PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress.

Molecular classification of gastric cancer (GC) identified a subgroup of patients showing chemoresistance and poor prognosis, termed SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type in this study. Here, we show that SEM-type GC exhibits a distinct metabolic profile characterized by high glutaminase (GLS) levels. Unexpectedly, SEM-type GC cells are resistant to glutaminolysis inhibition. We show that under glutamine starvation, SEM-type GC cells up-regulate the 3 phosphoglycerate dehydrogenase (PHGDH)-mediated mitochondrial folate cycle pathway to produce NADPH as a reactive oxygen species scavenger for survival. This metabolic plasticity is associated with globally open chromatin structure in SEM-type GC cells, with ATF4/CEBPB identified as transcriptional drivers of the PHGDH-driven salvage pathway. Single-nucleus transcriptome analysis of patient-derived SEM-type GC organoids revealed intratumoral heterogeneity, with stemness-high subpopulations displaying high GLS expression, a resistance to GLS inhibition, and ATF4/CEBPB activation. Notably, coinhibition of GLS and PHGDH successfully eliminated stemness-high cancer cells. Together, these results provide insight into the metabolic plasticity of aggressive GC cells and suggest a treatment strategy for chemoresistant GC patients.

Potential Use of Extracellular Vesicles for the HER2 Status Assessment in Breast Cancer Patients.

Human epithelial growth factor receptor 2 (HER2)-targeted therapies are effective in patients with HER2-positive breast cancer. Recent advances have shown that HER2-targeted therapies can also be of benefit when treating tumors expressing low levels of HER2, highlighting the importance of identifying the HER2-low subgroup. This clinical trend has opened new therapeutic avenues for patients who were previously ineligible for HER2-targeted therapies. Thus, the development of new diagnostic methods for real-time HER2 profiling is crucial for accurately tailoring the treatment for these patients. We hypothesized that tumor-derived extracellular vesicles (TEVs) could reflect the HER2 profiles of primary tumors and potentially serve as diagnostic tools for HER2 status. This approach was validated using six breast cancer cell lines, which confirmed that the TEVs accurately reflected the HER2 profiles of the tumor cells. TEVs were isolated using an immunoaffinity method, and copy number variation (CNV) in the ERBB2/EIF2C ratio was assessed using droplet digital PCR of DNA from these vesicles. Clinical validation using plasma samples from 33 breast cancer patients further reinforced the diagnostic potential of our method. Pearson's correlation coefficient analysis of the flow cytometry results demonstrated that TEVs reflected HER2 expression in primary cells. To distinguish between HER2-negative and HER2-low patients, the area under the curve (AUC) of the ROC curve in our method was 0.796, with a sensitivity of 53.8% and a specificity of 100%. These findings suggest the clinical utility of extracellular vesicles derived from plasma and emphasize the need for further research to distinguish HER2-negative from HER2-low patients.

Drug-resistant profiles of extracellular vesicles predict therapeutic response in TNBC patients receiving neoadjuvant chemotherapy.

BACKGROUND: Predicting tumor responses to neoadjuvant chemotherapy (NAC) is critical for evaluating prognosis and designing treatment strategies for patients with breast cancer; however, there are no reliable biomarkers that can effectively assess tumor responses. Therefore, we aimed to evaluate the clinical feasibility of using extracellular vesicles (EVs) to predict tumor response after NAC. METHODS: Drug-resistant triple-negative breast cancer (TNBC) cell lines were successfully established, which developed specific morphologies and rapidly growing features. To detect resistance to chemotherapeutic drugs, EVs were isolated from cultured cells and plasma samples collected post-NAC from 36 patients with breast cancer. RESULTS: Among the differentially expressed gene profiles between parental and drug-resistant cell lines, drug efflux transporters such as MDR1, MRP1, and BCRP were highly expressed in resistant cell lines. Drug efflux transporters have been identified not only in cell lines but also in EVs released from parental cells using immunoaffinity-based EV isolation. The expression of drug resistance markers in EVs was relatively high in patients with residual disease compared to those with a pathological complete response. CONCLUSIONS: The optimal combination of drug-resistant EV markers was significantly efficient in predicting resistance to NAC with 81.82% sensitivity and 92.86% specificity.

Distinctively different human neurobiological responses after trauma exposure and implications for posttraumatic stress disorder subtyping.

Trauma elicits various adaptive and maladaptive responses among all exposed people. There may be distinctively different patterns of adaptation/maladaptation or types according to neurobiological predisposition. The present study aims to dissect the heterogeneity of posttraumatic conditions in order to identify clinically meaningful subtypes in recently traumatized individuals and evaluate their neurobiological correlates and long-term prognosis. We implemented a data-driven classification approach in both discovery (n = 480) and replication (n = 220) datasets of trauma-exposed and trauma-unexposed individuals based on the clinical data across a wide range of assessments. Subtype-specific patterns of functional connectivity in higher-order cortical networks, longitudinal clinical outcomes, and changes in functional connectivity were also evaluated. We identified four distinct and replicable subtypes for trauma-exposed individuals according to posttraumatic stress symptoms. Each subtype was distinct in clinical characteristics, brain functional organization, and long-term trajectories for posttraumatic symptoms. These findings help enhance current understanding of mechanisms underlying the human-specific heterogeneous responses to trauma. Furthermore, this study contributes data towards the development of improved interventions, including targeting of subtype-specific characteristics, for trauma-exposed individuals and those with PTSD.

Radiomics model versus 2017 revised international consensus guidelines for predicting malignant intraductal papillary mucinous neoplasms.

OBJECTIVES: To evaluate a CT-based radiomics model for identifying malignant pancreatic intraductal papillary mucinous neoplasms (IPMNs) and compare its performance with the 2017 international consensus guidelines (ICGs). MATERIALS AND METHODS: We retrospectively included 194 consecutive patients who underwent surgical resection of pancreatic IPMNs between January 2008 and December 2020. Surgical histopathology was the reference standard for diagnosing malignancy. Using radiomics features from preoperative contrast-enhanced CT, a radiomics model was built with the least absolute shrinkage and selection operator by a five-fold cross-validation. CT and MR images were independently reviewed based on the 2017 ICGs by two abdominal radiologists, and the performances of the 2017 ICGs and radiomics model were compared. The areas under the curve (AUCs) were compared using the DeLong method. RESULTS: A total of 194 patients with pancreatic IPMNs (benign, 83 [43%]; malignant, 111 [57%]) were chronologically divided into training (n = 141; age, 65 ± 8.6 years; 88 males) and validation sets (n = 53; age, 66 ± 9.7 years; 31 males). There was no statistically significant difference in the diagnostic performance of the 2017 ICGs between CT and MRI (AUC, 0.71 vs. 0.71; p = 0.93) with excellent intermodality agreement (k = 0.86). In the validation set, the CT radiomics model had higher AUC (0.85 vs. 0.71; p = 0.038), specificity (84.6% vs. 61.5%; p = 0.041), and positive predictive value (84.0% vs. 66.7%; p = 0.044) than the 2017 ICGs. CONCLUSION: The CT radiomics model exhibited better diagnostic performance than the 2017 ICGs in classifying malignant IPMNs. CLINICAL RELEVANCE STATEMENT: Compared with the radiologists' evaluation based on the 2017 international consensus guidelines, the CT radiomics model exhibited better diagnostic performance in classifying malignant intraductal papillary mucinous neoplasms. KEY POINTS: • There is a paucity of comparisons between the 2017 international consensus guidelines (ICGs) and radiomics models for malignant intraductal papillary mucinous neoplasms (IPMNs). • The CT radiomics model developed in this study exhibited better diagnostic performance than the 2017 ICGs in classifying malignant IPMNs. • The radiomics model may serve as a valuable complementary tool to the 2017 ICGs, potentially allowing a more quantitative assessment of IPMNs.

Prognostic value of CT body composition analysis for 1-year mortality after transcatheter aortic valve replacement.

OBJECTIVES: To investigate the value of body composition indices derived from pre-procedural computed tomography (CT) in predicting 1-year mortality among patients who underwent transcatheter aortic valve replacement (TAVR). MATERIALS AND METHODS: We assessed consecutive patients who underwent TAVR between June 2016 and December 2021 at a single academic medical center. Skeletal muscle and subcutaneous fat area at the T4, T12, and L3 levels on pre-procedural CT were measured. The association between body composition and 1-year mortality was evaluated using Cox proportional hazard regression analysis. RESULTS: Finally, 408 patients were included (185 men and 223 women; mean age, 81.7 ± 5.1 years; range, 62-98 years). Post-procedural death occurred in 13.2% of patients. The muscle-height index and fat-height index at the L3 level were more strongly correlated with those at the T12 level (r = 0.765, p < 0.001 and r = 0.932, p < 0.001, respectively) than with those at the T4 level (r = 0.535, p < 0.001 and r = 0.895, p < 0.001, respectively). The cumulative 1-year mortality rate was highest for patients with both sarcopenia and adipopenia (26%), followed by those with adipopenia only (17%), those with sarcopenia only (12%), and those with neither sarcopenia nor adipopenia (8%, p = 0.002). Multivariable analysis revealed that body composition at the T12 level was an independent risk factor for 1-year mortality (hazard ratio: 4.09, 95% confidence interval: 2.01-8.35) in patients with both sarcopenia and adipopenia (p < 0.001). CONCLUSION: Sarcopenia or adipopenia assessed with CT at the thoracic level may be valuable for stratifying 1-year all-cause mortality in patients who undergo TAVR. CLINICAL RELEVANCE STATEMENT: Skeletal muscle and subcutaneous fat mass indices at the level of T12, measured on pre-procedural CT, have value for risk stratification of 1-year all-cause mortality in patients who undergo transcatheter aortic valve replacement. KEY POINTS: Sarcopenia and adipopenia are associated with the prognosis of patients undergoing transcatheter aortic valve replacement. Body composition at the T12 level was an independent risk factor for 1-year all-cause mortality. Sarcopenia or adipopenia assessed at T12 with pre-procedural CT is valuable for risk stratification.

Impact of Neoadjuvant Chemotherapy (NAC) on Biomarker Expression in Breast Cancer.

Background and Objectives: This study aimed to explore biomarker change after NAC (neoadjuvant chemotherapy) and to investigate biomarker expression as a prognostic factor in patients with residual disease (RD) after NAC. Materials and Methods: We retrospectively evaluated 104 patients with invasive breast cancer, who underwent NAC and surgery at Pusan National University Hospital from 2015 to July 2022. The expression of the biomarker was assessed, and the overall survival (OS) and disease-free survival (DFS) were investigated. Results: After NAC, 24 patients (23.1%) out of 104 total patients had a pathological complete response (pCR). We found that changes in at least one biomarker were observed in 41 patients (51.2%), among 80 patients with RD. In patients with RD after NAC (n = 80), a subtype change was identified in 20 patients (25.0%). Any kind of change in the HER2 status was present 19 (23.7%) patients. The hormone receptor (HR)+/HER2+ subtype was significantly associated with better disease-free survival (DFS) (HR, 0.13; 95% CI, 0.02-0.99; p = 0.049). No change in p53 was associated with better DFS, and negative-to-positive change in p53 expression after NAC was correlated with worse DFS (p < 0.001). Negative-to-positive change in p53 was an independent, worse DFS factor in the multivariate analysis (HR,18.44; 95% CI, 1.86-182.97; p = 0.013). Conclusions: Biomarker change and subtype change after NAC were not infrequent, which can affect the further treatment strategy after surgery. The expression change of p53 might have a prognostic role. Overall, we suggest that the re-evaluation of biomarkers after NAC can provide a prognostic role and is needed for the best decision to be made on further treatment.

Differential alterations in brain structural network organization during addiction between adolescents and adults.

BACKGROUND: The adolescent brain may be susceptible to the influences of illicit drug use. While compensatory network reorganization is a unique developmental characteristic that may restore several brain disorders, its association with methamphetamine (MA) use-induced damage during adolescence is unclear. METHODS: Using independent component (IC) analysis on structural magnetic resonance imaging data, spatially ICs described as morphometric networks were extracted to examine the effects of MA use on gray matter (GM) volumes and network module connectivity in adolescents (51 MA users v. 60 controls) and adults (54 MA users v. 60 controls). RESULTS: MA use was related to significant GM volume reductions in the default mode, cognitive control, salience, limbic, sensory and visual network modules in adolescents. GM volumes were also reduced in the limbic and visual network modules of the adult MA group as compared to the adult control group. Differential patterns of structural connectivity between the basal ganglia (BG) and network modules were found between the adolescent and adult MA groups. Specifically, adult MA users exhibited significantly reduced connectivity of the BG with the default network modules compared to control adults, while adolescent MA users, despite the greater extent of network GM volume reductions, did not show alterations in network connectivity relative to control adolescents. CONCLUSIONS: Our findings suggest the potential of compensatory network reorganization in adolescent brains in response to MA use. The developmental characteristic to compensate for MA-induced brain damage can be considered as an age-specific therapeutic target for adolescent MA users.

Feasibility of UTE-MRI-based radiomics model for prediction of histopathologic subtype of lung adenocarcinoma: in comparison with CT-based radiomics model.

OBJECTIVES: To assess the feasibility of the UTE-MRI radiomic model in predicting the micropapillary and/or solid (MP/S) patterns of surgically resected lung adenocarcinoma. MATERIALS AND METHODS: We prospectively enrolled 74 lesions from 71 patients who underwent UTE-MRI and CT before curative surgery for early lung adenocarcinoma. For conventional radiologic analysis, we analyzed the longest lesion diameter and lesion characteristics at both UTE-MRI and CT. Radiomic features were extracted from the volume of interest of the lesions and Rad-scores were generated using the least absolute shrinkage and selection operator with fivefold cross-validation. Six models were constructed by combining the conventional radiologic model, UTE-MRI Rad-score, and CT Rad-score. The areas under the curves (AUCs) of each model were compared using the DeLong method. Early recurrence after curative surgery was analyzed, and Kaplan-Meier survival analysis was performed. RESULTS: Twenty-four lesions were MP/S-positive, and 50 were MP/S-negative. The longitudinal size showed a small systematic difference between UTE-MRI and CT, with fair intermodality agreement of lesion characteristic (kappa = 0.535). The Rad-scores of the UTE-MRI and CT demonstrated AUCs of 0.84 and 0.841, respectively (p = 0.98). Among the six models, mixed conventional, UTE-MRI, and CT Rad-score model showed the highest diagnostic performance (AUC = 0.879). In the survival analysis, the high- and low-risk groups were successfully divided by the Rad-score in UTE-MRI (p = 0.01) and CT (p < 0.01). CONCLUSION: UTE-MRI radiomic model predicting MP/S positivity is feasible compared with the CT radiomic model. Also, it was associated with early recurrence in the survival analysis. CLINICAL RELEVANCE STATEMENT: A radiomic model utilizing UTE-MRI, which does not present a radiation hazard, was able to successfully predict the histopathologic subtype of lung adenocarcinoma, and it was associated with the patient's recurrence-free survival. KEY POINTS: • No studies have reported the ultrashort echo time (UTE)-MRI-based radiomic model for lung adenocarcinoma. • The UTE-MRI Rad-score showed comparable diagnostic performance with CT Rad-score for predicting micropapillary and/or solid histopathologic pattern. • UTE-MRI is feasible not only for conventional radiologic analysis, but also for radiomics analysis.

Patterns of Postoperative Changes in Lung Volume and Perfusion Assessed by Dual-Energy CT: Comparison of Lobectomy and Limited Resection.

BACKGROUND. Pulmonary function tests (PFTs) and perfusion scintigraphy have limited utility for evaluating postoperative changes in regional pulmonary function after lung cancer resection surgery. OBJECTIVE. The purpose of this study is to compare postoperative changes in lung volume and perfusion, as assessed by dual-energy CT (DECT), between patients undergoing surgical resection of lung cancer by lobectomy versus limited resection as well as to assess associations between such changes and the lobar location of the resected tumor. METHODS. This study entailed a retrospective post hoc analysis of a prospective study that enrolled patients awaiting lung cancer resection surgery between March 2019 and February 2020. Eighty-one patients (38 men and 43 women; mean age, 60.5 ± 8.9 [SD] years), 43 of whom underwent lobectomy and 38 of whom underwent limited resection, were included. Patients underwent thoracic DECT and PFT evaluation preoperatively and at 6 months postoperatively. Pulmonary lobes were segmented. Lobar lung volume and lung perfusion ratios (both relative to whole-lung values) were computed. Perfusion measures reflected DECT-derived iodine content. Patients completed 6-month postoperative quality-of-life (QOL) questionnaires. RESULTS. Patients undergoing lobectomy, compared with those undergoing limited resection, had greater increases in the lung volume ratio of the ipsilateral nonresected lobe(s) (mean, 42.3% ± 24.2% [SD] vs 22.9% ± 13.2%, p < .001) and the contralateral lung (mean, 14.6% ± 14.0% vs 6.4% ± 6.9%, p = .002) as well as greater increases in the lung perfusion ratio of the ipsilateral nonresected lobe(s) (mean, 39.9% ± 20.7% [SD] vs 22.8% ± 17.8%, p < .001) and the contralateral lung (mean, 20.9% ± 9.4% vs 4.3% ± 5.6%, p < .001). In patients with right lower lobe tumors, the largest postoperative increases in the lung volume ratio were in the right middle lobe in those undergoing lobectomy (mean, 44.1% ± 21.0%) and limited resection (mean, 24.6% ± 14.5%), whereas the largest postoperative increase in the lung perfusion ratio was in the left lower lobe in those undergoing lobectomy (mean, 53.9% ± 8.6%) and in the right middle lobe in those undergoing limited resection (mean, 32.5% ± 24.1%). Otherwise, the largest increases in lung volume and perfusion ratios occurred in the ipsilateral nonresected lobes (vs the contra-lateral lobes), regardless of the operative approach used and the lobar location. Changes in the lung volume and perfusion ratios in the ipsilateral lobe(s) and the contralateral lung showed weak correlations with certain QOL scores (e.g., for role functioning: ρ = 0.234-0.279 [volume] and -0.233 to -0.284 [perfusion]). CONCLUSION. DECT depicts patterns of lung volume and perfusion changes after lung cancer surgery, depending on the surgical approach (lobectomy vs limited resection) used and the lobar location of the tumor. CLINICAL IMPACT. DECT-derived metrics can help understand variable physiologic impacts of lung cancer resection surgeries.

Genetic profile for dopamine signaling predicts brain functional reactivity to repetitive transcranial magnetic stimulation.

Research integrating molecular and imaging data provides important insights into how the genetic profile associated with dopamine signaling influences inter-individual differences in brain functions. However, the effects of genetic variations in dopamine signaling on the heterogeneity of brain changes induced by repetitive transcranial magnetic stimulation (rTMS) still remain unclear. The current study examined the composite effects of genetic variations in dopamine-related genes on rTMS-induced brain responses in terms of the functional network connectivity and working memory performance. Healthy individuals (n = 30) participated in a randomized, double-blind, sham-controlled study with a crossover design of five consecutive days where active rTMS or sham stimulation sessions were administered over the left dorsolateral prefrontal cortex (DLPFC) of the brain. Participants were mostly women (n = 29) and genotyped for polymorphisms in the catechol-O-methyltransferase and D2 dopamine receptor genes and categorized according to their genetic composite scores: high vs. low dopamine signaling groups. Pre- and post-intervention data of resting-state functional magnetic resonance imaging and working memory performance were obtained from 27 individuals with active rTMS and 30 with sham stimulation sessions. The mean functional connectivity within the resting-state networks centered on the DLPFC increased in the high dopamine signaling group. Working memory performance also improved with rTMS in the high dopamine signaling group compared to that in the low dopamine signaling group. The present results suggest that genetic predisposition to higher dopamine signaling may be a promising neurobiological predictor for rTMS effects on cognitive enhancement.Trial registration: ClinicalTrials.gov (NCT02932085).

Turn-On Fluorescent pH Probes for Monitoring Alkaline pHs Using Bis[2-(2'-hydroxyphenyl)benzazole] Derivatives.

For surveilling human health, industries, and the environment, pH monitoring is important. Numerous studies on fluorescent probes have been conducted to monitor various pH ranges. However, fluorescent probes that are capable of sensing alkaline regions are rare. In this study, we propose turn-on-type fluorescent probes for detecting alkaline pHs using bis[2-(2'-hydroxyphenyl)benzazole] (bis(HBX)) derivatives. These probes have high pKa values (from 9.7 to 10.8) and exhibit strong fluorescence intensity and color changes at alkaline pHs. Probes derived from bis(HBX) exhibit good photostability, reversibility, and anti-interference toward pH variations, which can be identified as a certain fluorescence change toward a basic pH. Therefore, compounds would be advantageous to use fluorescent probes for monitoring alkaline pH changes.

Automated Immunoassay Performed on a 3D Microfluidic Paper-Based Device for Malaria Detection by Ambient Mass Spectrometry.

Microfluidic paper-based analytical devices (µPADs) are emerging as a prominent platform for disease detection, specifically in developing countries. This paper device offer simplicity and affordability not typically seen in centralized laboratory settings. However, detection limits in µPADs are inadequate and often require test results to be read within a specific time interval to ensure accuracy. To overcome these challenges, we are developing an on-chip mass spectrometry (MS) detection strategy for immunoassays performed on paper substrates. Herein, we present our initial results from a proof-of-concept study toward the development of µPADs capable of storing immunoassay reagents within the confinements of the 3D device, automatic splitting of biofluid into four individual test zones, immuno-capture of the disease biomarker, and on-chip MS detection of the captured species. The reported study encourages the development of point-of-care and direct-to-customer testing using disposable µPADs to collect samples, followed by sensitive analysis using portable MSs. We demonstrate this capability using malaria Plasmodium falciparum histidine-rich protein 2 (PfHRP2) antigen detection.

Malaria Diagnosis Using Paper-Based Immunoassay for Clinical Blood Sampling and Analysis by a Miniature Mass Spectrometer.

In this work, we have developed a paper-based microfluidic device capable of remote biofluid collection followed by an analysis of the dried clinical samples using a miniature mass spectrometer. We have evaluated a portable mass spectrometer as a possible surveillance platform by analyzing the clinical malaria samples (whole blood) collected from Ghana. We synthesized pH-sensitive ionic probes and coupled them with monoclonal antibodies specific to the Plasmodium falciparum histidine-rich protein 2 (PfHRP2) malaria antigen. We then used the antibody-ionic probe conjugates in a paper-based immunoassay to capture PfHRP2 antigen from untreated whole blood. After the immunoassay, the bound ionic probes were cleaved, and the released mass tags were analyzed through an on-chip paper spray mass spectrometry strategy. During process optimization, we determined the detection limit for PfHRP2 in untreated human serum to be 0.216 nmol/L when using the miniature mass spectrometer. This sensitivity is comparable to the World Health Organization's suggested threshold of 0.227 nmol/L for PfHRP2, proving that our method will be applicable to diagnose symptomatic malaria infection (≥200 parasites per µL blood). The paper device can be stored at room temperature for at least 25 days without affecting the clinical outcome, with each stored paper chip offering good repeatability and reproducibility (RSD = 4-12%). The stability and sensitivity of the developed paper-based immunoassay platform will allow miniature mass spectrometers to be used for point-of-care malaria detection as well as in large-scale surveillance screening to aid eradication programs.

Gray matter volume reduction in the emotional brain networks in adults with anosmia.

Loss of olfaction, or anosmia, frequently accompanies emotional dysfunctions, partly due to the overlapping brain regions between the olfactory and emotional processing centers. Here, we investigated whether anosmia was associated with gray matter volume alterations at a network level, and whether these alterations were related to the olfactory-specific quality of life (QOL) and depressive symptoms. Structural brain magnetic resonance imaging was acquired in 22 individuals with postinfectious or idiopathic anosmia (the anosmia group) and 30 age- and sex-matched controls (the control group). Using independent component analysis on the gray matter volumes, we identified 10 morphometric networks. The gray matter volumes of these networks were compared between the two groups. Olfactory-specific QOL and depressive symptoms were assessed by self-report questionnaires and clinician-administered interviews, respectively. The anosmia group showed lower gray matter volumes in the hippocampus-amygdala and the precuneus networks, relative to the control group. Lower gray matter volumes in the hippocampus-amygdala network were also linearly associated with lower olfactory-specific QOL and higher depressive symptom scores. These findings suggest a close relationship between anosmia and gray matter volume alterations in the emotional brain networks, albeit without determined causal relations.

Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres.

INTRODUCTION: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. METHODS: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. RESULTS: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. CONCLUSION: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

Quality assessment of radiomics research in cardiac CT: a systematic review.

OBJECTIVES: To assess the quality of current radiomics research on cardiac CT using radiomics quality score (RQS) and Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) systems. METHODS: Systematic searches of PubMed and EMBASE were performed to identify all potentially relevant original research articles about cardiac CT radiomics. Fifteen original research articles were selected. Two cardiac radiologists assessed the quality of the methodology adopted in those studies according to the RQS and TRIPOD guidelines. Basic adherence rates for the following six key domains were evaluated: image protocol and reproducibility, feature reduction and validation, biologic/clinical utility, performance index, high level of evidence, and open science. RESULTS: Among the 15 included articles, six (40%) were about coronary artery disease and six (40%) were about myocardial infarction. The mean RQS was 9.9 ± 7.3 (27.4% of the ideal score of 36), and the basic adherence rate was 44.6%. Fourteen (93.3%) and nine (60%) studies performed feature selection and validation, but only two (13.3%) of them performed external validation. Two studies (13.3%) were prospective, and only one study (6.7%) conducted calibration analysis and stated the potential clinical utility. None of the studies conducted phantom study and cost-effective analysis. The overall adherence rate for TRIPOD was 63%. CONCLUSION: The quality of radiomics studies in cardiac CT is currently insufficient. A higher level of evidence is required, and analysis of clinical utility and calibration of model performance need to be improved. KEY POINTS: • The quality of science of radiomics studies in cardiac CT is currently insufficient. • No study conducted a phantom study or cost-effective analysis, with further limitations being demonstrated in a high level of evidence for radiomics studies. • Analysis of clinical utility and calibration of model performance need to be improved, and a higher level of evidence is required.

The image quality and diagnostic accuracy of T1-mapping-based synthetic late gadolinium enhancement imaging: comparison with conventional late gadolinium enhancement imaging in real-life clinical situation.

BACKGROUNDS: Synthetic late gadolinium enhancement (LGE) images are less sensitive to inversion time (TI) and robust to motion artifact, because it is generated retrospectively by post-contrast T1-mapping images. To explore the clinical applicability of synthetic LGE, we investigated the image quality and diagnostic accuracy of synthetic LGE images, in comparison to that of conventional LGE for various disease groups. METHOD AND MATERIALS: From July to November 2019, a total of 98 patients who underwent cardiovascular magnetic resonance imaging (CMR), including LGE and T1-mapping sequences, with suspicion of myocardial abnormality were retrospectively included. Synthetic magnitude inversion-recovery (IR) and phase-sensitive IR (PSIR) images were generated through calculations based on the post-contrast T1-mapping sequence. Three cardiothoracic radiologists independently analyzed the image quality of conventional and synthetic LGE images on an ordinal scale with per-segment basis and the image qualities were compared with chi-square test. The agreement of LGE detection was analyzed on per-patient and per-segment basis with Cohen's kappa test. In addition, the LGE area and percentage were semi-quantitatively analyzed for LGE positive ischemic (n = 14) and hypertrophic cardiomyopathy (n = 13) subgroups by two cardiothoracic radiologists. The difference of quantified LGE area and percentage between conventional and synthetic LGE images were assessed with Mann-Whitney U-test and the inter-reader agreement was assessed with Bland-Altman analysis. RESULTS: The image quality of synthetic images was significantly better than conventional images in both magnitude IR and PSIR through all three observers (P < 0.001, all). The agreements of per-patient and per-segment LGE detection rates were excellent (kappa = 0.815-0.864). The semi-quantitative analysis showed no significant difference in the LGE area and percentage between conventional and synthetic LGE images. In the inter-reader agreement showed only small systematic differences in both magnitude IR and PSIR and synthetic LGE images showed smaller systematic biases compared to conventional LGE images. CONCLUSION: Compared to conventional LGE images, synthetic LGE images have better image quality in real-life clinical situation.

Investigation of a benzodiazaborine library to identify new pH-responsive fluorophores.

The detection of pH is important owing to its significance in various processes, such as clinical and industrial processes. Numerous fluorescent pH probes have been developed using a variety of fluorophores; however, most are only suitable for application in a narrow pH range (between 5 and 8) owing to the lack of diversity of the pH-sensitive units. Furthermore, probes suitable for sensing high pHs have rarely been studied despite the importance of reliable detection of high pH in various industrial processes. In this study, we prepared a benzodiazaborine (bDAB) library consisting of 238 different bDABs through combinatorial synthesis to investigate their suitability as fluorescent pH probes. Informed by the results of a fluorescence-based, high-throughput screening of the library, we identified four bDABs that exhibit promising pH-sensitive ratiometric fluorescence responses. Their pKas vary significantly, ranging from 7.29 to 12.44, indicating their suitability for the detection of basic pHs even in extremely basic environments (pH > 10). Furthermore, their fluorescence responses show high stability, anti-interference, and reversibility under various pH conditions.

Changes in Isoflavone Profile from Soybean Seeds during Cheonggukjang Fermentation Based on High-Resolution UPLC-DAD-QToF/MS: New Succinylated and Phosphorylated Conjugates.

In this study, thirty-eight isoflavone derivatives were comprehensively identified and quantified from the raw, steamed and fermented seeds of four selected soybean cultivars based on UPLC-DAD-QToF/MS results with reference to the previously reported LC-MS library and flavonoid database, and summarized by acylated group including glucosides (Glu), malonyl-glucosides (Mal-Glu), acetyl-glucosides (Ac-Glu), succinyl-glucosides (Suc-Glu) and phosphorylated conjugates (Phos) in addition to aglycones. Among them, Suc-Glu and Phos derivatives were newly generated due to fermentation by B. subtilis AFY-2 (cheonggukjang). In particular, Phos were characterized for the first time in fermented soy products using Bacillus species. From a proposed roadmap on isoflavone-based biotransformation, predominant Mal-Glu (77.5-84.2%, raw) decreased rapidly by decarboxylation and deesterification into Ac-Glu and Glu (3.5-8.1% and 50.0-72.2%) during steaming, respectively. As fermentation continued, the increased Glu were mainly succinylated and phosphorylated as well as gradually hydrolyzed into their corresponding aglycones. Thus, Suc-Glu and Phos (17.3-22.4% and 1.5-5.4%, 36 h) determined depending on cultivar type and incubation time, and can be considered as important biomarkers generated during cheonggukjang fermentation. Additionally, the changes of isoflavone profile can be used as a fundamental report in applied microbial science as well as bioavailability research from fermented soy foods.