Deep learning-based analysis of EGFR mutation prevalence in lung adenocarcinoma H&E whole slide images.

EGFR mutations are a major prognostic factor in lung adenocarcinoma. However, current detection methods require sufficient samples and are costly. Deep learning is promising for mutation prediction in histopathological image analysis but has limitations in that it does not sufficiently reflect tumor heterogeneity and lacks interpretability. In this study, we developed a deep learning model to predict the presence of EGFR mutations by analyzing histopathological patterns in whole slide images (WSIs). We also introduced the EGFR mutation prevalence (EMP) score, which quantifies EGFR prevalence in WSIs based on patch-level predictions, and evaluated its interpretability and utility. Our model estimates the probability of EGFR prevalence in each patch by partitioning the WSI based on multiple-instance learning and predicts the presence of EGFR mutations at the slide level. We utilized a patch-masking scheduler training strategy to enable the model to learn various histopathological patterns of EGFR. This study included 868 WSI samples from lung adenocarcinoma patients collected from three medical institutions: Hallym University Medical Center, Inha University Hospital, and Chungnam National University Hospital. For the test dataset, 197 WSIs were collected from Ajou University Medical Center to evaluate the presence of EGFR mutations. Our model demonstrated prediction performance with an area under the receiver operating characteristic curve of 0.7680 (0.7607-0.7720) and an area under the precision-recall curve of 0.8391 (0.8326-0.8430). The EMP score showed Spearman correlation coefficients of 0.4705 (p = 0.0087) for p.L858R and 0.5918 (p = 0.0037) for exon 19 deletions in 64 samples subjected to next-generation sequencing analysis. Additionally, high EMP scores were associated with papillary and acinar patterns (p = 0.0038 and p = 0.0255, respectively), whereas low EMP scores were associated with solid patterns (p = 0.0001). These results validate the reliability of our model and suggest that it can provide crucial information for rapid screening and treatment plans.

Tailoring Lithium Horizontal Deposition for Long-Lasting High-Loading NCA (≥5 mA h cm-2)||Lithium-Metal Full Cells in Carbonate Electrolytes.

We report a design for a synergistic lithium (Li) metal hosting layer for high-loading Li(Ni,Co,Al)O2 (NCA) (≥5 mA h cm-2)||Li-metal full cells in carbonate electrolytes. Based on density functional theory calculations, the hosting layer was designed as a three-dimensional silver/carbon composite nanofiber (Ag/CNF) network with high Li affinity and a platinum (Pt)-coated polypropylene separator with low Li affinity. This design enabled the tailoring of horizontal Li deposition on the Ag/CNF hosting layer. The Li deposition behavior modulated by the hosting layer was thoroughly examined based on the initial Li deposition and cycling behaviors of the Li||Li symmetric cell configuration. Cryogenic focused-ion beam cross-sectional images of the cycled Li anodes clearly demonstrated that dense lithium deposition was enabled by the synergistic hosting layer high-loading NCA (≥5 mA h cm-2)||Li-metal full cells. When the hosting layer was used, the average cycling performance improved by 78.27% under various cycling conditions. Our work demonstrates that the synergistic hosting layer design is a fruitful pathway to accelerate the commercialization of high-energy-density Li-metal batteries in carbonate electrolytes.

Amplifying mutational profiling of extracellular vesicle mRNA with SCOPE.

Sequencing of messenger RNA (mRNA) found in extracellular vesicles (EVs) in liquid biopsies can provide clinical information such as somatic mutations, resistance profiles and tumor recurrence. Despite this, EV mRNA remains underused due to its low abundance in liquid biopsies, and large sample volumes or specialized techniques for analysis are required. Here we introduce Self-amplified and CRISPR-aided Operation to Profile EVs (SCOPE), a platform for EV mRNA detection. SCOPE leverages CRISPR-mediated recognition of target RNA using Cas13 to initiate replication and signal amplification, achieving a sub-attomolar detection limit while maintaining single-nucleotide resolution. As a proof of concept, we designed probes for key mutations in KRAS, BRAF, EGFR and IDH1 genes, optimized protocols for single-pot assays and implemented an automated device for multi-sample detection. We validated SCOPE's ability to detect early-stage lung cancer in animal models, monitored tumor mutational burden in patients with colorectal cancer and stratified patients with glioblastoma. SCOPE can expedite readouts, augmenting the clinical use of EVs in precision oncology.

Corrigendum: Treatment sequence after initiating biologic therapy for patients with rheumatoid arthritis in Korea: a nationwide retrospective cohort study.

[This corrects the article on p. 26 in vol. 30, PMID: 37476522.].

Lectin histochemistry in the small intestines of piglets naturally infected with porcine epidemic diarrhea virus.

IMPORTANCE: Porcine epidemic diarrhea virus (PEDV) binds to particular cell surface receptors to penetrate cells. The virus specifically identifies certain carbohydrate structures present on the surface of the cell to facilitate the binding process. Nevertheless, the influence of viral infections on specific alterations of glycoconjugates in the small intestines remains unexplored. OBJECTIVE: This work aimed to examine the alterations in glycoconjugates in the small intestines of piglets naturally infected with PEDV using lectin histochemistry. METHODS: Six piglets including three PEDV-infected and three non-infected piglets were evaluated. Small intestinal samples were histopathologically examined, and lectin histochemistry was performed. RESULTS: Piglets infected with PEDV had significant histological abnormalities in their small intestines, such as pronounced villous atrophy, varying degrees of villous fusion, and diverse mucosal alterations. Specific regions of the duodenum, jejunum, and ileum showed discernible variations in glycoconjugate distribution, as determined by lectin histochemistry. Compared with the controls, the PEDV-infected piglets showed significant changes in N-acetylglucosamine- and galactose-binding lectins (particularly wheat germ agglutinin and Arachis hypogaea (peanut) agglutinin) in multiple intestinal regions. CONCLUSIONS AND RELEVANCE: These findings can enhance understanding of how viruses such as PEDV impact the glycoconjugate composition of the small intestines and emphasize the potential connection between the pathogenesis of PEDV and glycoconjugate.

Multifaceted neuroprotective approach of Trolox in Alzheimer's disease mouse model: targeting Aß pathology, neuroinflammation, oxidative stress, and synaptic dysfunction.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an Aß1 - 42-induced AD mouse model. Aß1 - 42 5µL/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of Aß, phosphorylated tau (p-tau), and ß-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-κB (pNF-κB) and interleukin-1ß (IL-1ß), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases.

Geometric isomerization of dietary monounsaturated fatty acids by a cis/trans fatty acid isomerase from Pseudomonas putida KT2440.

Pseudomonas putida KT2440 encodes a defense system that rigidifies membranes by a cytochrome c-type cis/trans fatty acid isomerase (CTI). Despite its potential as an industrial biocatalyst for directly regulating the geometric isomerism of monounsaturated fatty acids, its original catalytic and structural properties have remained elusive. In this study, the catalytic nature of wild-type CTI purified P. putida KT2440 against dietary monounsaturated fatty acids was investigated. It showed substrate preference for palmitoleic acid (C16:1, cis-Δ9), along with substrate promiscuity with chain length and double bond position (palmitoleic acid>cis-vaccenic acid>oleic acid). Under determined optimum reaction conditions, its catalytic efficiency (kcat/Km) was evaluated as 5.13 × 102 M-1·sec-1 against palmitoleic acid. Furthermore, computational predictions of the protein structure revealed its monoheme cytochrome c-type domain and a parasol-like transmembrane domain, suggesting its catalytic mode of action. For effective cis/trans isomerization, the ethylene double bond of monounsaturated fatty acids should be precisely positioned at the heme center of CTI, indicating that its substrate specificity can be determined by the alkyl chain length and the double bond position of the fatty acid substrates. These findings shed light on the potential of CTI as a promising biocatalyst for the food and lipid industry.

Efficacy of Nd:YAG Laser and Intralesional Triamcinolone Injection Combination Therapy in the Postoperative Management of Keloids.

BACKGROUND: Keloids, characterized by protruding scars that extend beyond the original skin damage site, cause significant emotional stress and reduced quality of life. Their exact pathogenesis remains unclear, with various hypotheses including growth factor imbalances and extracellular matrix changes. No single treatment is universally accepted, but multiple modalities like triamcinolone acetonide injection (TAC), laser therapies, and surgery are commonly used. METHODS: This retrospective study involved East Asian patients who underwent keloid scar excision between March 2019 and June 2022. Patients were divided into two groups: one receiving only TAC injections and the other a combination of TAC and Nd:YAG laser therapy. The efficacy of treatments was evaluated using the modified Vancouver Scar Scale (mVSS) and the Patient and Observer Scar Assessment Scale (POSAS), with follow-ups at six and twelve months after operation. RESULTS: The study involved 111 patients. Both treatment groups showed significant improvements in mVSS and POSAS scores, but the combination therapy group demonstrated a statistically significant improvement in POSAS scores and lower recurrence rates at 12 months compared to the TAC-only group. However, there was no significant difference in patient satisfaction between the groups. CONCLUSION: Dual therapy involving TAC injection and Nd:YAG laser treatment was more effective than TAC injection alone for managing keloid scars after surgery. This combination therapy showed better outcomes in preventing keloid recurrence and improving scar status at 12 months after operation, along with significant improvements in patient-reported outcomes. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Differential genotoxicity of Polygoni Multiflori in rat and human: insights from Ames test and S9 metabolic activation system.

The Ames test is used worldwide to initially screen the mutagenic potential of new chemicals. In the standard Ames test, S. typhimurium strains (TA100, TA98, TA1535, and TA1537) and Escherichia coli (WP2uvrA) are treated with substances with/without cytochrome P450s (CYPs)-induced rat S9 fractions for identifying mutagens and pro-mutagens. However, many substances show completely different toxicity patterns depending on whether the liver S9 fraction belongs to rats or humans. The natural product Polygoni Multiflori Radix (PMR) can also show bacterial reverse mutation, followed by the rat or human liver S9 fraction. While PMR elicits reverse mutations in the TA1537 strain in rat liver S9 but not in human liver S9, this mechanism has not been verified yet. To explain this, the differences in metabolic enzymes compositions commonly observed between rats and humans have been implicated. This study aimed to explore the key factors that cause differences in the genotoxicity of PMR between rat and human liver S9 metabolic enzymes. The results of next-generation sequencing (NGS) analysis showed that both rat and human metabolic enzymes caused similar mutations in TA1537. However, when the metabolic enzymes in each S9 fraction were analyzed using ion mobility tandem mass spectrometry (IM-MS), rat- and human-specific enzymes were identified among the cytochrome (CYP) family, especially aryl hydrocarbon receptor (AHR)-related CYPs. These findings suggest that CYP1A1 isoforms contribute to the mechanism of PMR in the Ames test. Therefore, an in vitro Ames test might be more reliable in predicting genotoxicity for both rodents and humans. This will also help overcome the limitations of laboratory animal-based toxicity evaluations, which provide unreliable results due to interspecies differences between humans and rodents.

Enhanced lithium host performance of multi-walled carbon nanotubes through acidic functionalization for lithium-sulfur batteries.

Carbon nanotubes (CNTs) have been explored as a potential cathode material for lithium-sulfur (Li-S) batteries owing to their unique structure. However, traditional CNTs exhibit poor dispersion properties when preparing electrodes. The non-uniform distribution of the conductive agents hinders the formation of enough sites for sulfur loading, which results in the aggregation of sulfur/Li2S and severe polarization. In this study, we propose the acidic functionalization of CNTs in the cathode structure as a practical solution for mitigating the poor dispersion and polysulfide shuttling in lithium-sulfur batteries. Multiwalled CNTs were functionalized by oxidation through acidic treatment using sulfuric, nitric, and mixed acids. The cathode prepared with a mixture of sulfuric and nitric acids showed a coulombic efficiency of 99 % after 100 cycles, with a discharge capacity of 743 mAh g-1. These findings demonstrate the effectiveness of the acidic functionalization of CNTs as a promising approach for enhancing the electrochemical performance and commercial viability of lithium-sulfur batteries.

Dexamethasone nanocrystals-embedded hydroxypropyl methylcellulose hydrogel increases cochlear delivery and attenuates hearing loss following intratympanic injection.

Herein, dexamethasone (DEX) nanocrystalline suspension (NS)-embedded hydrogel (NS-G) was constructed using a hydroxypropyl methylcellulose (HPMC) polymer to enhance cochlear delivery and attenuate hearing loss following intratympanic (IT) injection. Hydrophobic steroidal nanocrystals were prepared using a bead milling technique and incorporated into a polysaccharide hydrogel. The NS-G system with HPMC (average molecular weight, 86,000 g/mol; 15 mg/mL) was characterized as follows: rod-shaped drug crystalline; particle size <300 nm; and constant complex viscosity ≤1.17 Pa·s. Pulverization of the drug particles into submicron diameters enhanced drug dissolution, while the HPMC matrix increased the residence time in the middle ear cavity, exhibiting a controlled release profile. The IT NS-G system elicited markedly enhanced and prolonged drug delivery (> 9 h) to the cochlear tissue compared with that of DEX sodium phosphate (DEX-SP), a water-soluble prodrug. In mice with kanamycin- and furosemide-induced ototoxicity, NS-G markedly enhanced hearing preservation across all frequencies (8-32 kHz), as revealed by an auditory brainstem response test, compared with both saline and DEX-SP. Moreover, treatment with NS-G showed enhanced anti-inflammatory effects, as evidenced by decreased levels of inflammation-related cytokines. Therefore, the IT administration of DEX NS-loaded HPMC hydrogels is a promising strategy for treating hearing loss.

A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance. METHODS: A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from 6 centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n=944), internal validation (n=1,102), and external validation (n=2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death. RESULTS: During a median follow-up of 55.2 (interquartile range=30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. A model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and 7 variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all P<0.001; area under the receiver operating characteristic curve: 0.86 vs. 0.62-0.72, all P<0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all P<0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test P>0.05) and these results were reproduced in the internal and external validation cohorts. CONCLUSION: This novel machine learning model consisting of 7 variables provides reliable risk prediction of LRO after HBsAg seroclearance that can be used for personalized surveillance.

Automated Association for Osteosynthesis Foundation and Orthopedic Trauma Association classification of pelvic fractures on pelvic radiographs using deep learning.

High-energy impacts, like vehicle crashes or falls, can lead to pelvic ring injuries. Rapid diagnosis and treatment are crucial due to the risks of severe bleeding and organ damage. Pelvic radiography promptly assesses fracture extent and location, but struggles to diagnose bleeding. The AO/OTA classification system grades pelvic instability, but its complexity limits its use in emergency settings. This study develops and evaluates a deep learning algorithm to classify pelvic fractures on radiographs per the AO/OTA system. Pelvic radiographs of 773 patients with pelvic fractures and 167 patients without pelvic fractures were retrospectively analyzed at a single center. Pelvic fractures were classified into types A, B, and C using medical records categorized by an orthopedic surgeon according to the AO/OTA classification system. Accuracy, Dice Similarity Coefficient (DSC), and F1 score were measured to evaluate the diagnostic performance of the deep learning algorithms. The segmentation model showed high performance with 0.98 accuracy and 0.96-0.97 DSC. The AO/OTA classification model demonstrated effective performance with a 0.47-0.80 F1 score and 0.69-0.88 accuracy. Additionally, the classification model had a macro average of 0.77-0.94. Performance evaluation of the models showed relatively favorable results, which can aid in early classification of pelvic fractures.

The association between initial post-resuscitation diastolic blood pressure and survival after pediatric cardiac arrest: a retrospective study.

BACKGROUND: Limited research has analyzed the association between diastolic blood pressure (DBP) and survival after pediatric cardiopulmonary resuscitation (CPR). This study aimed to explore the association between post-resuscitation diastolic blood pressure and survival in pediatric patients who underwent CPR. METHOD: This retrospective single-center study included pediatric patients admitted to the pediatric intensive care unit of Asan Medical Center between January 2016 to November 2022. Patients undergoing extracorporeal CPR and those with unavailable data were excluded. The primary endpoint was survival to ICU discharge. RESULTS: A total of 106 patients were included, with 67 (63.2%) achieving survival to ICU discharge. Multivariate logistic regression analysis identified DBP within 1 h after ROSC as the sole significant variable (p = 0.002, aOR, 1.043; 95% CI, 1.016-1.070). Additionally, DBP within 1 h demonstrated an area under the ROC curve of 0.7 (0.592-0.809) for survival to ICU discharge, along with mean blood pressure within the same timeframe. CONCLUSION: Our study highlights the importance of DBP within 1-hour post-ROSC as a significant prognostic factor for survival to ICU discharge. However, further validation through further prospective large-scale studies is warranted to confirm the appropriate post-resuscitation DBP of pediatric patients.

Association between intra-articular hyaluronic acid injections in delaying total knee arthroplasty and safety evaluation in primary knee osteoarthritis: analysis based on Health Insurance Review and Assessment Service (HIRA) claim database in Republic of Korea.

BACKGROUND: The prevalence of knee osteoarthritis (KOA), a progressive degenerative disease, is gradually increasing, and it is a progressive degenerative disease. In patients with mild-to-moderate KOA, intra-articular hyaluronic acid (IA-HA) has been shown to be an effective non-operative treatment option that can provide significant pain relief and symptom improvement by increasing intra-articular viscoelasticity. This study aimed to evaluate the efficacy of IA-HA injections in delaying total knee arthroplasty (TKA) and the safety of IA-HA according to IA-HA type and combination with intra-articular corticosteroid (IA-CS) using a large health insurance claim database. METHODS: For this retrospective cohort study, the study population included patients aged ≥ 50 years with a first diagnosis of KOA between 2009 and 2014, who underwent TKA by 2020, using the Health Insurance Review and Assessment Service claim database in Republic of Korea. IA-HA injections were categorized as single or multiple injection regimen agents. Cox proportional hazard models estimated hazard ratios (HR) for TKA risk, adjusted for covariates. Logistic regression assessed the occurrence of adverse events after IA-HA administration. RESULTS: In all, 36,983 patients were included. Patients who received IA-HA injections had a significantly longer time to TKA compared to those who did not (mean delay of approximately 1 year). The IA-HA group had a significantly lower risk of TKA (HR: 0.61, 95% CI: 0.60-0.62) than non-IA-HA group after adjusting for covariates, which included age, sex, medical history, number of hospital beds, and CS injection. Single injection IA-HA regimen agents showed the longest time to TKA and lowest risk (HR: 0.56, 95% CI: 0.53-0.59). TKA risk decreased with the number of IA-HA cycles. Adverse events occurred in 6.7% of IA-HA cases without CS, with very low incidence of infection. Multiple injection regimen agents (multiple injection regimen 7.0% vs. single injection regimen 3.6%) and concurrent IA-CS use (concurrent IA-CS use 13.9% vs. IA-HA only 6.7%) were associated with higher infection risk. CONCLUSION: IA-HA injections were associated with a significant delay in TKA among patients with KOA. Single-injection regimen agents had the lowest TKA risk. Infection risk increased with multiple injections and concurrent IA-CS use. These findings could suggest the use of IA-HA as an effective non-operative intervention option for managing KOA and delaying TKA. Careful selection of IA-HA type and consideration of concurrent IA-CS use could play a role in delaying the time to TKA and reducing complications.

Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.

Association between personality, lifestyle behaviors, and cardiovascular diseases in type 2 diabetes mellitus: a population-based cohort study of UK Biobank data.

INTRODUCTION: Various strategies aim to better assess risks and refine prevention for patients with type 2 diabetes mellitus (T2DM), who vary in cardiovascular disease (CVD) risk. However, the prognostic value of personality and its association with lifestyle factors remain elusive. RESEARCH DESIGN AND METHODS: We identified 8794 patients with T2DM from the UK Biobank database between 2006 and 2010 and followed them up until the end of 2021. We assessed personality traits using the Big Five proxies derived from UK Biobank data: sociability, warmth, diligence, curiosity, and nervousness. Healthy lifestyle behaviors were determined from information about obesity, smoking status, and physical activity. The primary outcome was a composite of incident CVD, including myocardial infarction (MI), ischemic stroke (IS), atrial fibrillation (AF), and heart failure (HF). RESULTS: During a median follow-up of 13.6 years, a total of 2110 patients experienced CVDs. Among personality traits, diligence was significantly associated with a reduced risk of primary and secondary outcomes. The adjusted HRs with 95% CIs were: composite CVD, 0.93 (0.89-0.97); MI 0.90 (0.82-1.00); IS 0.83 (0.74-0.94); AF 0.92 (0.85-0.98); HF 0.84 (0.76-0.91). Healthy lifestyle behaviors significantly reduced the risk of composite CVDs in groups with high and low diligence. The findings of a structural equation model showed that diligence directly affected the risk of the primary outcome or indirectly by modifying lifestyle behaviors. CONCLUSION: This study revealed which personality traits can influence CVD risk during T2DM and how patients might benefit from adopting healthy lifestyle behaviors in relation to personality.

Target-Enhanced Whole-Genome Sequencing (TE-WGS) Shows Clinical Validity Equivalent to Commercially Available Targeted Oncology Panel.

Purpose: Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS. Materials and Methods: This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches. Results: TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions (VAF) was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability (MSI), and homologous-recombination deficiency (HRD) scores, which were essential for clinical decision-making. Conclusion: TE-WGS is a comprehensive approach in personalized oncology, matching TSO500's key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Interferon-Induced Transmembrane Protein 1 (IFITM1) Is Downregulated in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.