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Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract: Signaling pathways mediated by receptor tyrosine kinases (RTKs) and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. Keywords: hepatocyte growth factor, ligands, receptor tyrosine kinase, signaling pathway, therapeutic agent

Cervical cancer, which is mainly caused by oncogenic human papillomavirus subtypes, remains a significant global health challenge. Recent studies have indicated a connection between cervical cancer and the uterine microbiome, underscoring its importance. This study explored the potential of liquid-based cytology (LBC) samples, which are typically used for cytological analysis, in investigating the cervical microbiome. Thirty women participated in the study and provided clinical information. Three samples were obtained from each participant: one for clinical purposes using LBC, another for microbiome sampling using LBC, and a third using the SWAB Microbiome kit. The LBC and traditional swab (SWAB) samples were subjected to high-throughput 16S rRNA gene sequencing for microbiome analysis. The results revealed a consistent dominance of key taxa, particularly Lactobacillus spp. The analysis of differential abundance highlighted variations in microbial abundance among individuals, which were more prominent than those resulting from the sampling methods. Functional analysis identified arachidonic acid and alpha-linolenic acid metabolism, along with a cautionary note regarding the low mean proportion values. The network analysis revealed positive correlations between indicators of structure among the networks, highlighting the robustness of microbiome similarities despite the diversity of sampling methods. Supervised machine learning has revealed challenges in distinguishing LBC and SWAB samples based on their microbiome features. Weighted co-expression network analysis revealed that the correlation between microbial clusters and the sampling method with clinical data was not significant. This study emphasizes the similarity in microbial communities observed using the LBC and SWAB methods, highlighting the potential of using dual diagnostic approaches. Additionally, the use of residual LBC samples in large-scale microbiological studies can provide comprehensive insights into cervical health and disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: The authors report no conflicts of interest.

Southern Africa has experienced multiple occurrences of drought episodes, which is projected to persist in the future, considering all climate scenarios. Despite the documented change in a meteorological, agricultural, and hydrological drought situation in the region, few studies are yet to explore the changes in flash drought (hereafter; FD), which is characterized by a rapid reduction in root-zone soil moisture and more substantial intensification in few days to weeks. Here, we analyze the observed FD and related underlying drivers during the past 34 years. Also, we estimate the future changes in FD using the severity-duration magnitude matrix under the middle of the road (SSP2-4.5) and business as usual (SSP5-8.5), scenario. Lastly, the study investigates the role of anthropogenic warming using the fraction of attributable risk (FAR) approach and possible bivariate return periods of FD events. Our results demonstrate that the region has experienced multiple occurrences up to 72 pentads from 1980 to 2014. Underlying mechanisms revealed the compounding influence of Vapor Pressure Deficit (VPD), Potential Evapotranspiration (PET), and precipitation deficit that have a significant impact on the abrupt onset and rapid intensification of FD events and other hot extremes over the SAF region. Under a high emission scenario, the region will experience FD duration lasting for 30 days with >40 % severity projected to impact the region. Anthropogenic climate change and land use and land cover changes remain the most dominant drivers altering the FD events over the SAF region. The return period of FD events under the SSP5-8.5 scenario shows that the SAF region will witness multiple FD events of up to 80 pentads in the far future. These findings reinforce the need to limit the emission of greenhouse gases. Sustained warming of the climate will exacerbate the extreme events and other compounding factors, thus affecting the livelihoods of humans and life-supporting strata., Competing Interests: Declaration of competing interest No conflict of interest detected., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: Metastatic or recurrent adrenocortical carcinoma is a potentially lethal malignancy, presenting significant challenges in disease management owing to absence of effective systemic treatments. Significantly diminished survival rates necessitate rapid identification of specific molecules for the development of targeted therapeutics. Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts have been a major breakthrough causing a paradigm shift in targeted theranostics focusing on the tumor microenvironment. The effectiveness of various FAP inhibitors (FAPis) and FAP targeting peptide has been extensively documented in diverse clinical investigations. We have evaluated 3 molecules, that is, DOTA.SA.FAPi (SA.FAPi), FAPi46, and FAP2286, as potential theranostic probes for adrenocortical carcinoma., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: We investigated the prevalence of amyloid beta (Aβ) positivity (+) and cognitive trajectories in Koreans and non-Hispanic Whites (NHWs)., Methods: We included 5121 Koreans from multiple centers across South Korea and 929 NHWs from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent Aβ positron emission tomography and were categorized into cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia stages. Age, sex, education, and apolipoprotein E. genotype were adjusted using multivariable logistic regression and stabilized inverse probability of treatment weights based on the propensity scores to mitigate imbalances in these variables., Results: The prevalence of Aβ+ was lower in CU Koreans than in CU NHWs (adjusted odds ratio 0.60). Aβ+ Koreans showed a faster cognitive decline than Aβ+ NHWs in the CU (B = -0.314, p = .004) and MCI stages (B = -0.385, p < .001)., Discussion: Ethnic characteristics of Aβ biomarkers should be considered in research and clinical application of Aβ-targeted therapies in diverse populations., Highlights: Koreans have a lower prevalence of Aβ positivity compared to NHWs in the CU stage. The effects of Alzheimer's risk factors on Aβ positivity differ between Koreans and NHWs. Aβ-positive (Aβ+) Koreans show faster cognitive decline than Aβ+ NHWs in the CU and MCI stages., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and iron accumulation, has been implicated in the progression of metabolic-dysfunction-associated steatohepatitis (MASH) in obesity. This study investigated the role of ferroptosis in the development of hepatic steatosis and MASH in obese mice and assessed the therapeutic potential of ferrostatin-1, a ferroptosis inhibitor. C57BL/6J wild-type (n = 8) and ob/ob mice (n = 16) were maintained on a standard chow diet. Mice were divided into three groups that included C57BL/6 (n = 8), ob/ob (n = 8), and ob/ob + ferrostatin-1 (FER) (n = 8), with the latter group receiving an intraperitoneal injection of 5 μM/kg ferrostatin three times per week for eight weeks. Following treatment, serum and tissue samples were collected for analysis. Significant hepatic steatosis and increased lipogenesis markers were observed in ob/ob mice, which were restored to baseline levels in the ob/ob + FER group treated with ferrostatin-1. Elevated oxidative stress was indicated by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the ob/ob group, while glutathione peroxidase 4 (GPX4) activity was significantly reduced. Ferrostatin-1 treatment decreases MDA levels and restores GPX4 activity. Additionally, ferrostatin mitigates iron overload and promotes macrophage polarization from M1 to M2, thereby reducing liver inflammation and fibrosis. Ferrostatin treatment reversed mitochondrial dysfunction in ob/ob mice. Our findings revealed that ferroptosis plays a significant role in the progression of obesity to hepatic steatosis and MASH. Inhibiting ferroptosis using ferrostatin-1 effectively improves liver histology, reduces oxidative stress, normalizes lipogenesis, and modulates macrophage polarization. This study highlights the potential of targeting ferroptosis as a therapeutic strategy for obesity-related liver diseases, warranting further investigation in clinical settings.

Despite the high incidence of dry mouth in postmenopausal women, its underlying mechanisms and therapeutic interventions remain underexplored. Using ovariectomized (OVX) mouse models, here this study identifies ferroptosis, an iron-dependent regulated cell death, as a central mechanism driving postmenopausal salivary gland (SG) dysfunction. In the OVX-SGs, TGFβ signaling pathway is enhanced with the aberrant TGFβ2 expression in SG mesenchymal cells. Intriguingly, TGFβ2 treatment reduces iron-storing ferritin levels, leading to lipid peroxidation and ferroptotic death in SG epithelial organoids (SGOs). Mechanistically, TGFβ2 promotes the autophagy-mediated ferritin degradation, so-called ferritinophagy. A notable overexpression of the type III TGFβ receptor (TβRIII) is found in the OVX-SGs and TGFβ2-treated SGOs, while the silencing of TβRIII mitigates the ferroptosis-mediated deleterious effects of TGFβ2 on SGOs. Finally, administration of ferroptosis inhibitor, Liproxstatin-1 (Lip-1), improves saliva secretion in OVX mice. Present findings collectively suggest a link between TGFβ signaling, ferroptosis, and SG injury, offering new therapeutic avenues for postmenopausal xerostomia., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Despite effective countermeasures, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists worldwide because of its ability to diversify and evade human immunity. This evasion stems from amino acid substitutions, particularly in the receptor binding domain (RBD) of the spike protein that confers resistance to vaccine-induced antibodies and antibody therapeutics. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different RBD sites into multispecific antibodies. Here, we describe multispecific antibodies, including a trivalent trispecific antibody that potently neutralized diverse SARS-CoV-2 variants and prevented virus escape more effectively than single antibodies or mixtures of the parental antibodies. Despite being generated before the appearance of Omicron, this trispecific antibody neutralized all major Omicron variants through BA.4/BA.5 at nanomolar concentrations. Negative stain electron microscopy suggested that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated binding across more than one spike protein. Moreover, a tetravalent trispecific antibody containing the same variable regions as the trivalent trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2, and BA.5 challenge, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. These results demonstrated that multispecific antibodies have the potential to provide broad SARS-CoV-2 coverage, decrease the likelihood of escape, simplify treatment, and provide a strategy for antibody therapies that could help eliminate pandemic spread for this and other pathogens.

Background and Purpose: We aimed to develop the diagnostic matrix of the Seoul Cognitive Status Test (SCST) and compare its performance with traditional paper-and-pencil neuropsychological tests, including the Seoul Neuropsychological Screening Battery-II (SNSB-II) and the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K)., Methods: We recruited 197 participants from the head-to-head SCST-SNSB cohort, and 204 participants from the head-to-head SCST-CERAD cohort. They underwent either SNSB-II or CERAD-K, in addition to SCST. The diagnostic matrix was developed by combining cognitive function, determined by neuropsychological tests, and activities of daily living (ADL), determined by Instrumental-ADL scales., Results: The diagnostic agreement between the SCST and the SNSB-II was 83.9% (weighted kappa=0.87). The agreement between the SCST and the CERAD-K was 84.3% (weighted kappa=0.88). In the SCST-SNSB cohort, all differences in SCST scores between the cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia diagnosed with the SNSB-II were significant in all cognitive domains (all p <0.01), except for the executive domain between CU and MCI ( p =0.145). In the SCST-CERAD cohort, all differences in SCST scores between the 3 groups diagnosed with the CERAD-K were significant in all cognitive domains (all p <0.01), except for the language and visuospatial domains between MCI and dementia ( p =0.169 and p =0.778, respectively)., Conclusions: Our findings suggest that the tablet-based SCST may be another option to traditional paper-and-pencil neuropsychological tests, especially in situations where time and space are relatively limited, and neuropsychological testing specialists are not available., Competing Interests: Conflict of Interest: Duk L. Na and Sang Won Seo are scientific co-founders of BeauBrain Healthcare, a company aiming to commercialize the Seoul Cognitive Status Test. Young Ju Kim and Joon Soo Shin are employed at BeauBrain Healthcare. Duk L. Na, Sang Won Seo, and Joon Soo Shin had no role in the analysis and interpretation of the data. The remaining authors have no conflicts of interest to declare., (© 2024 Korean Dementia Association.)

Abstract: We report a case of a 48-year-old man with recurrent hepatocellular carcinoma, who underwent FDG PET for restaging and demonstrated mildly tracer-avid arterial enhancing lesion in segment III (SUV max , 5.7). Owing to low FDG uptake, patient was planned for 68 Ga-SA.FAPi PET, which demonstrated higher tracer avidity in the lesion (SUV max , 24.4). Subsequently, patient underwent 177 Lu-microsphere SIRT (2.2 GBq) in segment III. The 3- and 6-month posttherapy SA.FAPi PET demonstrated an interval decrease in tracer uptake and size of treated lesion. This case highlighted the promising role of SA.FAPi PET in patient selection for 177 Lu-SIRT and subsequent response assessment., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Mercury ions (Hg 2+ ) are toxic heavy metals present in the environment that pose significant health risks. An advanced detection system could allow for a prompt response and alleviate serious damage to humans. In this study, we developed a cost-effective, on-site detection method for Hg 2+ using a multicomponent nucleic acid enzyme (MNAzyme)-assisted nucleic acid lateral flow assay (NALFA). The MNAzyme, which was engineered to contain thymine-thymine mismatches, is responsive only to the presence of Hg 2+ and exerts efficient cleavage activity on substrates that can be captured by the NALFA strip, and thus the proposed system enables the visual detection of Hg 2+ in the NALFA strip. Our assay demonstrated sufficient detection sensitivity and specificity to meet the WHO standards, offering a good practical alternative for rapid environmental and public health monitoring.

Colorectal cancer (CRC) remains one of the most formidable challenges in the global health arena. To address this challenge, extensive research has been directed toward developing targeted drug delivery systems (DDS). Cell-derived vesicles (CDV), which mirror the lipid bilayer structure of cell membranes, have garnered tremendous attention as ideal materials for DDS owing to their scalability in production and high biocompatibility. In this study, a novel method, termed colorectal cancer overall Dukes' staging Systematic Evolution of Ligands by Exponential enrichment (CROSS), was developed to identify Toggle Cell 1 (TC1) aptamers with high binding affinity to CRC cells at various Dukes' stages (A-D). Furthermore, a novel DDS was developed by incorporating a cholesterol-modified TC1 aptamer into CDV, which exhibited improved targeting ability and cellular uptake efficiency toward CRC cells compared to CDV alone. The results of this study highlight the potential efficacy of CDV in constructing a targeted DDS while overcoming the current challenges associated with other lipid-based DDS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The beneficial effects of probiotics for the improvement of metabolic disorders have been studied intensively; however, these effects are evident in a probiotic strain-specific and disease-specific manner. Thus, it is still essential to evaluate the efficacy of each strain against a target disease. Here, we present an anti-obese and anti-diabetic probiotic strain, Lactiplantibacillus plantarum APsulloc331261 (GTB1™), which was isolated from green tea and tested for safety previously. In high-fat-diet-induced obese mice, GTB1™ exerted multiple beneficial effects, including significant reductions in adiposity, glucose intolerance, and dyslipidemia, which were further supported by improvements in levels of circulating hormones and adipokines. Lipid metabolism in adipose tissues was restored through the activation of PPAR/PGC1α signaling by GTB1™ treatment, which was facilitated by intestinal microbiota composition changes and short-chain fatty acid production. Our findings provide evidence to suggest that GTB1™ is a potential candidate for probiotic supplementation for comprehensive improvement in metabolic disorders.

Background and Purpose: We developed a new digital cognitive assessment called Seoul Cognitive Status Test (SCST), formerly called Inbrain Cognitive Screening Test. The purpose of this study was to validate the clinical utility of the SCST by comparing its scores of those with subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and dementia diagnosed by the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K)., Methods: All participants (n=296) who completed the CERAD-K, SCST, and Instrumental Activities of Daily Living tests were included in this study. Total score, cognitive domain scores, and subtest scores of the SCST were compared among the 3 groups (SCD, aMCI, and dementia). Additionally, correlations between SCST and CERAD-K subtests were examined., Results: Cognitive domain scores and total score of the SCST showed significant differences among the three groups, with scores being the highest in the order of SCD, aMCI, and dementia ( p <0.001). Most subtests of the SCST also showed higher scores in the order of SCD, aMCI, and dementia ( p <0.001). However, SCD and aMCI groups showed no significant differences in scores of the Phonemic Word Fluency Test ( p =0.083) or Korean Trail Making Test-Elderly version Part A ( p =0.434). Additionally, there was no significant difference in the score of Place Recognition ( p =0.274) of the Word-Place Association Test between aMCI and dementia groups., Conclusions: In conclusion, differences in total score, cognitive domain scores, and subtest scores of the SCST among the 3 groups of participants diagnosed using CERAD-K confirm the clinical utility of the SCST for cognitive assessment., Competing Interests: Conflict of Interest: Duk L. Na is one of the scientific co-founders of BeauBrain Healthcare, a company aiming to commercialize the SCST. Joon Soo Shin is employed at BeauBrain Healthcare and participated in the development of SCST. Duk L. Na and Joon Soo Shin had no role in the analysis and interpretation of the data. The remaining authors have no conflicts of interest to declare., (© 2024 Korean Dementia Association.)

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean IC 80 s of 0.314 and 0.033 µg mL -1 , respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi) 2 , labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs., Methods: The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [ 68 Ga]Ga-DOTA.SA.FAPi and [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 . [ 177 Lu]Lu-DOTA.SA.FAPi and [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 , were evaluated in PC3 xenografts. Biodistribution studies of [ 68 Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice., Results: All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 was retained longer in CAFs. [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 and [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 displayed elevated lipophilicity and affinity for human serum proteins compared to [ 68 Ga]Ga-DOTA.SA.FAPi and [ 177 Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 within 3 h compared to [ 68 Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 versus [ 68 Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 maintained a significant tumor uptake even after 96 h p.i. compared to [ 177 Lu]Lu-DOTA.SA.FAPi., Conclusions: Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.

Proteins with multiple domains play pivotal roles in various biological processes, necessitating a thorough understanding of their structural stability and functional interplay. Here, a structure-guided protein engineering approach is proposed to develop thermostable Cas9 (CRISPR-associated protein 9) variant for CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference applications. By employing thermodynamic analysis, combining distance mapping and molecular dynamics simulations, deletable domains are identified to enhance stability while preserving the DNA recognition function of Cas9. The resulting engineered Cas9, termed small and dead form Cas9, exhibits improved thermostability and maintains target DNA recognition function. Cryo-electron microscopy analysis reveals structural integrity with reduced atomic density in the deleted domain. Fusion with functional elements enables intracellular delivery and nuclear localization, demonstrating efficient gene suppression in diverse cell types. Direct delivery in the mouse brain shows enhanced knockdown efficiency, highlighting the potential of structure-guided engineering to develop functional CRISPR systems tailored for specific applications. This study underscores the significance of integrating computational and experimental approaches for protein engineering, offering insights into designing tailored molecular tools for precise biological interventions., (© 2024 Wiley‐VCH GmbH.)

Background: Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis., Methods: We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg -1 ) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism., Results: In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe's mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3., Conclusion: This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Suh, Jung, Lee, Liu, Do, Lee and Park.)

Background: Although various pathological grading systems are available for evaluating the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant therapy (NAT), their prognostic value has not been thoroughly validated. This study examined whether microscopic tumor mapping of post-NAT specimens could predict tumor recurrence., Methods: This prospective study enrolled 52 patients who underwent pancreaticoduodenectomy after NAT for PDAC between 2019 and 2021. Microscopic mapping was performed to identify residual tumor loci within the tumor bed using 4 mm 2 pixels. Patients were divided into small extent (SE; n = 26) and large extent (LE; n = 26) groups using a cutoff value of 226 mm 2 . The diagnostic performance for predicting tumor recurrence was evaluated using receiver operating characteristic (ROC) curves., Results: Carbohydrate antigen 19-9 levels were normalised after NAT in more patients in the SE group (SE 21 [80.8%] vs. LE 13 [50.0%]; P = 0.041). Tumor size (P < 0.001), T stage (P < 0.001), positive lymph node yield (P = 0.024), and perineural invasion rate (P = 0.018) were significantly greater in the LE group. The 3-year disease-free survival rate was significantly lower in the LE group (SE 83.3% vs. LE 50.0%, P = 0.004). The area under the ROC curve for mapping extent was 0.743, which was greater than that of the other tumor response scoring systems., Conclusions: Microscopic tumor mapping of the residual tumor in post-NAT specimens is a significant predictor of post-surgical recurrence, and offers better prognostic performance than the current grading systems., Competing Interests: Declaration of competing interest None., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Rationale and Objectives: Fibroblast Activation Protein (FAP) expressing cancer-associated fibroblasts has been a major breakthrough causing a paradigm shift in targeted theranostics focusing on the tumor microenvironment. In this study, a squaric acid derivative DOTA.SA.FAPi (SA.FAPi) has been evaluated as a potential diagnostic probe in diverse epithelial cancers and compared to the standard-of-care 18 F-FDG., Methods: 25 patients enrolled in this prospective study underwent 18 F-FDG and 68 Ga-SA.FAPi PET scans on two different days. For biodistribution, standardized uptake values (SUV) were computed by delineating region-of-interest on various body organs. For comparative analysis in disease identification, lesion tracer uptake was quantified using SUVs corrected for lean body mass (SUL), SUV max , tumor-to-background ratio (TBR) with liver and blood pool as the reference, total lesion glycolysis (TLG for 18 F-FDG) and total lesion FAP expression (TLF for 68 Ga-SA.FAPi)., Results: 25 patients (mean age: 58 ± 8 years) with four types of cancers including hepatocellular carcinoma (HCC, 56% of cohort), gall bladder carcinoma (GB Ca, 12%), adrenocortical carcinoma (ACC, 16%), and breast carcinoma (breast Ca, 16%) were prospectively evaluated. Physiological tracer uptake of 68 Ga-SA.FAPi was noted in the salivary glands, thyroid, liver, pancreas, muscles and kidneys with variable uptake in the lacrimal glands, extra-ocular muscles, oral mucosa and uterus. Lesion-based comparative analysis between both the radiotracers demonstrated complete concordant findings in detection of all primary lesions and distant metastases in liver, bones, adrenals and peritoneum whereas discordant findings were noted in lung nodules (20%) and lymph nodes (13%). In overall analysis, 68 Ga-SA.FAPi exhibited significantly higher SUV max (10.3 vs 8.8, p-0.019), SUL peak (6.8 vs 4.9, p-0.000) and SUL avg (5.4 vs 4.1, p-0.019) in comparison to 18 F-FDG whereas TBR was comparable for both the tracers [TBR Liver : median 1.9 (IQR: 2.6-1.4) vs 1.8 (2.6-1.1), p-0.275; TBR Bloodpool : 2.1 (3.7-1.4) vs 2.0 (2.7-1.4), p-0.207]. In subcategorical analysis, 68 Ga-SA.FAPi demonstrated higher SUV max , SUL peak and SUL avg values for primary disease (SUV max : 14.8 (18.7-9.7) vs (12.9-6.6), p-0.087; SUL peak : 8.2 (11.2-6.8) vs 6.3 (8.5-4.4), p-0.037; SUL avg : 6.9 ± 2.5 vs 5.1 ± 2.2, p-0.023] and distant metastases (8.8 vs 7.2, p-0.038); 6.3 (8.8-4.4) vs 3.6 (4.4-2.0), p-0.000; 5.4 vs 3.5, p-0.000] whereas comparable values were noted for both the tracers in nodal metastases [9 (13.5-4.1) vs 8 (12.7-4.7), p-0.726; 4.5 (6.2-1.8) vs 4.3 (5.7-2.2), p-0.727; 4.1 ± 2.3 vs 3.7 ± 1.8, p-0.129]. In primary disease, highest 68 Ga-SA.FAPi avidity was noted in ACC followed by GB Ca and HCC. In distant metastases, gall bladder, lung and skeletal lesions demonstrated higher 68 Ga-SA.FAPi avidity. Moreover, 68 Ga-SA.FAPi identified five additional lung lesions which were missed by 18 F-FDG in one case of ACC., Conclusion: 68 Ga-SA.FAPi emerged as an effective, versatile diagnostic probe for imaging various epithelial malignancies similar to 18 F-FDG., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Jaya Shukla reports financial support was provided by Post Graduate Institute of Medical Education and Research., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Fibromuscular dysplasia (FMD) is a noninflammatory arterial diseases that affects predominantly women. Multiple studies have demonstrated an increased prevalence of FMD in patients who experience carotid or vertebral artery dissection (VAD). This case report presents a 57-year-old female who presented with a headache and was diagnosed with partially thrombosed giant aneurysm of vertebral artery. This aneurysm was successfully treated with flow-diverter and coil, but new onset rupture of vertebral artery was detected two weeks later, leading to internal trapping. This case report underscores the need for awareness and understanding of treatment of dissection and aneurysm in patient who is suspected FMD.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by genetic predisposition, environmental factors, immune dysregulation, and skin barrier dysfunction. The skin microbiome and metabolome play crucial roles in modulating the skin's immune environment and integrity. However, their specific contributions to AD remain unclear. We aimed to investigate the distinct skin microbial communities and skin metabolic compounds in AD patients compared to healthy controls (HCs). Seven patients with AD patients and seven HCs were enrolled, from whom skin samples were obtained for examination. The study involved 16S rRNA metagenomic sequencing and bioinformatics analysis as well as the use of gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) to detect metabolites associated with AD in the skin. We observed significant differences in microbial diversity between lesional and non-lesional skin of AD patients and HCs. Staphylococcus overgrowth was prominent in AD lesions, while Cutibacterium levels were decreased. Metabolomic analysis revealed elevated levels of several metabolites, including hypoxanthine and glycerol-3-phosphate in AD lesions, indicating perturbations in purine metabolism and energy production pathways. Moreover, we found a positive correlation between hypoxanthine and glycerol-3-phosphate and clinical severity of AD and Staphylococcus overgrowth. These findings suggest potential biomarkers for monitoring AD severity. Further research is needed to elucidate the causal relationships between microbial dysbiosis, metabolic alterations, and AD progression, paving the way for targeted therapeutic interventions.

Fibroblast activation protein (FAP) is a very reliable biomarker for tissue remodeling. FAP has so far mainly been studied in oncology, but there is growing interest in the enzyme in other diseases like fibrosis. Recently, FAP-targeting diagnostics and therapeutics have emerged, of which the so-called FAPIs are among the most promising representatives. FAPIs typically have a relatively high molecular weight and contain very polar, multicharged chelator moieties. While this is not limiting the application of FAPIs in oncology, more druglike FAPIs could be required to optimally study diseases characterized by denser, less permeable tissue. In response, we designed the first druglike 18 F-labeled FAPIs. We report target potencies, biodistribution, and pharmacokinetics and demonstrate FAP-dependent uptake in murine tumor xenografts. Finally, this paper puts forward compound 10 as a highly promising, druglike FAPI for 18 F-PET imaging. This molecule is fit for additional studies in fibrosis and its preclinical profile warrants clinical investigation.

Development of assays to reliably identify and characterize anti-drug antibodies (ADAs) depends on positive control anti-idiotype (anti-id) reagents, which are used to demonstrate that the standards recommended by regulatory authorities are met. This work employs a set of therapeutic antibodies under clinical development and their corresponding anti-ids to investigate how different positive control reagent properties impact ADA assay development. Positive controls exhibited different response profiles and apparent assay analytical sensitivity values depending on assay format. Neither anti-id affinity for drug, nor sensitivity in direct immunoassays related to sensitivity in ADA assays. Anti-ids were differentially able to detect damage to drug conjugates used in bridging assays and were differentially drug tolerant. These parameters also failed to relate to assay sensitivity, further complicating selection of anti-ids for use in ADA assay development based on functional characteristics. Given this variability among anti-ids, alternative controls that could be employed across multiple antibody drugs were investigated as a more uniform means to define ADA detection sensitivity across drug products and assay protocols, which could help better relate assay results to clinical risks of ADA responses. Overall, this study highlights the importance of positive control selection to reliable detection and clinical interpretation of the presence and magnitude of ADA responses., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Epidermoid cysts are generally benign lesions surrounded by squamous epithelium with cystic contents. The lining of the cysts produce keratin, which resemble a cheese-like material. They typically occur in the skin and mucous membranes and are congenital in origin; iatrogenic epidermoid cysts are rare. Epidermoid cysts are usually painless and asymptomatic, and their diagnosis is based on histological examination. This paper aims to present the case report of a 23-year-old patient with an iatrogenic epidermoid cyst that occurred following tracheostomy. The importance of preoperative radiological imaging in the diagnosis of epidermoid cysts is also highlighted., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We devised a novel strategy that relies on a combination of the primer exchange reaction (PER) with transcription isothermal amplification, termed PER-Trap, for a sensitive biomolecular assay. Its design allowed light-up RNA aptamers to be produced as the final product, leading to the generation of an amplified fluorescence signal. The utility of PER-Trap was successfully demonstrated by the detection of exosomes.

This study introduces an innovative detection system for multiple cancer biomarkers, employing transcription isothermal amplification methods in conjunction with a tetrahedral DNA nanostructure (TDN). We demonstrate that TDN enhances various transcription isothermal amplification methods by placing DNA probes in proximity. Notably, the TDN-enhanced split T7 promoter-based isothermal transcription amplification with light-up RNA aptamer (STAR) system stands out for its optimal performance and operational simplicity, especially in identifying non-coding RNAs such as microRNAs and long non-coding RNAs (lncRNAs). Multiplex detection of lncRNAs was also achieved by generating distinct light-up RNA aptamers, each emitting unique fluorescence signals. The system effectively identified the target lncRNAs, demonstrating high sensitivity and selectivity in both cell lines and clinical samples. The system, utilizing the single enzyme T7 RNA polymerase, can be easily tailored for alternative targets by substituting target-specific sequences in DNA probes and seamlessly integrated with other isothermal amplification methods for greater sensitivity and accuracy in the detection of multiple cancer biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: We conducted a one-year, retrospective, mirror-image study to investigate the clinical effectiveness and safety of aripiprazole once monthly (AOM) in patients with bipolar disorder (BD). We compared pre-treatment conditions with outcomes after 12 months of AOM treatment., Methods: Seventy-five bipolar patients were recruited from 12 hospitals in Korea. We included 75 patients with BD who had received at least three AOM treatments from September 2019 to September 2022 and had accessible electronic medical record (EMRs) for the year before and after the baseline visit., Results: The overall number of mood episodes significantly decreased from a mean of 1.5 ± 1.2 episodes pre-AOM to 0.5 ± 1.2 episodes post-AOM. Manic episodes significantly decreased from 0.8 ± 0.8 episodes pre-AOM to 0.2 ± 0.5 episodes post-AOM, and depressive episodes significantly decreased from 0.5 ± 0.8 episodes pre-AOM to 0.2 ± 0.6 episodes post-AOM (p = 0.017). Moreover, the number of psychiatric medications and pills and the proportion of patients treated with complex polypharmacy were significantly decreased post-AOM., Limitations: The small sample size was insufficient to fully represent the entire population of individuals with BD, and potential selection bias was introduced due to only including subjects who received AOM three or more times., Conclusion: The results of this study suggest that AOM can reduce mood episode relapse and may be clinically beneficial in the treatment of BD patients, potentially reducing issues associated with polypharmacy in some individuals., Competing Interests: Declaration of competing interest The authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Xenotransplantation, particularly when involving pig donors, presents challenges related to the transmission of porcine cytomegalovirus (pCMV) and its potential impact on recipient outcomes. This study aimed to investigate the relationship between pCMV positivity in both donors and recipients and the survival time of cynomolgus monkey recipients after xenogeneic kidney transplantation., Methods: We conducted 20 cynomolgus xenotransplants using 18 transgenic pigs. On the surgery day, donor pig blood was sampled, and DNA was extracted from serum and peripheral blood mononuclear cells. Recipient DNA extraction followed the same protocol from pre-transplantation to post-transplantation. Porcine cytomegalovirus detection used real-time polymerase chain reaction (real-time PCR) with the ViroReal kit, achieving a sensitivity of 50 copies/reaction. A Ct value of 37.0 was the pCMV positivity threshold., Results: Of 20 cynomolgus recipients, when donors tested negative for pCMV, recipients also showed negative results in 9 cases. In 4 cases where donors were negative, recipients tested positive. All 5 cases with pCMV-positive donors resulted in positive assessments for recipients. Detection of donor pCMV correlated with shorter recipient survival. Continuous recipient positivity during observation correlated with shorter survival, whereas transient detection showed no significant change in survival rates. However, donor pig phenotypes and transplantation protocols did not significantly impact survival., Conclusion: The detection of pCMV in both donors and recipients plays a crucial role in xenotransplantation outcomes. These findings suggest the importance of monitoring and managing pCMV in xenotransplantation to enhance long-term outcomes., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Although non-human primates are the closest animals to humans to simulate physiological and metabolic responses, there is a paucity of primate hemorrhagic shock models that are standardized and reproducible. Herein, we describe a model that is a clinical replica of extreme class IV hemorrhagic shock with a step-by-step description of the procedure in cynomolgus macaque monkeys., Methods: The physiological changes that occurred during the process were evaluated using hemodynamic parameters, echocardiogram, and laboratory values. Five female monkeys were subjected to trauma laparotomy, followed by cannulation of the abdominal aorta to achieve graded hemorrhage. A central line was placed in the right internal jugular vein, which was subsequently used for laboratory sampling and volume resuscitation. The withdrawal of blood was ceased when a predefined cardiac endpoint with cardiac arrhythmia or bradycardia was reached. The animals were then immediately resuscitated with transfusion. The primary cardiac endpoint was consistently reached in all 5 animals during the fourth hemorrhage when more than 70% of the estimated total blood volume was lost., Results: No mortality occurred during the process. The blood pressure, cardiac output measured from an echocardiogram, and hemoglobin correlated well with increasing loss of circulating volume, whereas the pulse pressure variation did not. The echocardiogram was also a useful predictor for urgent volume replacement., Conclusion: This model offers a safe and reproducible surgical hemorrhagic model in non-human primates and simulates clinical practice. This could provide a useful platform on which further studies can be carried out to address unanswered questions in trauma management., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Skin electrodes have been reported to be a useful alternative recording method for intraoperative neuromonitoring (IONM) and show typical electromyography (EMG) waveforms while overcoming the shortcomings of the EMG endotracheal tube. However, the skin electrodes showed relatively lower evoked amplitudes than other recording methods. In this study, we analyzed normative EMG data using skin electrodes and factors that affect the evoked amplitude of thyroid IONM., Methods: In total, 167 patients [242 nerves at risk (NAR)] who underwent thyroidectomy under IONM with adhesive skin electrodes were analyzed. A pair of skin electrodes was attached to the lateral border of the lamina of the thyroid cartilage. Evoked EMG data, including mean amplitude and latency, obtained after stimulation of the recurrent laryngeal nerve (RLN) and vagus nerve (VN), were collected and analyzed., Results: The mean amplitudes of RLN and VN recorded via skin electrodes were 255.48±96.53 and 236.15±69.72 μV, respectively. The mean latency of the right and left RLN was 3.22±0.03 and 3.49±0.08 mS, respectively. The mean latency of the right and left VN was 5.37±0.80 and 7.57±0.10 mS, respectively. The mean amplitude was significantly lower in the obesity, male, and total thyroidectomy (TT) groups. As body mass index (BMI) and age increased, the amplitude of EMG tended to decrease significantly., Conclusions: The evoked amplitude recorded with the skin electrodes was relatively low. A larger surgical extent, obesity, male sex, and age >55 years showed significantly lower evoked amplitudes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-428/coif). The authors have no conflicts of interest to declare., (2024 Gland Surgery. All rights reserved.)

Neuroendocrine tumors (NETs) are slow-growing tumors that express high levels of somatostatin receptors (SSTRs). Recent studies have shown the superiority of radiolabeled SSTR antagonists in theranostics compared to agonists. In this prospective study, we compared the diagnostic efficacy between [ 68 Ga]Ga-DOTANOC and [ 68 Ga]Ga-DATA 5m -LM4 in the detection of primary and metastatic lesions in patients with well differentiated gastroenteropancreatic (GEP) NETs. Histologically proven GEP-NET patients underwent [ 68 Ga]Ga-DOTANOC & [ 68 Ga]Ga-DATA 5m -LM4 PET/CT scans, which were analyzed. The qualitative analysis involved the visual judgment of radiotracer uptake validated by the morphological findings using CT, which was considered as the reference standard. Quantitative comparisons were presented as the standardized uptake value (SUV) corrected for lean body mass: SULpeak, SULavg, and tumor-to-background ratios (TBR). In total, 490 lesions were confirmed via diagnostic CT. The lesion-based sensitivity of [ 68 Ga]Ga-DATA 5m -LM4 PET/CT was 94.28% (462/490) and 83.46% (409/490) for [ 68 Ga]Ga-DOTANOC PET/CT ( p < 0.0001). [ 68 Ga]Ga-DATA 5m -LM4 had statistical significance over [ 68 Ga]Ga-DOTANOC in liver metastases [100% vs. 89.4%; p < 0.0001 (292 vs. 253 {283 lesions on CT})] and bone metastases [100% vs. 82.9%; p = 0.005 (45 vs. 34 {41 lesions on CT})]. Statistical significance was also noted for the TBR SULpeak of the primary and liver lesions. [ 68 Ga]Ga-DATA 5m -LM4 showed better sensitivity and a higher target-to-background ratio than [ 68 Ga]Ga-DOTANOC PET/CT. [ 68 Ga]Ga-DATA 5m -LM4 PET/CT can be used to quantify the extent of skeletal and liver metastases for better planning of SSTR agonist- or antagonist-based therapy.

A high-fiber diet is widely recognized for its positive effects on the gut microbiome. However, the specific impact of a high-fiber diet on the gut microbiome and bowel habits of patients with colon cancer remains poorly understood. In this study, we aimed to assess the effects of a modified microbiota-accessible carbohydrate (mMAC) diet on gut microbiota composition and clinical symptoms in colon cancer patients who underwent surgical resection. To achieve this, we enrolled 40 patients in two groups: those who received adjuvant chemotherapy and those who did not. Fecal samples were collected before and after dietary interventions for microbial and metabolite analyses. Each group was randomized in a 1: 1 ratio to follow either a 3-week conventional diet followed by a 3-week mMAC diet, or the reverse sequence. Although there were no significant differences in the microbial diversity data before and after the mMAC diet in both the non-chemotherapy and chemotherapy groups, distinct differences in gut microbial composition were revealed after the mMAC diet. Specifically, the abundance of Prevotella , which is associated with high-fiber diets, was further elevated with increased concentrations of acetate and propionate after the mMAC diet. Additionally, patients who experienced improved diarrhea and constipation after the mMAC diet exhibited an enrichment of beneficial bacteria and notable changes in metabolites. In conclusion, this study provides valuable insights into the potential benefits of the mMAC diet, specifically its impact on the gut microbiome and clinical symptoms in postoperative colorectal cancer (CRC) patients. These findings emphasize the potential role of a high-fiber diet in influencing the gut microbiome, and the clinical symptoms warrant further investigation., Competing Interests: ESJ, SuL, DHS, and YJP were employed by HEM Pharma Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Lee, Jung, Lee, Suh, Park, Kim, Kwak and Lee.)

Purpose of Review: This review considers recent observations on vestibular syncope in terms of clinical features, laboratory findings, and potential mechanisms., Recent Findings: Vestibular syncope, potentially associated with severe fall-related injuries, may develop multiple times in about one-third of patients. Meniere's disease and benign paroxysmal positional vertigo are the most common causes of vestibular syncope, but the underlying disorders remain elusive in 62% of cases with vestibular syncope. The postictal orthostatic blood pressure test exhibits a lower diagnostic yield. Vestibular function tests, such as cervical vestibular-evoked myogenic potentials and video head impulse tests, can reveal one or more abnormal findings, suggesting compensated or ongoing minor vestibular dysfunctions. The pathomechanism of syncope is assumed to be the erroneous interaction between the vestibulo-sympathetic reflex and the baroreflex that have different operating mechanisms and action latencies. The central vestibular system, which estimates gravity orientation and inertia motion may also play an important role in abnormal vestibulo-sympathetic reflex., Summary: Vestibular disorders elicit erroneous cardiovascular responses by providing false vestibular information. The results include vertigo-induced hypertension or hypotension, which can ultimately lead to syncope in susceptible patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We aimed to evaluate the clinical and imaging factors associated with hemorrhagic complications and patient discomfort following ultrasound (US)-guided breast biopsy., Materials and Methods: We prospectively enrolled 94 patients who were referred to our hospital between June 2022 and December 2022 for US-guided breast biopsy. After obtaining informed consent, two breast radiologists independently performed US-guided breast biopsy and evaluated the imaging findings. A hemorrhagic complication was defined as the presence of bleeding or hematoma on US. The patients rated symptoms of pain, febrile sensation, swelling at the biopsy site, and dyspnea immediately, 20 minutes, and 2 weeks after the procedure on a visual analog scale, with 0 for none and 10 for the most severe symptoms. Additional details recorded included those of nausea, vomiting, bleeding, bruising, and overall satisfaction score. We compared the clinical symptoms, imaging characteristics, and procedural features between patients with and those without hemorrhagic complications., Results: Of 94 patients, 7 (7%) developed hemorrhagic complications, while 87 (93%) did not. The complication resolved with 20 minutes of manual compression, and no further intervention was required. Vascularity on Doppler examination ( P = 0.008), needle type ( P = 0.043), and lesion location ( P < 0.001) were significantly different between the groups. Patients with hemorrhagic complications reported more frequent nausea or vomiting than those without hemorrhagic complications (29% [2/7] vs. 2% [2/87], respectively; P = 0.027). The overall satisfaction scores did not differ between the two groups ( P = 0.396). After 2 weeks, all symptoms subsided, except bruising (50% 2/4 in the complication group and 25% [16/65] in the no-complication group)., Conclusion: US-guided breast biopsy is a safe procedure with a low complication rate. Radiologists should be aware of hemorrhagic complications, patient discomfort, and overall satisfaction related to this procedure., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Background and Purpose: Tolosa-Hunt Syndrome (THS) is a rare disorder, and detailed clinical information and treatment outcomes have yet to be fully elucidated. This study aims to investigate the clinical features and factors associated with the treatment outcomes of THS, as defined by the established diagnostic criteria., Methods: This study retrospectively recruited 91 patients with a diagnosis of THS from 2003 to 2020. We analyzed the clinical features and outcomes, the initial treatment response, recurrences, and the final treatment response., Results: Isolated ocular motor nerve palsy was the most common (82.4%) finding of ophthalmoplegia, involving the oculomotor nerve in more than half of the cases (52.0%). The MRI lesions were mostly observed in the cavernous sinus (94.5%) with an extracavernous extension in about one-third of them. Five patients showed only extracavernous lesions. A total of 25 (27.5%) patients experienced recurrence. Recurrence occurred during steroid tapering as part of the initial treatment in seven, while in 18 patients, it happened after the successful termination of the initial treatment. However, all patients achieved complete remission at the final. Age was associated with a decrease in initial symptom duration (HR = 1.023, CI = 1.004-1.044) as well as an increase in recurrence-free duration (HR = 0.944, CI = 0.911-0.978). High-dose corticosteroid treatment was associated with a decrease in initial symptom duration (HR = 1.642, CI = 1.001-2.695) and total treatment duration (HR = 2.203 CI = 1.302-3.730)., Conclusions: THS can recur frequently especially in younger but have a favorable prognosis. High-dose corticosteroids can be an effective initial treatment and reduce the total treatment duration., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Biological macromolecules, such as DNA, RNA, and proteins in living organisms, form an intricate network that plays a key role in many biological processes. Many attempts have been made to build new networks by connecting non-communicable proteins with network mediators, especially using antibodies. In this study, we devised an aptamer-based switching system that enables communication between non-interacting proteins. As a proof of concept, two proteins, Cas13a and T7 RNA polymerase (T7 RNAP), were rationally connected using an aptamer that specifically binds to T7 RNAP. The proposed switching system can be modulated in both signal-on and signal-off manners and its responsiveness to the target activator can be controlled by adjusting the reaction time. This study paves the way for the expansion of biological networks by mediating interactions between proteins using aptamers.

Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest.

Importance: Consumer-level sleep analysis technologies have the potential to revolutionize the screening for obstructive sleep apnea (OSA). However, assessment of OSA prediction models based on in-home recording data is usually performed concurrently with level 1 in-laboratory polysomnography (PSG). Establishing the predictability of OSA using sound data recorded from smartphones based on level 2 PSG at home is important., Objective: To validate the performance of a prediction model for OSA using breathing sound recorded from smartphones in conjunction with level 2 PSG at home., Design, Setting, and Participants: This diagnostic study followed a prospective design, involving participants who underwent unattended level 2 home PSG. Breathing sounds were recorded during sleep using 2 smartphones, one with an iOS operating system and the other with an Android operating system, simultaneously with home PSG in participants' own home environment. Participants were 19 years and older, slept alone, and had either been diagnosed with OSA or had no previous diagnosis. The study was performed between February 2022 and February 2023., Main Outcomes and Measures: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the predictive model based on the recorded breathing sounds., Results: Of the 101 participants included during the study duration, the mean (SD) age was 48.3 (14.9) years, and 51 (50.5%) were female. For the iOS smartphone, the sensitivity values at apnea-hypopnea index (AHI) levels of 5, 15, and 30 per hour were 92.6%, 90.9%, and 93.3%, respectively, with specificities of 84.3%, 94.4%, and 94.4%, respectively. Similarly, for the Android smartphone, the sensitivity values at AHI levels of 5, 15, and 30 per hour were 92.2%, 90.0%, and 92.9%, respectively, with specificities of 84.0%, 94.4%, and 94.3%, respectively. The accuracy for the iOS smartphone was 88.6%, 93.3%, and 94.3%, respectively, and for the Android smartphone was 88.1%, 93.1%, and 94.1% at AHI levels of 5, 15, and 30 per hour, respectively., Conclusions and Relevance: This diagnostic study demonstrated the feasibility of predicting OSA with a reasonable level of accuracy using breathing sounds obtained by smartphones during sleep at home.

Small-molecular fibroblast activation protein inhibitor (FAPI)-based tracer have been shown to be promising Positron Emission Tomography (PET) 68 Ga-labeled radiopharmaceuticals to image a variety of tumors including pancreatic, breast, and colorectal cancers, among others. In this study, we developed a novel 18 F-labeled FAPI derivative. [ 18 F]6 was labeled using a synthon approach based on the tetrazine ligation. It showed subnanomolar affinity for the FAP protein and a good selectivity profile against known off-target proteases. Small animal PET studies revealed high tumor uptake and good target-to-background ratios. [ 18 F]6 was excreted via the liver. Overall, [ 18 F]6 showed promising characteristics to be used as a PET tracer and could serve as a lead for further development of halogen-based theranostic FAPI radiopharmaceuticals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Matthias M. herth reports a relationship with Tetrakit Technologies that includes: board membership, consulting or advisory, and equity or stocks. Christian B. M. Poulie reports a relationship with Tetrakit Technologies that includes: board membership, employment, and equity or stocks. Vladimir Shalgunov reports a relationship with Tetrakit Technologies that includes: board membership, employment, and equity or stocks. Umberto Maria Battisti reports a relationship with Tetrakit technologies that includes: board membership, employment, and equity or stocks., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

High-density lipoprotein (HDL) therapy has demonstrated beneficial effects in acute stroke and acute myocardial infarction models by reducing infarct size. In this study, we investigated the inhibitory effects of reconstituted HDL (rHDL) on neointimal hyperplasia and elucidated its underlying mechanism using a balloon injury rat model. Our finding revealed a significant 37% reduction in the intima to media ratio in the arteries treated with 80 mg/kg rHDL compared to those subjected to injury alone (p < 0.05), indicating a specific inhibition of neointimal hyperplasia. In vivo analysis further supported the positive effects of rHDL by demonstrating a reduction in smooth muscle cell (SMC) proliferation and an increase in endothelial cell (EC) proliferation. Additionally, rHDL treatment led to decreased infiltration of leukocytes and downregulated the expression of matrix metallopeptidase 9 (MMP9) in the neointimal area. Notably, rHDL administration resulted in decreased expression of VCAM1 and HIF1α, alongside increased expression of heme oxygenase 1 (HO1) and heat shock protein 27 (HSP27). Overexpression of HSP27 and HO1 effectively inhibited SMC proliferation. Moreover, rHDL-mediated suppression of injury-induced HIF1α coincided with upregulation of HSP27. Interestingly, HSP27 and HO1 had varying effects on the expression of chemokine receptors and rHDL did not exert significant effect on chemokine receptor expression in THP1 cells. These findings underscore the distinct roles of HSP27 and HO1 as potential regulatory factors in the progression of restenosis. Collectively, our study demonstrates that rHDL exerts a potent anti-neointimal hyperplasia effect by reducing leukocytes infiltration and SMC proliferation while promoting EC proliferation., (© 2023. The Author(s).)

Objective: While patients with medically intractable acute cerebellar infarction typically undergo suboccipital craniectomy and removal of the infarcted tissue, this procedure is associated with long operating times and postoperative complications. This study aimed to investigate the effectiveness of minimally invasive navigationguided burr hole aspiration surgery for the treatment of acute cerebellar infarction., Methods: Between January 2015 and December 2021, 14 patients with acute cerebellar infarction, who underwent navigation-guided burr hole aspiration surgery, were enrolled in this study., Results: The preoperative mean Glasgow Coma Scale (GCS) score was 12.7, and the postoperative mean GCS score was 14.3. The mean infarction volume was 34.3 cc at admission and 23.5 cc immediately following surgery. Seven days after surgery, the mean infarction volume was 15.6 cc. There were no surgery-related complications during the 6-month follow-up period and no evidence of clinical deterioration. The mean operation time from skin incision to catheter insertion was 28 min, with approximately an additional 13 min for extra-ventricular drainage. The mean Glasgow Outcome Scale score after 6 months was 4.8., Conclusions: Navigation-guided burr hole aspiration surgery is less time-consuming and invasive than conventional craniectomy, and is a safe and effective treatment option for acute cerebellar infarction in selected cases, with no surgery-related complication.

Purpose: In the context of radioiodine-resistant follicular-cell derived thyroid cancers (RAI-R-FCTC), [ 18 F]F-FDG PET/CT serves as a widely used and valuable diagnostic imaging method. However, there is growing interest in utilizing molecular imaging probes that target cancer-associated fibroblasts (CAFs) as an alternative approach. This study sought to compare the diagnostic capabilities of [ 68 Ga]Ga-DOTA.SA.FAPi and [ 18 F]F-FDG PET/CT in patients with RAI-R-FCTC., Methods: In this retrospective study, a total of 117 patients with RAI-R-FCTC were included. The study population consisted of 68 females and 49 males, with a mean age of 53.2 ± 11.7 years. The aim of the study was to perform a comprehensive qualitative and quantitative assessment of [ 68 Ga]Ga-DOTA.SA.FAPi and [ 18 F]F-FDG PET/CT scans in RAI-R-FCTC patients. The qualitative assessment involved comparing patient-based and lesion-based visual interpretations of both scans, while the quantitative assessment included analyzing standardized uptake values corrected for lean body mass (SULpeak and SULavg). The findings obtained from the scans were validated by correlating them with morphological findings from diagnostic computed tomography and/or histopathological examination., Results: Among the 117 RAI-R-FCTC patients, 60 had unilateral local disease, and 9 had bilateral lesions with complete concordance in the detection rate on both PET scans. [ 68 Ga]Ga-DOTA.SA.FAPi had a higher detection rate for lymph nodes (95.4% vs 86.6%, p<0.0001), liver metastases (100% vs. 81.3%, p<0.0001), and brain metastases (100% vs. 39%, p<0.0001) compared to [ 18 F]F-FDG. The detection rates for pleural and bone metastases were similar between the two radiotracers. For lung metastases, [ 68 Ga]Ga-DOTA.SA.FAPi showed a detection rate of 81.7%, whereas [ 18 F]F-FDG had a detection rate of 64.6%. Remarkably, [ 68 Ga]Ga-DOTA.SA.FAPi was able to detect a bowel metastasis that was missed on [ 18 F]F-FDG scan. The median standardized uptake values (SUL) were generally comparable between the two radiotracers, except for brain metastases (SULpeak [ 68 Ga]Ga-DOTA.SA.FAPi vs. [ 18 F]F-FDG: 13.9 vs. 6.7, p-0.0001) and muscle metastases (SULpeak [ 68 Ga]Ga-DOTA.SA.FAPi vs. [ 18 F]F-FDG: 9.56 vs. 5.62, p-0.0085), where [ 68 Ga]Ga-DOTA.SA.FAPi exhibited higher uptake., Conclusion: The study results demonstrate the superior performance of [ 68 Ga]Ga-DOTA.SA.FAPi compared to [ 18 F]F-FDG PET/CT in detecting lymph nodal, liver, bowel, and brain metastases in patients with RAI-R-FCTC. These findings highlight the potential of [ 68 Ga]Ga-DOTA.SA.FAPi as a theranostic tool that can complement the benefits of [ 18 F]F-FDG PET/CT in the imaging of RAI-R-FCTC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Immunosenescence gradually deteriorates the function of the immune system, making elderly patients susceptible to infection, while reducing rejection of organ transplants. Therefore, age-adaptive immunosuppression is necessary in the elderly. We evaluated clinical outcomes such as rejection and infection rate when using basiliximab and rabbit anti-thymocyte globulin (r-ATG) as induction agents in elderly and young organ transplant recipients., Methods: We retrospectively reviewed patients who underwent kidney transplantation (KT) between June 2011 and April 2019. We enrolled 704 adult KT patients and classified the patients into groups according to patient age. We compared the outcomes of infection and biopsy-proven acute rejection (BPAR) according to the type of induction agent (basiliximab and r-ATG [4.5 mg/kg])., Results: The patient group included 520 recipients (74.6%) in the younger recipient group and 179 recipients (25.4%) in the older recipient group. When r-ATG was used as an induction agent, BPAR within 6 months occurred less (p = 0.03); however, infections within 6 months were higher in older recipients. Deaths due to infection were more common in older recipients (p = 0.003)., Conclusion: It may be necessary to use less intensive induction therapy for older recipients, of which dose reduction of r-ATG is one option.