for investigating radiation biomarkers.

A novel biguanide (IM1761065) inhibits bioenergetics of glioblastoma tumorspheres.

PURPOSE: Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs). METHODS: The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model. RESULTS: IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test). CONCLUSION: IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.

Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres.

PURPOSE: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). METHODS: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. RESULTS: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. CONCLUSION: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.