Association of clozapine with structural and resting-state functional abnormalities of the hippocampus in chronic schizophrenia.

Introduction: Abnormalities in the hippocampus have been extensively reported in schizophrenia research. However, inconsistent findings exist, and how structural and functional abnormalities of the hippocampus are associated with clinical symptoms in schizophrenia, especially concerning clozapine treatment, remains uncertain. Methods: We recruited 52 patients with schizophrenia, each with an illness duration of at least 5 years, and categorized them based on clozapine treatment. T1-weighted images and resting-state functional magnetic resonance imaging scans were obtained and analyzed to perform group comparisons of the structural and functional changes in the hippocampus. Volumes of the hippocampal subregions, as well as resting-state functional connectivity maps from these areas were compared between the groups. Associations with clinical symptoms, including the severity of psychiatric symptoms and cognitive functions, were investigated. Results: The clozapine group (n=23) exhibited smaller volumes in several hippocampal subregions, including the CA1, CA4, granule cell and molecular layers of the dentate gyrus, compared to the non-clozapine group (n=29). Seven clusters with significant group differences in functional connectivity with these hippocampal subregions were identified, with six of these clusters showing increased functional connectivity in the clozapine group. The reduced volumes of the hippocampal subregions were moderately associated with the severity of negative symptoms, general intelligence, and executive function. Discussion: Patients with schizophrenia undergoing clozapine treatment exhibited smaller volumes in the hippocampal subregions, which were moderately associated with negative symptoms and cognitive functions, compared to those without clozapine treatment.

A male mouse model for metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma.

The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Here, we develop a mouse model (Streptozotocin with high-fat diet, STZ + HFD) that gradually develops fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. The hepatic transcriptomic features of STZ + HFD mice closely reflect those of patients with obesity accompanying type 2 diabetes mellitus, MASH, and MASLD-related HCC. Dietary changes and tirzepatide administration alleviate MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ + HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients is successfully established.

Comparative clinical outcomes of irrigation techniques in burr-hole craniostomy for chronic subdural hemorrhage: a multicenter cohort study.

BACKGROUND: Chronic Subdural Hemorrhage(cSDH) is often treated with surgical blood drainage, but concerns about recurrence and outcomes persist. Surgical techniques, including irrigation, vary. This study compares the outcomes of irrigation in cSDH surgery. MATERIALS AND METHODS: From September 2020 to September 2022, 92 cSDH patients underwent surgery. Two different irrigation methods were used: extensive irrigation (IG) and non-irrigation (NIG). Method of irrigation was selected by each surgeon's preference. Parameters measured included volume of hematoma changes, midline shifting, complications, and basic demographics. Recurrence was defined as symptomatic or hematoma expansion more than double the volume before surgery. Factors predicting recurrence and irrigation method impact were analyzed. RESULTS: Eleven patients were excluded because of bilateral or related to other disease. We analyzed 81 patients (44 NIG, 37 IG). Recurrence occurred in 6 IG cases (16.2%) and 1 NIG case (2.3%). Irrigation method significantly affected recurrence (P = 0.043). Age, gender, medication, medical history, and preoperative measurements had no major impact on recurrence. NIG had unexpected cases of intracerebral hemorrhage. CONCLUSION: Extensive irrigation may increase recurrence in cSDH drainage. Non-irrigation drainage had fewer recurrences, but unexpected complications arose. Careful drainage in non-irrigated cases is crucial.

Mitochondrial DNA mosaicism in normal human somatic cells.

Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.

Optimization of turbidity removal and floc formation for ballasted flocculation using magnetite-based agents by response surface methodology.

In this study, a static mixer was used as an alternative to the existing flash mixing method for ballasted flocculation to assess the turbidity removal and ballasted floc formation characteristics. Synthetic magnetite exhibits excellent properties, such as high specific gravity, hydrophobicity, and wear resistance, making it a suitable ballast agent (BA). The experimental design was optimized using the response surface methodology. To evaluate turbidity removal, a model based on polyaluminum chloride dosage, BA surface charge, and pH was developed. To assess the ballasted floc characteristics, the BA dosage, BA size, and G value of the static mixer were used. During ballasted flocculation, the impact of the zeta potential of the BA was minimal. Consequently, bonding primarily resulted from the viscosity of the floc caused by physical collisions rather than electrostatic forces stemming from the BA charge. The findings of this study demonstrated promising outcomes, including potential energy savings and process streamlining, by identifying crucial design elements for implementing a static mixer in the ballasted flocculation process.

A Rare Case of Delayed Ventriculoperitoneal Shunt Catheter Migration Into the Heart: A Case Report.

The treatment of hydrocephalus with a ventriculoperitoneal (VP) shunt can lead to complications such as shunt migration. A 67-year-old male, who had previously undergone VP shunt surgery for normal-pressure hydrocephalus, presented approximately five years later with symptoms of general weakness and abdominal pain. Imaging revealed shunt malpositioning, with the catheter passing through an abnormal route to the heart. The catheter was successfully removed under fluoroscopic guidance while monitoring patient's electrocardiogram to prevent potential secondary complications. Although rare, cardiac migration of VP shunts can lead to life-threatening secondary complications. Our case highlights the possibility of delayed upward migration of the shunt catheter in patients with VP shunts, emphasizing the need for various strategies to address and manage this issue.

Multilayer network analysis in patients with juvenile myoclonic epilepsy.

INTRODUCTION: We conducted a multilayer network analysis in patients with juvenile myoclonic epilepsy (JME) and healthy controls, to investigate the gray matter layer using a morphometric similarity network and analyze the white matter layer using structural connectivity. METHODS: We enrolled 42 patients with newly diagnosed JME and 53 healthy controls. Brain magnetic resonance imaging (MRI) using a three-tesla MRI scanner, including T1-weighted imaging and diffusion tensor imaging (DTI) were performed. We created a gray matter layer matrix with a morphometric similarity network using T1-weighted imaging, and a white matter layer matrix with structural connectivity using the DTI. Subsequently, we performed a multilayer network analysis by applying graph theory. RESULTS: There were significant differences in network at the global level in the multilayer network analysis between the groups. The average multiplex participation of patients with JME was lower than that of healthy controls (0.858 vs. 0.878, p = 0.007). In addition, several regions showed significant differences in multiplex participation at the nodal level in the multilayer network analysis. Multiplex participation in the right entorhinal cortex was lower, whereas multiplex participation in the right supramarginal gyrus was higher at the nodal level in the multilayer network analysis of patients with JME compared to healthy controls. CONCLUSION: We demonstrated differences in network at the global and nodal levels in the multilayer network analysis between patients with JME and healthy controls. These features may be associated with the pathophysiology of JME and could help us understand the complex brain network in patients with JME.

The Clinical Effects of C2 and C3 Medial Branch Block for Medically Intractable Headache : a Retrospective Study.

Objective: This study aimed to evaluate the clinical effects of medial branch blocks (MBB) C2 and C3 in treating patients with medically intractable headaches. Methods: The medical records of 81 patients with medically intractable headaches who underwent a C2/3 MBB between January 2019 and March 2022 were retrospectively reviewed. The degrees of pain were evaluated using a visual analogue scale (VAS) score (rating 0-10) on baseline and after procedures. To evaluate patients' satisfaction for the treatment, self-reporting measurements were examined and were categorized as excellent (>90% pain relief), good (50%-90% pain relief), fair (10%-50% pain relief), and none (<10% pain relief). Results: The total number of MBB procedure was 107. The average baseline VAS score was 7.4 ±1.5, which improved significantly to 2.6 ±2.3, 3.6 ±2.6, and 4.5 ±3.2 on 1-3 days, 3-7 days, and 3 months after the procedure, respectively (Wilks' lambda within group test, P <0.001). For the subjective feeling of pain relief, percentages of "excellent" response in the self-reporting measurements were significantly decreased over time (chi-square test; P= 0.001). Conclusion: This study demonstrates clinical effectiveness of C2/3 MBB in patients with medically intractable headaches, with both early and prolonged benefits.

Classification of Three Anesthesia Stages Based on Near-Infrared Spectroscopy Signals.

Proper monitoring of anesthesia stages can guarantee the safe performance of clinical surgeries. In this study, different anesthesia stages were classified using near-infrared spectroscopy (NIRS) signals with machine learning. The cerebral hemodynamic variables of right proximal oxyhemoglobin (HbO2) in maintenance (MNT), emergence (EM) and the consciousness (CON) stage were collected and then the differences between the three stages were compared by phase-amplitude coupling (PAC). Then combined with time-domain including linear (mean, standard deviation, max, min and range), nonlinear (sample entropy) and power in frequency-domain signal features, feature selection was performed and finally classification was performed by support vector machine (SVM) classifier. The results show that the PAC of the NIRS signal was gradually enhanced with the deepening of anesthesia level. A good three-classification accuracy of 69.27% was obtained, which exceeded the result of classification of any single category feature. These results indicate the feasibility of NIRS signals in performing three or even more anesthesia stage classifications, providing insight into the development of new anesthesia monitoring modalities.

Temporal Muscle Thickness and Sarcopenia Components in Healthy Adults, Validated through Allgeun Diagnostic Tool.

Sarcopenia, characterized by progressive muscle loss and functional decline, poses significant risks, including falls, impaired daily activities, and increased mortality. We developed Allgeun, a novel device that measures handgrip strength, muscle mass, and physical performance. This study aimed to investigate whether temporal muscle thickness (TMT) could be used as a sarcopenia marker and to evaluate the usability of Allgeun. This prospective study enrolled 28 participants without medical or neurological disorders. They underwent three-dimensional T1-weighted imaging using a 3 Tesla magnetic resonance imaging scanner. TMT was measured based on T1-weighted images by a board-certified neuroradiologist. Allgeun was used to measure the following three key components of sarcopenia: muscle strength (handgrip strength), muscle mass (calf and thigh circumference), and physical performance (five times the chair stand test). Correlation analysis was conducted between TMT and the results of the handgrip strength, calf and thigh circumferences, and chair stand tests. There were moderate positive correlations between TMT and calf circumference (r = 0.413, p = 0.029), thigh circumference (r = 0.486, p = 0.008), and handgrip strength (r = 0.444, p = 0.018). However, no significant correlation was observed between TMT and physical performance (r = -0.000, p = 0.998). Our findings underscore TMT's potential as an indicator of sarcopenia, particularly regarding muscle mass and strength. Additionally, we demonstrated that the new device, Allgeun, is useful for screening and diagnosing the severity of sarcopenia.

Correlation of diffusion tensor tractography with obstructive sleep apnea severity.

INTRODUCTION: Using correlation tractography, this study aimed to find statistically significant correlations between white matter (WM) tracts in participants with obstructive sleep apnea (OSA) and OSA severity. We hypothesized that changes in certain WM tracts could be related to OSA severity. METHODS: We enrolled 40 participants with OSA who underwent diffusion tensor imaging (DTI) using a 3.0 Tesla MRI scanner. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and quantitative anisotropy (QA)-values were used in the connectometry analysis. The apnea-hypopnea index (AHI) is a representative measure of the severity of OSA. Diffusion MRI connectometry that was used to derive correlational tractography revealed changes in the values of FA, MD, AD, RD, and QA when correlated with the AHI. A false-discovery rate threshold of 0.05 was used to select tracts to conduct multiple corrections. RESULTS: Connectometry analysis revealed that the AHI in participants with OSA was negatively correlated with FA values in WM tracts that included the cingulum, corpus callosum, cerebellum, inferior longitudinal fasciculus, fornices, thalamic radiations, inferior fronto-occipital fasciculus, superior and posterior corticostriatal tracts, medial lemnisci, and arcuate fasciculus. However, there were no statistically significant results in the WM tracts, in which FA values were positively correlated with the AHI. In addition, connectometry analysis did not reveal statistically significant results in WM tracts, in which MD, AD, RD, and QA values were positively or negatively correlated with the AHI. CONCLUSION: Several WM tract changes were correlated with OSA severity. However, WM changes in OSA likely involve tissue edema and not neuronal changes, such as axonal loss. Connectometry analyses are valuable tools for detecting WM changes in sleep disorders.

Assessing Radiation Exposure and Contrast Agent Utilization: A Comparative Analysis of the Woven EndoBridge Device and Stent-Assisted Coil Embolization for Managing Unruptured Wide-Neck Bifurcation Aneurysms.

PURPOSE: In this study, we determined whether there were significant differences in procedure time, radiation dose, fluoroscopy time, and total contrast media dose when unruptured wideneck bifurcation aneurysms (WNBAs) were treated with the Woven EndoBridge (WEB) device and stent-assisted coil (SAC) embolization. MATERIALS AND METHODS: The WEB device and SAC embolization (14:17) were used to treat 31 cases of internal carotid artery bifurcation, anterior communicating artery, middle cerebral artery bifurcation, and basilar bifurcation aneurysms between August 2021 and December 2022. The procedure time, radiation dose, fluoroscopy time, and total contrast medium dose between the 2 treatment groups were compared and analyzed. In the WEB device group, the results between operators were compared, and the follow-up radiologic outcomes were investigated. RESULTS: The procedure and fluoroscopy times were significantly shorter in the WEB device group. Radiation and total contrast media dose were also significantly smaller in the WEB device, but there was no significant difference in results between operators. The follow-up radiological outcome showed adequate occlusion in 83.3% (10/12) of cases. CONCLUSION: The WEB device can be used as an alternative treatment method among the available endovascular treatment methods for WNBAs to reduce radiation exposure and the dose of contrast media when used adequately with appropriate indications.

Deep Learning Super-Resolution Technique Based on Magnetic Resonance Imaging for Application of Image-Guided Diagnosis and Surgery of Trigeminal Neuralgia.

This study aimed to implement a deep learning-based super-resolution (SR) technique that can assist in the diagnosis and surgery of trigeminal neuralgia (TN) using magnetic resonance imaging (MRI). Experimental methods applied SR to MRI data examined using five techniques, including T2-weighted imaging (T2WI), T1-weighted imaging (T1WI), contrast-enhancement T1WI (CE-T1WI), T2WI turbo spin-echo series volume isotropic turbo spin-echo acquisition (VISTA), and proton density (PD), in patients diagnosed with TN. The image quality was evaluated using the peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM). High-quality reconstructed MRI images were assessed using the Leksell coordinate system in gamma knife radiosurgery (GKRS). The results showed that the PSNR and SSIM values achieved by SR were higher than those obtained by image postprocessing techniques, and the coordinates of the images reconstructed in the gamma plan showed no differences from those of the original images. Consequently, SR demonstrated remarkable effects in improving the image quality without discrepancies in the coordinate system, confirming its potential as a useful tool for the diagnosis and surgery of TN.

Alterations in the multilayer network in patients with rapid eye movement sleep behaviour disorder.

This study aimed to reveal the pathophysiology of isolated rapid eye movement sleep behaviour disorder (RBD) in patients using multilayer network analysis. Participants eligible for isolated RBD were included and verified via polysomnography. Both iRBD patients and healthy controls underwent brain MRI, including T1-weighted imaging and diffusion tensor imaging. Grey matter matrix was derived from T1-weighted images using a morphometric similarity network. White matter matrix was formed from diffusion tensor imaging-based structural connectivity. Multilayer network analysis of grey and white matter was performed using graph theory. We studied 29 isolated RBD patients and 30 healthy controls. Patients exhibited a higher average overlap degree (27.921 vs. 23.734, p = 0.002) and average multilayer clustering coefficient (0.474 vs. 0.413, p = 0.002) compared with controls. Additionally, several regions showed significant differences in the degree of overlap and multilayer clustering coefficient between patients with isolated RBD and healthy controls at the nodal level. The degree of overlap in the left medial orbitofrontal, left posterior cingulate, and right paracentral nodes and the multilayer clustering coefficients in the left lateral occipital, left rostral middle frontal, right fusiform, right inferior posterior parietal, and right parahippocampal nodes were higher in patients with isolated RBD than in healthy controls. We found alterations in the multilayer network at the global and nodal levels in patients with isolated RBD, and these changes may be associated with the pathophysiology of isolated RBD. Multilayer network analysis can be used widely to explore the mechanisms underlying various neurological disorders.

Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.

BACKGROUND: Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined. METHODS: Using human induced pluripotent stem cells-derived cardiomyocytes and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity. RESULTS: Proteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor 2α) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector-ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD+ precursor, supplementation. Genetic inhibition of ATP synthase also activated GCN2. Interestingly, we showed that the decreased abundance of ATP also facilitated direct binding of ponatinib to GCN2, unexpectedly causing its activation most likely because of a conformational change in its structure. Importantly, administering an ISR inhibitor protected human induced pluripotent stem cell-derived cardiomyocytes against ponatinib. Ponatinib-treated mice also exhibited reduced cardiac function, effects that were attenuated upon systemic ISRIB administration. Importantly, ISRIB does not affect the antitumor effects of ponatinib in vitro. CONCLUSIONS: Neutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.

Microsurgical treatment of distal middle cerebral artery aneurysm: A single-center review.

OBJECTIVE: To review the characteristics of distal middle cerebral artery (MCA) aneurysm treated by microsurgery, the detailed surgical options, and the clinical result. METHODS: We retrospectively reviewed cerebral aneurysm in the M2 and M3 segments of the MCA surgically treated between January 2015 and December 2022. The demographic data, aneurysm-related findings, type of surgical approach, surgical technique, and clinical outcomes of the enrolled patients were analyzed. RESULTS: Sixteen distal MCA aneurysms were treated with microneurosurgery (incidence, 1.0%; female, 12; mean age, 58.1 years; ruptured, three). Twelve aneurysms were in the M2 segment (insular segment), two aneurysms at the M2-M3 junction, and two aneurysms in the M3 segment (opercular segment). Twelve aneurysms were saccular (average size, 4.9 mm; multiplicity, 50%; average aneurysms, 3.0; partially thrombosed, 1; sidewall aneurysm, 2). Three aneurysms were fusiform, of which two were ruptured. Of the ruptured aneurysms, one was a ruptured dissecting aneurysm. The trans-sylvian and trans-sulcal approaches were used in fourteen and two patients, respectively. Neck clipping, wrap clipping, and surgical trapping were performed in twelve, one, and one patient, respectively. Proximal occlusion was performed in one patient. Bypass technique was required in two patients (neck clipping and proximal occlusion). The modified Rankin Score was 6 in the two patients with ruptured aneurysms. The remaining patients did not show further neurological deterioration after microneurosurgery. CONCLUSIONS: Distal MCA aneurysms had a high incidence of being diagnosed with multiple other aneurysms and were relatively non-saccular.

Structural variability of the cerebral cortex in schizophrenia and its association with clinical symptoms.

BACKGROUND: Substantial evidence indicates structural abnormalities in the cerebral cortex of patients with schizophrenia (SCZ), although their clinical implications remain unclear. Previous case-control studies have investigated group-level differences in structural abnormalities, although the study design cannot account for interindividual differences. Recent research has focused on the association between the heterogeneity of the cerebral cortex morphometric features and clinical heterogeneity. METHODS: We used neuroimaging data from 420 healthy controls and 695 patients with SCZ from seven studies. Four cerebral cortex measures were obtained: surface area, gray matter volume, thickness, and local gyrification index. We calculated the coefficient of variation (CV) and person-based similarity index (PBSI) scores and performed group comparisons. Associations between the PBSI scores and cognitive functions were evaluated using Spearman's rho test and normative modeling. RESULTS: Patients with SCZ had a greater CV of surface area and cortical thickness than those of healthy controls. All PBSI scores across cortical measures were lower in patients with SCZ than in HCs. In the patient group, the PBSI scores for gray matter volume and all cortical measures taken together positively correlated with the full-scale IQ scores. Patients with deviant PBSI scores for gray matter volume and all cortical measures taken together had lower full-scale IQ scores than those of other patients. CONCLUSIONS: The cerebral cortex in patients with SCZ showed greater regional and global structural variability than that in healthy controls. Patients with deviant similarity of cortical structural profiles exhibited a lower general intelligence than those exhibited by the other patients.

The association of tonsillar microbiota with biochemical indices based on obesity and tonsillar hypertrophy in children.

The correlation between tonsil microbiome and tonsillar hypertrophy has not been well established. Given that oral dysbiosis is related to several metabolic diseases and that tonsillar hypertrophy leads to disordered breathing during sleep and obesity in children, it is necessary to investigate the relationship between the oral microbiome and tonsillar hypertrophy. After 16S rRNA amplicon sequencing of tonsillectomy samples, we evaluated the correlation between the tonsil microbiome and biochemical blood indices in pediatric patients who underwent tonsillectomy. Groups are classified into two categories: based on BMI, and grades 2, 3, and 4 based on tonsil size. Children with obesity and tonsillar hypertrophy have similar microbiome compositions and induce comparable changes in microbiome abundance and composition, confirming the association from a metagenomic perspective. In addition, obesity and tonsillar hypertrophy demonstrated a strong correlation with the Proteobacteria to Firmicutes (P/F) ratio, and among various biochemical indicators, alanine aminotransferase (ALT) levels increase with obesity and tonsillar hypertrophy, indicating a possible association of tonsil microbiome and liver metabolism. These novel findings demonstrate the significance of the tonsil microbiome and suggest the need for tonsil regulation, particularly during childhood.

MRI radiomics may predict early tumor recurrence in patients with sinonasal squamous cell carcinoma.

OBJECTIVES: Sinonasal squamous cell carcinoma (SCC) follows a poor prognosis with high tendency for local recurrence. We aimed to evaluate whether MRI radiomics can predict early local failure in sinonasal SCC. METHODS: Sixty-eight consecutive patients with node-negative sinonasal SCC (January 2005-December 2020) were enrolled, allocated to the training (n = 47) and test sets (n = 21). Early local failure, which occurred within 12 months of completion of initial treatment, was the primary endpoint. For clinical features (age, location, treatment modality, and clinical T stage), binary logistic regression analysis was performed. For 186 extracted radiomic features, different feature selections and classifiers were combined to create two prediction models: (1) a pure radiomics model; and (2) a combined model with clinical features and radiomics. The areas under the receiver operating characteristic curves (AUCs) were calculated and compared using DeLong's method. RESULTS: Early local failure occurred in 38.3% (18/47) and 23.8% (5/21) in the training and test sets, respectively. We identified several radiomic features which were strongly associated with early local failure. In the test set, both the best-performing radiomics model and the combined model (clinical + radiomic features) yielded higher AUCs compared to the clinical model (AUC, 0.838 vs. 0.438, p = 0.020; 0.850 vs. 0.438, p = 0.016, respectively). The performances of the best-performing radiomics model and the combined model did not differ significantly (AUC, 0.838 vs. 0.850, p = 0.904). CONCLUSION: MRI radiomics integrated with a machine learning classifier may predict early local failure in patients with sinonasal SCC. CLINICAL RELEVANCE STATEMENT: MRI radiomics intergrated with machine learning classifiers may predict early local failure in sinonasal squamous cell carcinomas more accurately than the clinical model. KEY POINTS: • A subset of radiomic features which showed significant association with early local failure in patients with sinonasal squamous cell carcinomas was identified. • MRI radiomics integrated with machine learning classifiers can predict early local failure with high accuracy, which was validated in the test set (area under the curve = 0.838). • The combined clinical and radiomics model yielded superior performance for early local failure prediction compared to that of the radiomics (area under the curve 0.850 vs. 0.838 in the test set), without a statistically significant difference.

E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension.

BACKGROUND: Rare genetic variants and genetic variation at loci in an enhancer in SOX17 (SRY-box transcription factor 17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutations in SOX17 in PAH pathogenesis has not been reported. METHODS: SOX17 expression was evaluated in the lungs and pulmonary endothelial cells (ECs) of patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion were generated to determine the role of SOX17 deficiency in the pathogenesis of PAH. Human pulmonary ECs were cultured to understand the role of SOX17 deficiency. Single-cell RNA sequencing, RNA-sequencing analysis, and luciferase assay were performed to understand the underlying molecular mechanisms of SOX17 deficiency-induced PAH. E2F1 (E2F transcription factor 1) inhibitor HLM006474 was used in EC-specific Sox17 mice. RESULTS: SOX17 expression was downregulated in the lung and pulmonary ECs from patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion induced spontaneously mild pulmonary hypertension. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced pulmonary hypertension in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and antiapoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP (bone morphogenetic protein) signaling. E2F1 signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction. Pharmacological inhibition of E2F1 in Sox17 EC-deficient mice attenuated pulmonary hypertension development. CONCLUSIONS: Our study demonstrated that endothelial SOX17 deficiency induces pulmonary hypertension through E2F1. Thus, targeting E2F1 signaling represents a promising approach in patients with PAH.