Comparison of clinical and MRI features of hepatic angiosarcoma and epithelioid hemangioendothelioma.

OBJECTIVE: Differentiating hepatic epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), the two most common vascular tumors in the liver, is important due to disparities in their prognosis and treatment. We aimed to compare clinical and MRI features of the two tumors. METHODS: This retrospective study included patients with pathologically-confirmed AS or EHE who underwent MRI using gadoxetate disodium between 2008 and 2023. Two radiologists independently reviewed MR images. Wilcoxon rank sum and Fisher's exact tests were used to compare clinical and imaging features. Overall survival was compared using restricted mean survival time at 3 years. RESULTS: 32 patients with AS (18 women [56.3%]; median age, 68 years) and 38 with EHE (24 women [63.2%]; 51 years) were included. Patients with AS were generally older (81.3% ≥ 60 years; P < 0.001), had more frequent laboratory abnormalities (P ≤ 0.018), and poorer overall survival (11.2 vs. 31.8 months; P < 0.001) than those with EHE. On MRI, a large dominant mass accompanied by smaller nodules (14/32, 43.8%), often with ill-defined margins (15/32, 46.9%) was prevalent in AS; compared with nodules of similar sizes (24/38, 63.2%; P = 0.015) with well-defined margin (30/38, 78.9%; P = 0.002) in EHE. Cirrhotic appearance of the liver was more frequent in AS (62.5%, P < 0.001), along with decreased parenchymal enhancement on hepatobiliary phase (31.3%, P < 0.001) and ascites (37.5%, P = 0.010). AS frequently presented with avid enhancement of bizarrely-shaped foci, with a centrifugal enhancement pattern. In comparison, targetoid appearance was characteristic of EHE (78.9% on T2-weighted, 54.1% on diffusion-weighted, 65.8% on multiphase images) (P ≤ 0.002), with enhancement degree typically lower than that of the aorta. On hepatobiliary phase, all the AS exhibited hypointensity, while 39.5% of EHE showed targetoid appearance (P < 0.001). CONCLUSION: Patients aged ≥ 60 years presenting with laboratory abnormalities, typically with a large dominant mass accompanied by smaller nodules, exhibiting avid, bizarre, and centrifugal enhancement-particularly in the cirrhotic-appearing liver-suggests the likelihood of AS over EHE.

Push-Pull Mechanism of Attention and Emotion in Children with Attention Deficit Hyperactivity Disorder.

Background/Objectives: While deficits in executive attention and alerting systems in children with attention deficit hyperactivity disorder (ADHD) are well-documented, findings regarding orienting attention in ADHD have been inconsistent. The current study investigated the mechanism of attentional orienting in children with ADHD by examining their attentional bias towards threatening stimuli. Furthermore, we explored the modulating role of anxiety levels in ADHD on this attentional bias. Methods: In Experiment 1, 20 children with ADHD and 26 typically developing children (TDC) performed a continuous performance task that included task-irrelevant distractions consisting of angry faces and neutral places. In Experiment 2, 21 children with ADHD and 25 TDC performed the same task, but with angry and neutral faces as distractors. To measure children's anxiety levels, the State-Trait Anxiety Inventory was administered before each experiment. Results: In Experiment 1, results revealed no attentional bias effects in children with ADHD, whereas TDC exhibited attentional capture effects by both types of distractors. However, in Experiment 2, ADHD children demonstrated an attentional bias towards angry faces, which revealed a significant positive correlation with their trait anxiety levels (r = 0.61, p < 0.05). Further analyses combining all ADHD children showed that trait anxiety levels in Experiment 2 were significantly higher than those in Experiment 1. Finally, a significant positive correlation was found between anxiety levels and attentional bias towards angry faces in all ADHD children (r = 0.36, p < 0.01). Conclusions: Children with ADHD exhibited atypical attentional-orienting effects to threats, and their levels of trait anxiety appeared to modulate such attentional-orienting mechanisms.

Repurposing of the analgesic Neurotropin for MASLD/MASH treatment.

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased in recent decades. Approximately 25% of patients with MASLD progress to metabolic dysfunction-associated steatohepatitis, which is characterized by hepatic steatosis plus hepatocyte damage, inflammation, and fibrosis. We previously reported that Neurotropin (NTP), a drug used for relieving pain in Japan and China, inhibits lipid accumulation in hepatocytes by preventing mitochondrial dysfunction. We hypothesized that inhibiting hepatic steatosis and inflammation by NTP can be an effective strategy for treating MASLD and tested this hypothesis in a MASLD mouse model. METHODS: Six-week-old C57BL/6NJ male mice were fed a normal diet and normal drinking water or a high-fat diet with high fructose/glucose water for 12 weeks. During the last 6 weeks, the mice were also given high-dose NTP, low-dose NTP, or control treatment. Histologic, biochemical, and functional tests were conducted. MitoPlex, a new proteomic platform, was used to measure mitochondrial proteins, as mitochondrial dysfunction was previously reported to be associated with MASLD progression. RESULTS: NTP inhibited the development of hepatic steatosis, injury, inflammation, and fibrosis induced by feeding a high-fat diet plus high fructose/glucose in drinking water. NTP also inhibited HSC activation. MitoPlex analysis revealed that NTP upregulated the expression of mitochondrial proteins related to oxidative phosphorylation, the tricarboxylic acid cycle, mitochondrial dynamics, and fatty acid transport. CONCLUSIONS: Our results indicate that NTP prevents the development of hepatic steatosis, injury, and inflammation by preserving mitochondrial function in the liver and inhibits liver fibrosis by suppressing HSC activation. Thus, repurposing NTP may be a beneficial option for treating MASLD/metabolic dysfunction-associated steatohepatitis.

Geraniin from the methanol extract of Pilea mongolica suppresses LPS-induced inflammatory responses by inhibiting IRAK4/MAPKs/NF-κB/AP-1 pathway in HaCaT cells.

The skin acts as a vital barrier, shielding the body from external threats that can trigger dryness, itching, and inflammation. Pilea mongolica, a traditional Chinese medicinal herb, holds promise for various ailments, yet its anti-inflammatory properties remain understudied. This study aimed to explore the potential anti-inflammatory effects of the methanol extract of P. mongolica (MEPM) and its underlying molecular mechanisms and active compounds in LPS-stimulated human keratinocytes. MEPM treatment, at concentrations without cytotoxicity, significantly decreased NO productions and the iNOS, IL-6, IL-1ß, and TNF-α levels in LPS-induced HaCaT cells. Moreover, MEPM suppressed IRAK4 expression and phosphorylation of JNK, ERK, p38, p65, and c-Jun, suggesting that the anti-inflammatory effects of MEPM result from the inhibition of IRAK4/MAPK/NF-κB/AP-1 signaling pathway. Through LC/MS/MS analysis, 30 compounds and 24 compounds were estimated in negative and positive modes, respectively, including various anti-inflammatory compounds, such as corilagin and geraniin. Through HPLC analysis, geraniin was found to be present in MEPM at a concentration of 18.87 mg/g. Similar to MEPM, geraniin reduced iNOS mRNA expression and inhibited NO synthesis. It also decreased mRNA and protein levels of inflammatory cytokines, including IL-6 and TNF-α, and inhibited IRAK4 expression and the phosphorylation of MAPKs, NF-κB, and AP-1 pathways. Therefore, it can be inferred that the anti-inflammatory effects of MEPM are attributable to geraniin. Thus, MEPM and its active compound geraniin are potential candidates for use in natural functional cosmetics.

Sulfuryl Fluoride Fumigation as a Quarantine Treatment for the Control of Reticulitermes speratus Kolbe (Blattodea: Rhinotermitidae) in Wood.

High-risk termites in wood imported to the Republic of Korea are currently treated with methyl bromide (MB), which has ozone-depleting properties and is highly toxic. This study evaluated the effectiveness of sulfuryl fluoride (SF) as a quarantine treatment against Reticulitermes speratus Kolbe (Blattodea: Rhinotermitidae) in wood, along with its wood sorption and penetration capacity. The LCt50 and LCt99 values for SF were 30.87 and 42.53 mg h/L at 23 °C and 151.62 and 401.9 mg h/L at 5 °C, respectively. The SF Ct values did not significantly differ between dry and wet wood at loading ratios of 10%, 30%, and 50% at both 5 °C and 23 °C (p > 0.05). In a closed wooden cube, the LCt50 and LCt99 for SF for R. speratus were 31.59 and 53.34 mg h/L, respectively, indicating an excellent wood penetration ability. SF caused 100% termite mortality with a 90% loading ratio in the scale-up trials (500 L). The SF concentration during ventilation decreased below the threshold limit value (TLV) of 5 ppm within 30 min, confirming that the working conditions were safe. This study provides a basis for the use of SF as an alternative to MB for the treatment of termites in wood.

Simultaneous Analysis of Thirteen Compounds in Yeokwisan Using High-Performance Liquid Chromatography-Photodiode Array Detection and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry and Their Antioxidant Effects.

Yeokwisan (YWS) is an herbal medicine prescription consisting of six oriental herbal medicines, developed to treat reflux esophagitis. We focused on developing an analytical method capable of simultaneously quantifying 13 compounds in YWS samples using high-performance liquid chromatography-photodiode array detection (HPLC-PDA) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and exploring their antioxidant effects. All compounds examined in both analytical systems were chromatographically separated on a SunFireTM C18 (4.6 × 250 mm, 5 µm) column and an Acquity UPLC BEH C18 (2.1 × 100 mm, 1.7 µm) column using gradient elution of a water-acetonitrile mobile phase. Antioxidant effects were evaluated based on radical scavenging activity (DPPH and ABTS tests) and ferrous ion chelating activity. In two analytical methods, the coefficient of determination of the regression equation was ≥0.9965, the recovery range was 81.11-108.21% (relative standard deviation (RSD) ≤ 9.33%), and the precision was RSD ≤ 11.10%. Application of the optimized analysis conditions gave quantitative analysis results for YWS samples of 0.02-100.36 mg/g. Evaluation of the antioxidant effects revealed that baicalein and baicalin exhibit significant antioxidant activity, suggesting that they play an important role in the antioxidant effects of YWS.

Identification of Oil-Loving Cupriavidus necator BM3-1 for Polyhydroxyalkanoate Production and Assessing Contribution of Exopolysaccharide for Vegetable Oil Utilization.

Polyhydroxyalkanoates (PHA) have received attention owing to their biodegradability and biocompatibility, with studies exploring PHA-producing bacterial strains. As vegetable oil provides carbon and monomer precursors for poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (P(3HB-co-3HHx)), oil-utilizing strains may facilitate PHA production. Herein, Cupriavidus necator BM3-1, which produces 11.1 g/L of PHB with 5% vegetable oil, was selected among various novel Cupriavidus necator strains. This strain exhibited higher preference for vegetable oils over sugars, with soybean oil and tryptone determined to be optimal sources for PHA production. BM3-1 produced 33.9 g/L of exopolysaccharides (EPS), which was three-fold higher than the amount produced by H16 (10.1 g/L). EPS exhibited 59.7% of emulsification activity (EI24), higher than that of SDS and of EPS from H16 with soybean oil. To evaluate P(3HB-co-3HHx) production from soybean oil, BM3-1 was engineered with P(3HB-co-3HHx) biosynthetic genes (phaCRa, phaARe, and phaJPa). BM3-1/pPhaCJ produced 3.5 mol% of 3HHx and 37.1 g/L PHA. BM3-1/pCB81 (phaCAJ) produced 32.8 g/L PHA, including 5.9 mol% 3HHx. Physical and thermal analyses revealed that P(3HB-co-5.9 mol% 3HHx) was better than PHB. Collectively, we identified a novel strain with high vegetable oil utilization capacity for the production of EPS, with the option to engineer the strain for P(3HB-co-3HHx).

Cloning, Expression, Purification, and Characterization of Lactate Dehydrogenase from Plasmodium knowlesi: A Zoonotic Malaria Parasite.

Plasmodium knowlesi is the only Plasmodium that causes zoonotic disease among the Plasmodium that cause infection in humans. It is fatal due to its short asexual growth cycle within 24 h. Lactate dehydrogenase (LDH), an enzyme that catalyzes the final step of glycolysis, is a biomarker for diagnosing infection by Plasmodium spp. parasite. Therefore, this study aimed to efficiently produce the soluble form of P. knowlesi LDH (PkLDH) using a bacterial expression system for studying malaria caused by P. knowlesi. Recombinant pET-21a(+)-PkLDH plasmid was constructed by inserting the PkLDH gene into a pET-21a(+) expression vector. Subsequently, the recombinant plasmid was inserted into the protein-expressing Escherichia coli Rosetta(DE3) strain, and the optimal conditions for overexpression of the PkLDH protein were established using this strain. We obtained a yield of 52.0 mg/L PkLDH from the Rosetta(DE3) strain and confirmed an activity of 483.9 U/mg through experiments. This methodology for high-efficiency PkLDH production can be utilized for the development of diagnostic methods and drug candidates for distinguishing malaria caused by P. knowlesi.

Assessing the determinants of influenza and COVID-19 vaccine co-administration decisions in the elderly.

This research examines the low rate of co-administration of influenza and COVID-19 vaccines among seniors aged 65 and older in Korea, despite recommendations from authorities and academia worldwide. The study aimed to understand the influence of general characteristics and health beliefs on the vaccination choices of seniors, who were categorized into four groups based on their vaccination status: influenza only, COVID-19 only, both, or neither. A total of 400 participants, aged 65 and above, were selected through proportional stratified random sampling from five major Korean regions for a survey conducted between November 24th and December 15th, 2023. The results indicated no significant differences in general characteristics across these groups. However, regarding the health beliefs showed significant differences in perceived susceptibility and self-efficacy between the influenza-only and co-administration groups. Higher levels of perceived susceptibility and self-efficacy were associated with choosing co-administration. Contrary to previous studies focusing on safety concerns as a primary factor in vaccine hesitancy, this study highlights the role of individual health-related beliefs, particularly perceived susceptibility and self-efficacy, as critical in influencing the decision for co-administration among the elderly in Korea.

Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types.

The complexity of the tumor microenvironment poses significant challenges in cancer therapy. Here, to comprehensively investigate the tumor-normal ecosystems, we perform an integrative analysis of 4.9 million single-cell transcriptomes from 1070 tumor and 493 normal samples in combination with pan-cancer 137 spatial transcriptomics, 8887 TCGA, and 1261 checkpoint inhibitor-treated bulk tumors. We define a myriad of cell states constituting the tumor-normal ecosystems and also identify hallmark gene signatures across different cell types and organs. Our atlas characterizes distinctions between inflammatory fibroblasts marked by AKR1C1 or WNT5A in terms of cellular interactions and spatial co-localization patterns. Co-occurrence analysis reveals interferon-enriched community states including tertiary lymphoid structure (TLS) components, which exhibit differential rewiring between tumor, adjacent normal, and healthy normal tissues. The favorable response of interferon-enriched community states to immunotherapy is validated using immunotherapy-treated cancers (n = 1261) including our lung cancer cohort (n = 497). Deconvolution of spatial transcriptomes discriminates TLS-enriched from non-enriched cell types among immunotherapy-favorable components. Our systematic dissection of tumor-normal ecosystems provides a deeper understanding of inter- and intra-tumoral heterogeneity.

Prognostic implication of 1-year decline in diffusing capacity in newly diagnosed idiopathic pulmonary fibrosis.

The progression of idiopathic pulmonary fibrosis (IPF) is assessed through serial monitoring of forced vital capacity (FVC). Currently, data regarding the clinical significance of longitudinal changes in diffusing capacity for carbon monoxide (DLCO) is lacking. We investigated the prognostic implications of a 1-year decline in DLCO in 319 patients newly diagnosed with IPF at a tertiary hospital between January 2010 and December 2020. Changes in FVC and DLCO over the first year after the initial diagnosis were reviewed; a decline in FVC ≥ 5% and DLCO ≥ 10% predicted were considered significant changes. During the first year after diagnosis, a significant decline in FVC and DLCO was observed in 101 (31.7%) and 64 (20.1%) patients, respectively. Multivariable analysis showed that a 1-year decline in FVC ≥ 5% predicted (aHR 2.74, 95% CI 1.88-4.00) and 1-year decline in DLCO ≥ 10% predicted (aHR 2.31, 95% CI 1.47-3.62) were independently associated with a higher risk of subsequent mortality. The prognostic impact of a decline in DLCO remained significant regardless of changes in FVC, presence of emphysema, or radiographic indications of pulmonary hypertension. Therefore, serial monitoring of DLCO should be recommended because it may offer additional prognostic information compared with monitoring of FVC alone.

Artificial Synapse Based on a δ-FAPbI3/Atomic-Layer-Deposited SnO2 Bilayer Memristor.

Halide perovskite-based resistive switching memory (memristor) has potential in an artificial synapse. However, an abrupt switch behavior observed for a formamidinium lead triiodide (FAPbI3)-based memristor is undesirable for an artificial synapse. Here, we report on the δ-FAPbI3/atomic-layer-deposited (ALD)-SnO2 bilayer memristor for gradual analogue resistive switching. In comparison to a single-layer δ-FAPbI3 memristor, the heterojunction δ-FAPbI3/ALD-SnO2 bilayer effectively reduces the current level in the high-resistance state. The analog resistive switching characteristics of δ-FAPbI3/ALD-SnO2 demonstrate exceptional linearity and potentiation/depression performance, resembling an artificial synapse for neuromorphic computing. The nonlinearity of long-term potentiation and long-term depression is notably decreased from 12.26 to 0.60 and from -8.79 to -3.47, respectively. Moreover, the δ-FAPbI3/ALD-SnO2 bilayer achieves a recognition rate of ≤94.04% based on the modified National Institute of Standards and Technology database (MNIST), establishing its potential in an efficient artificial synapse.

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway.

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

Ultrasound-based steatosis grading system using 2D-attenuation imaging: An individual patient data meta-analysis with external validation.

BACKGROUND AND AIMS: Noninvasive tools assessing steatosis, such as ultrasonography-based 2D-attenuation imaging (ATI), are needed to tackle the worldwide burden of steatotic liver disease. This one-stage individual patient data (IPD) meta-analysis aimed to create an ATI-based steatosis grading system. APPROACH AND RESULTS: A systematic review (EMBASE + MEDLINE, 2018-2022) identified studies, including patients with histologically or magnetic resonance imaging proton-density fat fraction (MRI-PDFF)-verified ATI for grading steatosis (S0 to S3). One-stage IPD meta-analyses were conducted using generalized mixed models with a random study-specific intercept. Created ATI-based steatosis grading system (aS0 to aS3) was externally validated on a prospective cohort of patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (n=174, histologically and MRI-PDFF-verified steatosis). Eleven enrolled studies included 1374 patients, classified into S0, S1, S2, and S3 in 45.4%, 35.0%, 9.3%, and 10.3% of the cases. ATI was correlated with histological steatosis ( r = 0.60; 95% CI: 0.52, 0.67; p < 0.001) and MRI-PDFF ( r = 0.70; 95% CI: 0.66, 0.73; p < 0.001) but not with liver stiffness ( r = 0.03; 95% CI: -0.04, 0.11, p = 0.343). Steatosis grade was an independent factor associated with ATI (coefficient: 0.24; 95% CI: [0.22, 0.26]; p < 0.001). ATI marginal means within S0, S1, S2, and S3 subpopulations were 0.59 (95% CI: [0.58, 0.61]), 0.69 (95% CI [0.67, 0.71]), 0.78 (95% CI: [0.76, 0.81]), and 0.85 (95% CI: [0.83, 0.88]) dB/cm/MHz; all contrasts between grades were significant ( p < 0.0001). Three ATI thresholds were calibrated to create a new ATI-based steatosis grading system (aS0 to aS3, cutoffs: 0.66, 0.73, and 0.81 dB/cm/MHz). Its external validation showed Obuchowski measures of 0.84 ± 0.02 and 0.82 ± 0.02 with histologically based and MRI-PDFF-based references. CONCLUSIONS: ATI is a reliable, noninvasive marker of steatosis. This validated ATI-based steatosis grading system could be valuable in assessing patients with metabolic dysfunction-associated steatotic liver disease.

Trailblazing Kr/Xe Separation: The Birth of the First Kr-Selective Material.

Efficient separation of Kr from Kr/Xe mixtures is pivotal in nuclear waste management and dark matter research. Thus far, scientists have encountered a formidable challenge: the absence of a material with the ability to selectively adsorb Kr over Xe at room temperature. This study presents a groundbreaking transformation of the renowned metal-organic framework (MOF) CuBTC, previously acknowledged for its Xe adsorption affinity, into an unparalleled Kr-selective adsorbent. This achievement stems from an innovative densification approach involving systematic compression of the MOF, where the crystal size, interparticle interaction, defects, and evacuation conditions are synergistically modulated. The resultant densified CuBTC phase exhibits exceptional mechanical resilience, radiation tolerance, and notably an unprecedented selectivity for Kr over Xe at room temperature. Simulation and experimental kinetic diffusion studies confirm reduced gas diffusion in the densified MOF, attributed to its small pore window and minimal interparticle voids. The lighter Kr element demonstrates facile surface passage and higher diffusivity within the material, while the heavier Xe encounters increased difficulty entering the material and lower diffusivity. This Kr-selective MOF not only represents a significant breakthrough in Kr separation but also demonstrates remarkable processability and scalability to kilogram levels. The findings presented herein underscore the transformative potential of engineered MOFs in addressing complex challenges, heralding a new era of Kr separation technologies.

Clinical outcomes and safety of immune checkpoint inhibitors in patients with solid tumors and paraneoplastic syndromes.

BACKGROUND: Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce. METHODS: In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT). RESULTS: Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS. CONCLUSIONS: Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver.

MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver. While deficiency in methionine adenosyltransferase alpha 1 (MATα1), enzyme that catalyzes SAMe biosynthesis, leads to hepatic MCJ upregulation, MAT1A overexpression and SAMe treatment reduced MCJ expression. We found that MCJ is methylated at lysine residues and that it interacts with MATα1 in liver mitochondria, likely to facilitate its methylation. Lastly, we observed that MCJ is upregulated in alcohol-associated liver disease, a condition characterized by reduced MAT1A expression and SAMe levels along with mitochondrial injury. MCJ silencing protected against alcohol-induced mitochondrial dysfunction and lipid accumulation. Our study demonstrates a new role of MATα1 and SAMe in reducing hepatic MCJ expression.

Transdiagnostic clustering and network analysis for questionnaire-based symptom profiling and drug recommendation in the UK Biobank and a Korean cohort.

Clinical decision support systems (CDSSs) play a critical role in enhancing the efficiency of mental health care delivery and promoting patient engagement. Transdiagnostic approaches that utilize raw psychological and biological data enable personalized patient profiling and treatment. This study introduces a CDSS incorporating symptom profiling and drug recommendation for mental health care. Among the UK Biobank cohort, we analyzed 157,348 participants for symptom profiling and 14,358 participants with a drug prescription history for drug recommendation. Among the 1307 patients in the Samsung Medical Center cohort, 842 were eligible for analysis. Symptom profiling utilized demographic and questionnaire data, employing conventional clustering and community detection methods. Identified clusters were explored using diagnostic mapping, feature importance, and scoring. For drug recommendation, we employed cluster- and network-based approaches. The analysis identified nine clusters using k-means clustering and ten clusters with the Louvain method. Clusters were annotated for distinct features related to depression, anxiety, psychosis, drug addiction, and self-harm. For drug recommendation, drug prescription probabilities were retrieved for each cluster. A recommended list of drugs, including antidepressants, antipsychotics, mood stabilizers, and sedative-hypnotics, was provided to individual patients. This CDSS holds promise for efficient personalized mental health care and requires further validation and refinement with larger datasets, serving as a valuable tool for mental healthcare providers.