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Background: Understanding the mechanisms driving specific and nonspecific tissue uptake of antibodies can inform protein engineering strategies that maximize therapeutic efficacy in target tissues while minimizing off-target tissue toxicities. While in vitro cell assays are typically used to study these internalization mechanisms, there are few methods readily available to evaluate these pathways in vivo. Single photon emission computed tomography (SPECT) imaging with a non-residualizing radiohalogen probe can measure total levels of intact antibody, and a residualizing radiometal-chelate probe, in combination with a non-residualizing probe, can measure catabolized antibody associated with receptor-mediated and nonspecific internalization processes. Here, we describe a SPECT imaging study in human epidermal growth factor receptor 2 (HER2)-expressing tumor-bearing mice aimed at measuring whole body disposition kinetics of tumor-targeting trastuzumab (anti-HER2) and non-targeting (anti-gD) antibodies. Mice received these molecules labeled with either a non-residualizing prosthetic group ([ 125 I]SIB) or with a residualizing radiometal-chelate ( 111 In-DOTA)., Results: SPECT imaging data confirmed significant HER2-mediated tumor uptake and catabolism of anti-HER2, evidenced by the high 111 In-DOTA-anti-HER2 signal over time relative to 111 In-DOTA-anti-gD and the respective [ 125 I]SIB-labeled molecules. [ 125 I]SIB-anti-HER2 still showed noticeably higher tumor signal than [ 125 I]SIB-anti-gD, demonstrating a meaningful pool of intact anti-HER2 in the interstitial tumor compartment. Spleen showed the greatest catabolism of both mAbs amongst all non-tumor tissues. Compartmental modeling of the SPECT data demonstrated that cell-associated anti-HER2 was primarily receptor-bound, with a peak receptor occupancy of 35% at 13 h post administration of a 10 mg/kg dose, with minimal free and pinocytosed mAb., Conclusion: Here, we successfully developed an imaging and modeling approach to capture anti-HER2 antibody receptor binding as well as specific and nonspecific internalization over time in vivo. These data and analyses demonstrate the power of SPECT imaging using both non-residualizing and residualizing radioisotopes to better characterize the different biological states (free, bound, and catabolized) of antibodies within interstitial and intracellular compartments. Understanding these distinct antibody internalization mechanisms in tumor and non-tumor tissues enables more informed decisions on dose selection to optimize treatment of tumors with heterogeneous antigen expression while minimizing nonspecific toxicities., Competing Interests: Declarations. Ethics approval and consent to participate: Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council 2011). Genentech is an AAALAC-accredited facility and all animal activities in this research study were conducted under protocols approved by the Genentech Institutional Animal Care and Use Committee (IACUC). Consent for publication: Not applicable. Competing interests: All authors are employees of Genentech, a member of the Roche Group, and have financial interest in Roche., (© 2025. The Author(s).)

Background: South Korea is anticipated to enter a super-aged society by 2025, necessitating a focus on healthy aging. In Korean medicine (KM), aging and disease susceptibility are individual specific, emphasizing personalized treatments, and many Korean local governments have integrated KM services for elderly people into the public sector. However, there is a notable absence of research incorporating KM to treat older adults., Aim: The proposed study aims to examine the comprehensive health profiles of individuals entering old age in rural and urban areas and explore the significant correlations between healthy aging and four key factors: biological, psychological, social, and KM-based phenotype factors. It will also establish a database and blood biobank, serving as a platform for future research to develop a traditional KM-based healthy aging model., Methods: A multiple randomized controlled trial design will be adopted in this prospective, multicenter cohort study for the clinical investigation of the markers associated with KM-based healthy aging. The aim is to recruit 1,000 participants who are entering old age from both urban and rural settings for this study, and recruitment began in August 2023 with follow-up surveys planned at one-year intervals. Comprehensive health profiles, including biological, psychological, social, and KM-based phenotype factors, will be developed through the creation of a database, a blood biobank, and multi-omics data., Results: In the baseline phase of this study, we will focus on identifying markers for KM-based phenotypes and examining how these phenotypes relate to aging and associated diseases. In the next phase, we will implement interventions tailored to KM-based phenotypes to verify the effects of KM on healthy aging. Ultimately, we intend to develop a KM-based integrated health management model, with further substudies aiming to explore factors related to healthy aging. This protocol was approved by the institutional review board of Wonkwang University Korean Medicine Hospital, Iksan, Republic of Korea (approval number: WKUIOMH-IRB-2023-05) on August 16, 2023 and Jangheung Integrative Medical Hospital (approval number: WKUJIM-202307-001) on August 21, 2023. Recruitment started on August 16, 2023., Conclusion: The anticipated results of our study aim to establish personalized preventive and therapeutic interventions for individuals entering old age. Additionally, we seek to offer an KM-based integrated health management model that incorporates comprehensive diagnosis and an integrative medical treatment strategy for healthy aging., Trial Registration: Clinical Research Information Service: KCT0008863 (registered on October 11, 2023, https://cris.nih.go.kr/cris/search/detailSearch.do/25718)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Ko 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.)

Breast diffusion weighted MR imaging (DWI) is increasingly used, because it is fast and easy to be added in clinical protocol without contrast agent and provides information of cellularity or tissue microstructure. This review article explores the principles of breast DWI, the standardization of acquisition techniques, and its current clinical applications. We emphasize its role in differentiating benign from malignant lesions, reducing unnecessary biopsies, and discuss the evidence supporting DWI as a potential standalone screening tool. Prognostic indicators derived from DWI parameters and its utility in monitoring treatment responses are discussed. Finally, we look to the future, discussing emerging techniques. This review provides a comprehensive overview of breast DWI's current status and future potential.

Parkinson's disease (PD) is a significant source of morbidity, especially with an aging population. Gait problems, particularly freezing of gait (FOG), remain a persistent issue, causing falls and reduced quality of life without consistent responses to therapies. PD and related symptoms have classically been attributed to dopamine deficiency secondary to substantia nigra degeneration from Lewy body (LB) and Lewy neurite (LN) infiltration. However, Lewy-related pathology is present in other areas of the brainstem and spinal cord that control gait function, yet these other circuits have not been routinely considered in the design of current therapeutic options. In this review, we summarize changes in brainstem and spinal cord circuits in individuals affected by PD and the implications for understanding of gait dysfunction in PD., Competing Interests: Declaration of interests N.C. has no financial or nonfinancial competing interests. L.V.K. is a site subinvestigator for the Parkinson’s Progression Markers Initiative but declares no other financial or nonfinancial competing interests. S.K.K. has acted as a paid consultant for Medtronic, Novonordisk, and Blue Rock and received research support from Abott, Medtronic, and Boston Scientific but declares no other nonfinancial competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Teravoxel-scale, cellular-resolution images of cleared rodent brains acquired with light-sheet fluorescence microscopy have transformed the way we study the brain. Realizing the potential of this technology requires computational pipelines that generalize across experimental protocols and map neuronal activity at the laminar and subpopulation-specific levels, beyond atlas-defined regions. Here, we present artficial intelligence-based cartography of ensembles (ACE), an end-to-end pipeline that employs three-dimensional deep learning segmentation models and advanced cluster-wise statistical algorithms, to enable unbiased mapping of local neuronal activity and connectivity. Validation against state-of-the-art segmentation and detection methods on unseen datasets demonstrated ACE's high generalizability and performance. Applying ACE in two distinct neurobiological contexts, we discovered subregional effects missed by existing atlas-based analyses and showcase ACE's ability to reveal localized or laminar neuronal activity brain-wide. Our open-source pipeline enables whole-brain mapping of neuronal ensembles at a high level of precision across a wide range of neuroscientific applications., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: Hypertension, a common chronic disease, often leads to serious complications. While conventional management relies on antihypertensive drugs, which can cause side effects and adherence issues, alternative treatments like herbal medicine are gaining attention. This study examines the efficacy and safety of modified Saengmaeksan, an East Asian herbal remedy, in treating hypertension., Methods: This single-arm, prospective, observational study will be conducted at Kyunghee Bichedam Korean Medicine Clinic from October 23, 2023 to August 30, 2024, enrolling 30 hypertensive patients. Over 12 weeks, participants will undergo 4 visits, receiving modified Saengmaeksan twice daily for 8 weeks, with a subsequent 4-week follow-up. Primary outcome is the change in systolic blood pressure from the baseline to week 8. Secondary outcomes include diastolic blood pressure changes, radial artery tonometry, and quality of life evaluations. Safety assessments will include monitoring hematologic parameters and adverse events. Data will be analyzed using an ANCOVA model for adjusting confounders., Discussion: Modified Saengmaeksan has shown potential for lowering blood pressure in clinical settings, supported by animal and cell studies. However, human studies are scarce. This research will employ radial artery tonometry to analyze blood pressure comprehensively, exploring Saengmaeksan's hemodynamic effects. The study's goal is to support the approval of modified Saengmaeksan as a hypertension treatment by the South Korean Food and Drug Administration and to promote the industrialization of traditional herbal medicine in managing hypertension. The findings will provide essential data for future clinical research, aiding in feasibility assessments and sample size determinations for randomized controlled trials., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Cho 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.)

(Meth)acrylate polymers are commonly used as photoresist materials in photolithography. However, these polymers encounter the problem of swelling during the development process. To address this, we explored the use of a hydrophobic group to control the solubility in the hydrophilic developer. In this study, we synthesized two types of polymers to evaluate the impact of the developer on (meth)acrylate polymers for photoresist applications. Adamantyl methacrylate (AdMA) was selected as the hydrophobic group, while 2-ethoxyethyl acrylate (2-EEA) served as the hydrophilic group, enabling the synthesis of both hydrophilic and hydrophobic polymers. Our goal was to assess how the presence of adamantyl monomers influenced the solubility of the polymer. This study demonstrated that solubility was primarily influenced by functional groups, particularly hydrophobic groups, rather than other factors. Polymers with more than 50% hydrophobic groups can be effectively controlled for their solubility in TMAH. These findings show that the solubility of photoresist polymers in TMAH can be tuned by incorporating a high proportion of hydrophobic groups. The study further confirms the role of adamantyl monomers as effective hydrophobic (aliphatic) groups in modulating the solubility of (meth)acrylate polymers in developer solutions.

Background: Polydatin (3,4',5-trihydroxy-3-β-d-glucopyranoside, PD) is known for its antioxidant and anti-inflammatory properties. Oxaliplatin (OXA)-based chemotherapy is the first-line treatment for metastatic and recurrent colorectal cancer (CRC). However, the lack of selectivity for normal cells often results in side effects. Consequently, the search for anti-cancer components with high efficacy and low cytotoxicity has become a significant focus in recent years., Methods: The anti-tumor effects of PD, OXA or their combination were assessed by cell viability, colony formation, and wound-healing assays. Reactive oxygen species (ROS) generation was measured by flow cytometry and DNA damage was assessed by immunofluorescence assay. The relative gene and protein expressions were analyzed by quantitative real time-PCR (qRT-PCR) and Western blot assays. Molecular docking analysis predicted the interaction between PD and potential targets., Results: We found that PD exerted anti-CRC activity by promoting Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase 5 (NOX5)-mediated ROS production, activating the endoplasmic reticulum (ER) stress, and inducing DNA damage. Knocking down NOX5 attenuated the inhibition of proliferation and colony forming ability induced by PD in colon cancer cells and reversed the expression of C/EBP-homologous protein (CHOP) and activating transcription factor 4 (ATF4) proteins. In addition, combination of PD and OXA synergistically exerted anti-CRC activities by promoting DNA damage and activating ER stress signaling pathway., Conclusion: The combination of PD and OXA could be an effective treatment strategy for certain patients with CRC., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Zhao, Zhang, Liu, Chen, Onga, Cho, Cui and Zheng.)

Evidence suggests that paternal diet can influence offspring metabolic health intergenerationally but whether dietary animal and plant proteins differ in their impact on fathers and their offspring is not known. Our objective was to examine the effects of a paternal diet high in casein versus pea protein on fathers and their offspring. Five-week-old male rats were fed: (1) control, (2) high animal protein (AP, 36.1% of energy as casein), or (3) high plant protein (PP, 36.1% of energy as pea protein with added methionine) diets for 8-11 weeks before being mated. Offspring were challenged with a high fat/sucrose diet (HFD) from 10 to 16 weeks of age. Metabolic and microbial outcomes were assessed in both generations. In fathers fed PP diet, enhanced insulin sensitivity and lower liver triglycerides were seen alongside altered hepatic microRNA expression and gut microbial profiles. Few changes were seen in their offspring. In contrast, the paternal AP diet influenced adult offspring hepatic microRNA expression and programmed a latent increase in adiposity, dysregulated satiety hormones, and modified gut microbial composition in their adult offspring that occurred following the HFD. Overall, a diet high in pea protein with added methionine demonstrated protective effects on biomarkers of metabolic health in the fathers but led to minimal effects on the offspring while a paternal diet high in casein led to evidence of an increase in characteristics of metabolic dysfunction in their adult offspring when unmasked by exposure to a HFD for 6 weeks., Competing Interests: The authors declare no competing interests.

This review focuses on the use of Salting-Out Assisted Liquid-Liquid Extraction (SALLE) for blood sample processing prior analysis, exploring its principles, optimization parameters, and coupling with analytical techniques. SALLE is favored for its simplicity, cost-effectiveness, and rapid execution using the salting-out effect to induce phase separation in mixtures of aqueous samples and water-miscible organic solvents. The review categorizes and discusses the different types of blood samples, the main salts and solvents used, and the parameters affecting the extraction efficiency, such as solvent and salt type as well as ionic strength, pH, vortex mixing and centrifugation time. Advantages of SALLE over traditional methods like solid-phase extraction (SPE) and protein precipitation (PP) are highlighted, emphasizing its environmental friendliness, high extraction efficiency, and ease of automation. By examining recent literature and scientific publications (2014-2024), this review provides a comprehensive understanding of the factors influencing SALLE performance and its application in bioanalysis, particularly when coupled with separative techniques such as liquid chromatography (LC), capillary electrophoresis (CE), and mass spectrometry (MS)., 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 © 2025 Elsevier B.V. All rights reserved.)

This study aimed to profile metabolites from five Trichoderma strains and assess their cytotoxic and pharmacological activities, particularly targeting oral squamous cell carcinoma (OSCC). UHPLC-TOF-MS analysis revealed the presence of 25 compounds, including heptelidic acid, viridiol isomers, and sorbicillinol from the different Trichoderma extracts. Pharmacokinetic analysis showed moderate permeability and low interaction with P-glycoprotein, suggesting good drug absorption with minimal interference in cellular uptake. ADME-Tox analysis indicated limited inhibition of cytochrome P450 enzymes, low renal clearance, which are favorable for maintaining therapeutic levels. Toxicity predictions revealed some compounds with potential mutagenicity, but low hepatotoxicity and skin sensitization risks. Network pharmacology identified MAPK1 as a key target for oral cancer, and molecular docking and induced fit docking studies demonstrated strong binding affinities of Trichoderma metabolites, including stachyose and harzianol, to MAPK1. In addition, molecular dynamics (MD) simulations confirmed stable interactions. In vitro studies on NIH3T3 and YD-10B cells showed significant cytotoxicity, particularly with extracts CNU-05-001 (IC 50 :10.15 µg/mL) and CNU-02-009 (10.00 µg/mL) against YD-10B cells. These findings underscore the potential of Trichoderma metabolites in drug discovery, particularly for cancer therapies., 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 © 2025. Published by Elsevier Ltd.)

Objective: The ghost crab Ocypode stimpsoni (Decapoda) is designated as a protected marine species in Korea due to its declining population. In this study, we successfully identified 17 microsatellite markers for O. stimpsoni through next-generation sequencing., Results: Out of the 63 loci examined, 26 were effectively amplified in a sample of 100 individuals. These 17 loci, comprising four tri-nucleotide and 13 tetra-nucleotide repeats, exhibited a range of 4 to 26 alleles per locus (with an average of 14.1 alleles) across 100 samples from three O. stimpsoni populations. The mean observed and expected heterozygosities were calculated to be 0.885 and 0.836, respectively. These 17 newly identified polymorphic microsatellite loci hold valuable utility for investigating the genetic structure and diversity of this protected marine species., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Cerebellar deep brain stimulation (DBS) is gaining traction as a potential treatment for movement disorders and stroke, and there is renewed interest in the cerebellum as a target for neuromodulation. Despite the safety and accuracy of frame-based approaches to the posterior fossa, unconventional stereotactic frame placement may be necessary to allow for low posterior fossa trajectories. Current literature lacks a comprehensive protocol detailing inverted frame placement and targeting., Methods: Preoperative imaging was acquired prone. An inverted Leksell G frame was applied along with an open-topped CT fiducial box, followed by a prone CT with the scanner set to the "legs first, nose up" configuration. Target coordinates were extracted from navigation software after image fusion. Intraoperatively, the patient was positioned prone, and the stereotactic arc was mounted in the lateral-right orientation, with inverted arc supports. Confirmatory stereotaxy to a scalp staple was performed, and the DBS leads were then inserted., Conclusion: Our standardized protocol provides a flexible platform for posterior fossa DBS, allowing for low trajectories and multiple electrodes. Unlike conventional upright frame placement, an inverted frame permits an unobstructed view of suboccipital entry sites and incision placement. A conventional frame and regular planning software are sufficient, with no additional mathematical calculations required., (© 2024 S. Karger AG, Basel.)

Introduction: With the advancement of porous surface processing technology, cementless total knee arthroplasty (TKA) has once again garnered attention. Cementless TKA lacks cement sealing, raising concerns regarding potential blood loss. Recently, patient blood management (PBM) protocols have been introduced to mitigate postoperative blood loss and transfusions. In this systematic review, we aimed to address whether cementless TKA leads to increased blood loss and transfusion rates as compared with cemented TKA. Additionally, we explored the impact of contemporary PBM protocols on post-TKA hemodynamics., Methods: This systematic review included prospective randomized trials and retrospective studies that compared blood loss and PBM between cementless and cemented TKA. A comprehensive literature search for publications from 1980 onwards was conducted using databases such as PubMed, MEDLINE, and EMBASE. Furthermore, we conducted a thorough examination of the bibliographies of all relevant articles that were retrieved. Studies that met our inclusion criteria were assessed carefully for pertinent data. This systematic review followed the Preferred Reporting Items for Systematic Re-views and Meta-Analyses (PRISMA) statement and was registered in the PROSPERO register (CRD42024507236)., Results: A total of twelve studies were included in this study. Among these, six papers reported lower blood loss in cemented TKA, while the other six papers found no significant difference in perioperative blood loss between the two groups. From the perspective of PBM, seven studies applied PBM protocols including systematic and topical tranexamic acid, autogenous transfusion, strict transfusion threshold and drain clamping, while the remaining five studies did not. If PBM protocols were implemented, no significant difference in blood loss was observed based on the implant fixation method., Conclusion: In the context of recent studies implementing PBM protocols, the choice of implant fixation method appears to have no relevant impact on post-TKA blood loss. Nevertheless, it is important to note that the reporting of outcomes and PBM protocols exhibit considerable variation and heterogeneity., Competing Interests: Declarations. Institutional review board statement: This study was exempted from the requirement for local Institutional Review Board approval because it is a retrospective systematic review of the literature. Informed consent statement: Patient consent was waived because this study is a systematic review. Disclosure of interests: The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Usenamine A (UA) is a natural compound isolated from the lichen Usnea diffracta , and its therapeutic effects on rheumatic diseases are not well understood. This study aimed to evaluate the potential anti-inflammatory effects of UA and its therapeutic effects on rheumatoid arthritis (RA) and ankylosing spondylitis (AS)., Materials and Methods: Molecular docking was performed between the 3D structure of UA and the TNF-TNFR2 complex. Peripheral blood mononuclear cells (PBMCs) from RA and AS patients were treated with UA, and cell viability was measured using the MTS assay and flow cytometry. The in vitro effects of co-culture with UA were determined by measuring inflammatory cytokines, including IFN-γ, IL-17A, and GM-CSF, using flow cytometry and enzyme-linked immunosorbent assay (ELISA). The in vivo effects of UA were evaluated using an arthritis mouse model., Results: The docking complex of UA bound to the TNF-TNFR2 complex exhibited docking scores of -5.251 kcal/mol and -6.274 kcal/mol, confirming their active sites. UA did not affect cell viability and suppressed the production of inflammatory cytokines in the PBMCs of RA (IFN-γ, IL-17A, and GM-CSF) and AS (GM-CSF) patients. The ELISA also confirmed reduced cytokine levels in the co-culture of UA and PBMCs from RA or AS patients. In the arthritis mouse model, significantly reduced clinical and histological scores were observed in the UA treatment group., Conclusion: Our findings suggest that UA has potential as a binding target for TNF, suppresses inflammatory cytokines in PBMCs, and exhibits anti-inflammatory effects on arthritis in a mouse model., 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. The handling editor HF declared a past co-authorship with the author TJ., (Copyright © 2024 Lee, Li, Jang, Kim, Saravanakumar, Shim, Cho, Won and Kim.)

A spinal cord injury (SCI) disrupts the neuronal projections from the brain to the region of the spinal cord that produces walking, leading to various degrees of paralysis. Here, we aimed to identify brain regions that steer the recovery of walking after incomplete SCI and that could be targeted to augment this recovery. To uncover these regions, we constructed a space-time brain-wide atlas of transcriptionally active and spinal cord-projecting neurons underlying the recovery of walking after incomplete SCI. Unexpectedly, interrogation of this atlas nominated the lateral hypothalamus (LH). We demonstrate that glutamatergic neurons located in the LH (LH Vglut2 ) contribute to the recovery of walking after incomplete SCI and that augmenting their activity improves walking. We translated this discovery into a deep brain stimulation therapy of the LH (DBS LH ) that immediately augmented walking in mice and rats with SCI and durably increased recovery through the reorganization of residual lumbar-terminating projections from brainstem neurons. A pilot clinical study showed that DBS LH immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBS LH was turned off. There were no serious adverse events related to DBS LH . These results highlight the potential of targeting specific brain regions to maximize the engagement of spinal cord-projecting neurons in the recovery of neurological functions after SCI. Further trials must establish the safety and efficacy profile of DBS LH , including potential changes in body weight, psychological status, hormonal profiles and autonomic functions., Competing Interests: Competing interests: G.C., J.B., N.C., J.W.S., R.D., L.A. and L.B.-F. hold various patents in relation to the present work. G.C. is a consultant of ONWARD Medical. G.C. and J.B. are minority shareholders of ONWARD Medical, a company with partial relationships with the presented work. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Backgroud: The increasing prevalence of cementless total knee arthroplasty (TKA) necessitates a reliable assessment of bone quality. Central bone mineral density (BMD), measured by dual-energy x-ray absorptiometry (DEXA) in the lumbar spine and hip, is conventionally used to estimate bone quality. However, its effectiveness in predicting the actual bone strength at the knee, which is crucial for cementless TKA, is under scrutiny. This study investigated the relationship between central BMD and actual bone strength at the knee., Methods: This prospective study included 191 knees undergoing standard posterior-stabilized TKA between November 2021 and March 2023. Central BMD was assessed 3 months before TKA, and the failure load of bone fragments collected during box preparation was directly measured using an indentation test. Relationships between central BMD and failure load as a measure of the actual bone strength at the knee were analyzed., Results: Linear regression analysis revealed a weak correlation between central BMD and the actual bone strength at the knee (R 2 = 0.146 in all patients; < 0.001 in osteoporosis group; 0.126 in non-osteoporosis group). The correlation suggested by the regression models was particularly insignificant in the osteoporosis subgroup, showing that central BMD is not a reliable predictor of bone strength for cementless TKA., Conclusions: Central BMD measurements have limited utility in accurately predicting the real bone strength at the knee for cementless TKA. This study highlights the need for more specific and direct methods of assessing bone quality at the knee to ensure the success of cementless TKA., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2024 by The Korean Orthopaedic Association.)

Purpose: The purpose of this study was to assess whether kinematic alignment (KA) outperforms mechanical alignment (MA) in restoring patellar tracking to native patterns by using a clustering algorithm., Methods: Twenty cadavers (40 knees) were evaluated. For each cadaver, one knee was randomly assigned to KA and the other to MA. KA total knee arthroplasty (TKA) procedures were performed using a caliper-verified technique, while MA TKA procedures utilized a measured resection technique. Subsequently, all specimens were mounted on a customized knee-testing system, and patellar tracking was measured using a motion analysis system. All patellar tracking data were clustered using the density-based spatial clustering of applications with noise algorithm. Differences in patellar tracking patterns and the restoration of native patellar tracking were compared between the two alignment strategies., Results: Patellar tracking patterns following KA were considerably different from MA. Pre- and post-TKA patellar tracking patterns following MA were grouped into separate clusters, whereas a substantial proportion of patellar tracking patterns following KA were grouped into the pre-TKA dominant cluster. Compared to MA, a greater proportion of patellar tracking patterns following KA showed similar patterns to native knees (p < 0.05) and more patellar tracking patterns following KA paired with preoperative patterns (p < 0.01)., Conclusion: KA restored native patellar tracking patterns more closely compared to MA., Level of Evidence: Level I, therapeutic study., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Photopolymerization-based three-dimensional (3D) printing techniques such as stereolithography (SLA) attract considerable attention owing to their superior resolution, low cost, and relatively high printing speed. However, the lack of studies on improving the mechanical properties of 3D materials highlights the importance of delving deeper into additive manufacturing research. These materials possess considerable potential in the medical field, particularly for applications such as anatomical models, medical devices, and implants. In this study, we investigated the enhancement of mechanical strength in 3D-printed photopolymers through the incorporation of potassium titanate powder (K 2 Ti 8 O 17 ), with a particular focus on potential applications in medical devices. The mechanical strength of the photopolymer containing potassium titanate was analyzed by measuring its flexural strength, hardness, and tensile strength. Additionally, poly(ethylene glycol) (PEG) was used as a stabilizer to optimize the dispersion of potassium titanate in the photopolymer. The flexural strengths of the printed specimens were in the range of 15-39 MPa (Megapascals), while the measured surface hardness and tensile strength were in the range of 41-80 HDD (Hardness shore D) and 2.3-15 MPa, respectively. Furthermore, the output resolution was investigated by testing it with a line-patterned structure. The 3D-printing photopolymer without PEG stabilizers produced line patterns with a thickness of 0.3 mm, whereas the 3D-printed resin containing a PEG stabilizer produced line patterns with a thickness of 0.2 mm. These findings demonstrate that the composite materials not only exhibit improved mechanical performance but also allow for high-resolution printing. Furthermore, this composite material was successfully utilized to print implants for pre-surgical inspection. This process ensures the precision and quality of medical device production, emphasizing the material's practical value in advanced medical applications.

Photoresist polymers containing cycloaliphatic acrylic monomers have been synthesized for use in the microcircuits of semiconductors. Although cycloaliphatic acrylic monomers exhibit a high etch resistance and excellent thermal properties, their large size increases the distance between the main chains of the resulting polymers. This increased distance facilitates the penetration of a developer between the main chains, which leads to swelling and thus pattern collapse, distortion, and delamination, thereby complicating the fabrication of microcircuits. To solve this problem, various large developers were used in previous studies to reduce the swelling effect. However, these developers could not easily dissolve the unexposed regions of the resist. To overcome this issue, we designed photoresist polymers with smaller functional groups to decrease the degree of swelling. Specifically, ArF photoresist polymers were synthesized from monomers with various sizes of functional groups. We confirmed that the polymer synthesized using cyclohexyl methacrylate (CHMA), which had the smallest functional group, exhibited the shortest distance between the main chains. Consequently, this polymer showed the least swelling, with a swelling ratio of 109%. In contrast, the polymers synthesized using isobornyl acrylate (IBOA) and dicyclopentanyl methacrylate (TCDMA), which have large functional groups, exhibited greater distances between the main chains, resulting in swelling ratios of 114% and 112%, respectively. The polymer with a swelling ratio of 109% showed excellent patterning properties, while those with swelling ratios of 114% and 112% were delaminated by the developer. Our work introduces a novel approach to help reduce the swelling effect and achieve high-quality patterns in negative photoresists.

Alternative pre-mRNA splicing (AS) is a biological process that results in proteomic diversity. However, implications of AS alterations in cancer remain poorly understood. Herein, we performed a comprehensive AS analysis in cancer driver gene transcripts across fifteen cancer types and found global alterations in inclusion rates of the PBAF SWI/SNF chromatin remodeling complex subunit Polybromo 1 (PBRM1) exon 27 (E27) in most types of cancer tissues compared with those in normal tissues. Further analysis confirmed that PBRM1 E27 is excluded by the direct binding of RBFOX2 to intronic UGCAUG elements. In addition, the E27-included PBRM1 isoform upregulated PD-L1 expression via enhanced PBAF complex recruitment to the PD-L1 promoter. PBRM1 wild-type patients with clear cell renal cell carcinoma were resistant to PD-1 blockade therapy when they expressed low RBFOX2 mRNA levels. Overall, our study suggests targeting of RBFOX2-mediated AS of PBRM1 as a potential therapeutic strategy for immune checkpoint blockade., Competing Interests: Disclosure and competing interests statement The authors declare no competing interests., (© 2024. The Author(s).)

Distinguishing between pathologic complete response and residual cancer after neoadjuvant chemotherapy (NAC) is crucial for treatment decisions, but the current imaging methods face challenges. To address this, we developed deep-learning models using post-NAC dynamic contrast-enhanced MRI and clinical data. A total of 852 women with human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer were randomly divided into a training set (n = 724) and a validation set (n = 128). A 3D convolutional neural network model was trained on the training set and validated independently. The main models were developed using cropped MRI images, but models using uncropped whole images were also explored. The delayed-phase model demonstrated superior performance compared to the early-phase model (area under the receiver operating characteristic curve [AUC] = 0.74 vs. 0.69, P = 0.013) and the combined model integrating multiple dynamic phases and clinical data (AUC = 0.74 vs. 0.70, P = 0.022). Deep-learning models using uncropped whole images exhibited inferior performance, with AUCs ranging from 0.45 to 0.54. Further refinement and external validation are necessary for enhanced accuracy., (© 2024. The Author(s).)

Objective: To develop a nomogram that integrates clinical-pathologic and imaging variables to predict ipsilateral breast tumor recurrence (IBTR) in women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS)., Materials and Methods: This retrospective study included consecutive women with DCIS who underwent BCS at two hospitals. Patients who underwent BCS between 2003 and 2016 in one hospital and between 2005 and 2013 in another were classified into development and validation cohorts, respectively. Twelve clinical-pathologic variables (age, family history, initial presentation, nuclear grade, necrosis, margin width, number of excisions, DCIS size, estrogen receptor, progesterone receptor, radiation therapy, and endocrine therapy) and six mammography and ultrasound variables (breast density, detection modality, mammography and ultrasound patterns, morphology and distribution of calcifications) were analyzed. A nomogram for predicting 10-year IBTR probabilities was constructed using the variables associated with IBTR identified from the Cox proportional hazard regression analysis in the development cohort. The performance of the developed nomogram was evaluated in the external validation cohort using a calibration plot and 10-year area under the receiver operating characteristic curve (AUROC) and compared with the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram., Results: The development cohort included 702 women (median age [interquartile range], 50 [44-56] years), of whom 30 (4%) women experienced IBTR. The validation cohort included 182 women (48 [43-54] years), 18 (10%) of whom developed IBTR. A nomogram was constructed using three clinical-pathologic variables (age, margin, and use of adjuvant radiation therapy) and two mammographic variables (breast density and calcification morphology). The nomogram was appropriately calibrated and demonstrated a comparable 10-year AUROC to the MSKCC nomogram (0.73 vs. 0.66, P = 0.534) in the validation cohort., Conclusion: Our nomogram provided individualized risk estimates for women with DCIS treated with BCS, demonstrating a discriminative ability comparable to that of the MSKCC nomogram., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Lespedeza bicolor is a shrub plant that has been widely distributed in East Asia. The methanol extract from its LBR has been shown to exhibit anticancer and anti-bacterial effects. However, its anticancer efficacy in TNBC remains uncertain. This work aimed to study the anti-TNBC effect of LBR ethanol extract and its underlying mechanism. LBR triggered the cell death in TNBC through inhibiting cell proliferation, S-phase cell arrest, and induction of apoptosis. RNA-seq analysis revealed that the genes altered by LBR treatment were predominantly enriched in the cell adhesion. Notably, LBR inhibited phosphorylation and distribution of FAK. Furthermore, LBR demonstrated significant anticancer activity in xenograft tumors in mice through inhibiting cancer cell growth and inducing apoptosis. This work demonstrated the anticancer efficiency of LBR in TNBC without causing significant adverse effect, which providing a foundation for developing LBR based chemotherapeutic agents for breast cancer therapy., Competing Interests: None., (AJCR Copyright © 2024.)

Background Context: Degenerative cervical myelopathy (DCM) is the most common form of atraumatic spinal cord injury globally. Degeneration of spinal discs, bony osteophyte growth and ligament pathology results in physical compression of the spinal cord contributing to damage of white matter tracts and grey matter cellular populations. This results in an insidious neurological and functional decline in patients which can lead to paralysis. Magnetic resonance imaging (MRI) confirms the diagnosis of DCM and is a prerequisite to surgical intervention, the only known treatment for this disorder. Unfortunately, there is a weak correlation between features of current commonly acquired MRI scans ("community MRI, cMRI") and the degree of disability experienced by a patient., Purpose: This study examines the predictive ability of current MRI sequences relative to "advanced MRI" (aMRI) metrics designed to detect evidence of spinal cord injury secondary to degenerative myelopathy. We hypothesize that the utilization of higher fidelity aMRI scans will increase the effectiveness of machine learning models predicting DCM severity and may ultimately lead to a more efficient protocol for identifying patients in need of surgical intervention., Study Design/setting: Single institution analysis of imaging registry of patients with DCM., Patient Sample: A total of 296 patients in the cMRI group and 228 patients in the aMRI group., Outcome Measures: Physiologic measures: accuracy of machine learning algorithms to detect severity of DCM assessed clinically based on the modified Japanese Orthopedic Association (mJOA) scale., Methods: Patients enrolled in the Canadian Spine Outcomes Research Network registry with DCM were screened and 296 cervical spine MRIs acquired in cMRI were compared with 228 aMRI acquisitions. aMRI acquisitions consisted of diffusion tensor imaging, magnetization transfer, T 2 -weighted, and T 2 *-weighted images. The cMRI group consisted of only T 2 -weighted MRI scans. Various machine learning models were applied to both MRI groups to assess accuracy of prediction of baseline disease severity assessed clinically using the mJOA scale for cervical myelopathy., Results: Through the utilization of Random Forest Classifiers, disease severity was predicted with 41.8% accuracy in cMRI scans and 73.3% in the aMRI scans. Across different predictive model variations tested, the aMRI scans consistently produced higher prediction accuracies compared to the cMRI counterparts., Conclusions: aMRI metrics perform better in machine learning models at predicting disease severity of patients with DCM. Continued work is needed to refine these models and address DCM severity class imbalance concerns, ultimately improving model confidence for clinical implementation., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Drug-resistant infectious diseases pose a substantial challenge and threat to medical regimens. While adaptive laboratory evolution provides foresight for encountering such situations, it has inherent limitations. Novel drug delivery systems (DDSs) have garnered attention for overcoming these hurdles. Multi-stimuli responsive DDSs are particularly effective due to their reduced background leakage and targeted drug delivery to specific host sites for pathogen elimination. Bacterial infections create an acidic state in the microenvironment (pH: 5.0-5.5), which differs from normal physiological conditions (pH: 7.4). Infected areas are characterized by the overexpression of hyaluronidase, gelatinase, phospholipase, and other virulence factors. Consequently, several effective stimuli-responsive DDSs have been developed to target bacterial pathogens. Additionally, biofilms, structured communities of bacteria encased in a self-produced polymeric matrix, pose a significant challenge by conferring resistance to conventional antimicrobial treatments. Recent advancements in nano-drug delivery systems (nDDSs) show promise in enhancing antimicrobial efficacy by improving drug absorption and targeting within the biofilm matrix. nDDSs can deliver antimicrobials directly to the biofilm, facilitating more effective eradication of these resilient bacterial communities. Herein, this review examines challenges in DDS development, focusing on enhancing antibacterial activity and eradicating biofilms without adverse effects. Furthermore, advances in immune system modulation and photothermal therapy are discussed as future directions for the treatment of bacterial diseases.

Synthetic Notch (synNotch) receptors are genetically encoded, modular synthetic receptors that enable mammalian cells to detect environmental signals and respond by activating user-prescribed transcriptional programs. Although some materials have been modified to present synNotch ligands with coarse spatial control, applications in tissue engineering generally require extracellular matrix (ECM)-derived scaffolds and/or finer spatial positioning of multiple ligands. Thus, we develop here a suite of materials that activate synNotch receptors for generalizable engineering of material-to-cell signaling. We genetically and chemically fuse functional synNotch ligands to ECM proteins and ECM-derived materials. We also generate tissues with microscale precision over four distinct reporter phenotypes by culturing cells with two orthogonal synNotch programs on surfaces microcontact-printed with two synNotch ligands. Finally, we showcase applications in tissue engineering by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined micropatterns. These technologies provide avenues for spatially controlling cellular phenotypes in mammalian tissues., (© 2024. The Author(s).)

Background: Colon cancer, a prominent contributor to global cancer-related deaths, prompts the need for innovative treatment strategies. Euphorbia resinifera O. Berg (E. resinifera) and Euphorbia officinarum subsp. echinus Hook. f. & Coss Vindt (E. echinus) and their bee-derived products have been integral to traditional Moroccan medicine due to their potential health benefits. These plants have historical use in addressing various health issues, including cancer. However, their effects against colon cancer remain unclear, and the specific mechanisms underlying their anti-cancer effects lack comprehensive investigation., Methods: The study aimed to assess the potential anti-cancer effects of Euphorbia extract on colon cancer cell lines (DLD-1) through various techniques. The apoptosis, migration, and proliferation of DLD-1 cells were measured in DLD-1 cells. In addition, we conducted High-Performance Liquid Chromatography (HPLC) analysis to identify the profile of phenolic compounds present in the studied extracts., Results: The extracts demonstrated inhibition of colon cancer cell migration. E. resinifera flower and E. echinus stem extracts show significant anti-migratory effects. Regarding anti-proliferative activity, E. resinifera flower extract hindered proliferation, whereas E. echinus flower extract exhibited dose-dependent inhibition. Apoptosis assays revealed E. resinifera flower extract inducing early-stage apoptosis and E. echinus flower extract promoting late-stage apoptosis. While apoptotic protein expression indicated, E. resinifera stem and propolis extracts had minimal impact on apoptosis., Conclusion: The findings provide evidence supporting the beneficial effects of E resinifera and E. echinus extracts on colon cancer and exerting anti-cancer properties., (© 2024. The Author(s).)

Child physical abuse is a common cause of pediatric morbidity and mortality. Up to half of all children presenting with abusive injuries have a history of a prior suspicious injury, suggesting a pattern of repeated physical abuse. Medical providers are responsible for identifying children with suspicious injuries, completing mandated reporting to child protective services for investigation, and screening for occult injuries and underlying medical conditions that can predispose to injuries. Early identification of inflicted injuries appropriate evaluations may serve as an opportunity for life-saving intervention and prevent further escalation of abuse. However, identification of abuse can be challenging. This article will review both physical exam findings and injuries that suggest abuse as well as the evaluation and management of physical abuse., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Exposure to toxic molecules from food or oral medications induces toxicity in colon cells that cause various human diseases; however, in vitro monitoring systems for colon cell toxicity are not well established. Stress granules are nonmembranous foci that form in cells exposed to cellular stress. When cells sense toxic environments, they acutely and systemically promote stress granule formation, with Ras GTPase-activating protein-binding protein 1 (G3BP1) acting as a core component to protect their mRNA from abnormal degradation. Here, we knocked in green fluorescent protein (GFP)-coding sequences into the C-terminal region of the G3BP1 gene in a human colon cell line through CRISPR-Cas9-mediated homologous recombination and confirmed the formation of stress granules with the G3BP1-GFP protein in these cells under cellular stress exposure. We demonstrated the formation and dissociation of stress granules in G3BP1-GFP expressing colon cells through real-time monitoring using a fluorescence microscope. Furthermore, we validated the toxicity monitoring system in the established colon cell line by observing stress granule formation following exposure to dihydrocapsaicin, bisphenol A, and sorbitol. Taken together, we established a stress granule reporter system in a colon cell line, providing a novel assessment for the real-time monitoring of colon toxicity in response to various chemicals., Competing Interests: The authors report no declarations of interest., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

For pre-procedural planning of left atrial appendage (LAA) closure, sizing is crucial. Although transesophageal echocardiography (TEE) is a standard modality, cardiac computed tomography (CT) is also widely used. The virtual TEE (V-TEE) that our group developed enables us to reconstruct images similar to TEE images from CT images. The software should be helpful to understand and plan the procedure strategy. Accordingly, we investigated the utility of V-TEE. Sixty-six patients at 4 participating sites who completed both CT and TEE prior to LAA closure were included. The LAA diameter at the landing zone (LZ) for WATCHMAN™ device implantation was statistically compared at 0°, 45°, 90°, and 135° between V-TEE and TEE. Among 66 cases, only 3 cases were excluded due to poor imaging quality, and 63 cases were analyzed. The device LZ diameters based on V-TEE were strongly correlated with those based on TEE, despite the significantly greater diameter based on V-TEE with mean differences of 2.4 to 3.0 mm (all of them: P < 0.001). The discordances (V-TEE/TEE ratio) at most angles were significantly larger in the elliptical LAAs. V-TEE provides a valuable method for the evaluation of the LAA diameters. V-TEE-based measurements were larger than conventional TEE-based measurements, especially in cases of elliptical LAAs. The assessment by V-TEE has the potential benefit of ensuring proper device sizing regardless of the LAA morphology., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The ring finger protein 113A (RNF113A) serves as an E3 ubiquitin ligase and a subunit of the spliceosome. Mutations in the RNF113A gene are associated with X-linked trichothiodystrophy (TTD). However, the cellular roles of RNF113A remain largely unknown. In this study, we performed transcriptome profiling of RNF113A knockout (KO) HeLa cells using RNA sequencing and revealed the upregulation of NRF2 pathway-associated genes. Further analysis confirmed that the KO of RNF113A promotes nuclear localization of the NRF2 protein and elevates the mRNA levels of NRF2 target genes. RNF113A KO cells showed high levels of intracellular reactive oxygen species (ROS) and decreased resistance to cell death following H 2 O 2 treatment. Additionally, RNF113A KO cells more sensitively formed stress granules (SGs) under arsenite-induced oxidative stress. Moreover, RNF113A KO cells exhibited a decrease in glutathione levels, which could be attributed to a reduction in GLUT1 expression levels, leading to decreased glucose uptake reactions and lower intracellular glucose levels. These alterations potentially caused a reduction in ROS scavenging activity. Taken together, our findings suggest that the loss of RNF113A promotes oxidative stress-mediated activation of the NRF2 pathway, providing novel insights into RNF113A-associated human diseases., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Purpose: To investigate the association of mammographic breast density with treatment and survival outcomes in patients with triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy (NAC)., Methods: This retrospective study evaluated 306 women with TNBC who underwent NAC followed by surgery between 2010 and 2019. The baseline density and the density changes after NAC were evaluated. Qualitative breast density (a-d) was evaluated using the Breast Imaging Reporting and Data System. Quantitative breast density (%) was evaluated using fully automated software (the Laboratory for Individualized Breast Radiodensity Assessment) in the contralateral breast. Multivariable logistic regression analysis was used to evaluate the association between breast density and pathologic complete response (pCR), stratified by menopausal status. Cox proportional hazard regression analysis was used to evaluate the association among breast density, the development of contralateral breast cancer, and the development of locoregional recurrence and/or distant metastasis., Results: Contralateral density reduction ≥10 % was independently associated with pCR in premenopausal women (odds ratio [OR], 2.5; p = 0.022) but not in postmenopausal women (OR, 0.9; p = 0.823). During a mean follow-up of 65 months, 10 (3 %) women developed contralateral breast cancer, and 68 (22 %) women developed locoregional recurrences and/or distant metastases. Contralateral density reduction ≥10 % showed no association with the occurrence of contralateral breast cancer (hazard ratio [HR], 3.1; p = 0.308) or with locoregional recurrence and/or distant metastasis (HR, 1.1; p = 0.794)., Conclusion: In premenopausal women, a contralateral breast density reduction of ≥10 % after NAC was independently associated with pCR, although it did not translate into improved outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This work developed Acer tegmentosum extract-mediated silver nanoparticles (AgNPs) loaded chitosan (CS)/alginic acid (AL) scaffolds (CS/AL-AgNPs) to enhance the healing of E. coli-infected wounds. The SEM-EDS and XRD results revealed the successful formation of the CS/AL-AgNPs. FTIR analysis evidenced that the anionic group of AL (-COO-) and cationic amine groups of CS (-NH 3 + ) were ionically crosslinked to form scaffold (CS/AL). The CS/AL-AgNPs exhibited significant antimicrobial activity against both Gram-positive (G+) and Gram-negative (G-) bacterial pathogens, while being non-toxic to red blood cells (RBCs), the hen's egg chorioallantoic membrane (HET-CAM), and a non-cancerous cell line (NIH3T3). Treatment with CS/AL-AgNPs significantly accelerated the healing of E. coli-infected wounds by regulating the collagen deposition and blood parameters as evidenced by in vivo experiments. Overall, these findings suggest that CS/AL-AgNPs are promising for the treatment of infected wounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Compared to other organs, the brain has limited antioxidant defenses. In particular, the hippocampus is the central region for learning and memory and is highly susceptible to oxidative stress. Glial cells are the most abundant cells in the brain, and sustained glial cell activation is critical to the neuroinflammation that aggravates neuropathology and neurotoxicity. Therefore, regulating glial cell activation is a promising neurotherapeutic treatment. Quinic acid and its derivatives possess anti-oxidant and anti-inflammatory properties. Although previous studies have evidenced quinic acid's benefit on the brain, in vivo and in vitro analyses of its anti-oxidant and anti-inflammatory properties in glial cells have yet to be established. This study investigated quinic acid's rescue effect in lipopolysaccharide (LPS)-induced behavior impairment. Orally administering quinic acid restored social impairment and LPS-induced spatial and fear memory. In addition, quinic acid inhibited proinflammatory mediator, oxidative stress marker, and mitogen-activated protein kinase (MAPK) activation in the LPS-injected hippocampus. Quinic acid inhibited nitrite release and extracellular signal-regulated kinase (ERK) phosphorylation in LPS-stimulated astrocytes. Collectively, quinic acid restored impaired neuroinflammation-induced behavior by regulating proinflammatory mediator and ERK activation in astrocytes, demonstrating its potential as a therapeutic agent for neuroinflammation-induced brain disease treatments.

A novel, oral phosphodiesterase 4 (PDE4) inhibitor, ME3183, is under development for the treatment of psoriasis, atopic dermatitis, and other inflammatory diseases. To evaluate its safety, tolerability, and pharmacokinetics, double-blind, placebo-controlled, single ascending dose (SAD), and multiple ascending dose (MAD) phase 1 studies were conducted in 126 healthy adults. The food effect was evaluated in a randomized, open-label, crossover manner (n = 5). ME3183 was safe and tolerable up to 25 mg in the SAD part and up to 10 mg twice daily in the MAD part. Frequently observed treatment-emergent adverse events included diarrhea and headache, as commonly reported for approved PDE4 inhibitors, providing no novel safety concerns. Pharmacokinetic analysis showed dose-dependent increases in C max and AUC, with later t max and longer t 1/2 than apremilast, an approved PDE4 inhibitor. The food effect study showed slightly decreased systemic exposure. In the MAD part, plasma exposure levels of ME3183 were higher even at the minimal dose (2.5 mg twice daily) than the estimated therapeutically effective level. These results show the safe profile of ME3183 and support further studies to confirm the safety and efficacy of the drug in patients with psoriasis and other inflammatory diseases., (© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The colonization of pathogenic microbes poses a significant clinical barrier that hinders the physiological wound-healing process. Addressing this challenge, we developed a novel wound dressing using a modified cotton gauze dressing coated with fucoidan and functionalized with silver nanoparticles (LB-Ag NPs-FN-OCG) for the rapid treatment of infected wounds. Firstly, phytochemical-capped LB-Ag NPs were synthesized and characterized using high performance liquid chromatography (HPLC), transmission electron microscopy (TEM), and zeta potential analysis. Secondly, different concentrations of LB-Ag NPs (0.1%-1%) were functionalized into FN-OCG to identify appropriate concentrations that were non-toxic with superior antibacterial activities. Screening assays, including antibacterial, hemolysis, chick chorioallantoic membrane (CAM) assay, and cytotoxicity assay, revealed that LB-Ag NPs (0.5%)-FN-OCG were non-toxic and demonstrated greater efficiency in inhibiting bacterial pathogens (Escherichia coli, Salmonella enterica, Staphylococcus aureus, and Listeria monocytogenes) and promoting fibroblast cell (NIH3T3) migration. In vivo assays revealed that LB-Ag NPs (0.5%)-FN-OCG treatment exhibited excellent wound healing activity (99.73 ± 0.01%) compared to other treatments by inhibiting bacterial colonization, maintaining the blood parameters, developing granulation tissue, new blood vessels, and collagen deposition. Overall, this study highlights that LB-Ag NPs (0.5%)-FN-OCG serve as a antibacterial wound dressing for infected wound healing applications., 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 © 2023 Elsevier Inc. All rights reserved.)

Background: While breast ultrasound (US) is a useful tool for diagnosing breast masses, it can entail false-positive biopsy results because of some overlapping features between benign and malignant breast masses and subjective interpretation., Purpose: To evaluate the performance of conductivity imaging for reducing false-positive biopsy results related to breast US, as compared to diffusion-weighted imaging (DWI) and abbreviated MRI consisting of one pre- and one post-contrast T1-weighted imaging., Study Type: Prospective., Subjects: Seventy-nine women (median age, 44 years) with 86 Breast Imaging Reporting and Data System (BI-RADS) category 4 masses as detected by breast US., Field Strength/sequence: 3-T, T2-weighted turbo spin echo sequence, DWI, and abbreviated contrast-enhanced MRI (T1-weighted gradient echo sequence)., Assessment: US-guided biopsy (reference standard) was obtained on the same day as MRI. The maximum and mean conductivity parameters from whole and single regions of interest (ROIs) were measured. Apparent diffusion coefficient (ADC) values were obtained from an area with the lowest signal within a lesion on the ADC map. The performance of conductivity, ADC, and abbreviated MRI for reducing false-positive biopsies was evaluated using the following criteria: lowest conductivity and highest ADC values among malignant breast lesions and BI-RADS categories 2 or 3 on abbreviated MRI., Statistical Tests: One conductivity parameter with the maximum area under the curve (AUC) from receiver operating characteristics was selected. A P-value <0.05 was considered statistically significant., Results: US-guided biopsy revealed 65 benign lesions and 21 malignant lesions. The mean conductivity parameter of the single ROI method was selected (AUC = 0.74). Considering conductivity (≤0.10 S/m), ADC (≥1.60 × 10 -3  mm 2 /sec), and BI-RADS categories 2 or 3 reduced false-positive biopsies by 23% (15 of 65), 38% (25 of 65), and 43% (28 of 65), respectively, without missing malignant lesions., Data Conclusion: Conductivity imaging may show lower performance than DWI and abbreviated MRI in reducing unnecessary biopsies., Evidence Level: 2 TECHNICAL EFFICACY: Stage 2., (© 2023 International Society for Magnetic Resonance in Medicine.)

Helminth infections and their components has been recognized to have a positive impact on the immune system. This study aimed to investigate the potential of Metagonimus yokogawai-derived proteins (MYp) to provide protection against ankylosing spondylitis (AS) through modulation of immune responses. The cytotoxicity of MYp at various doses was first assessed using MTS and flow cytometry. Peripheral blood mononuclear cells (PBMCs) were collected from AS patients, and the production of inflammatory cytokines was analyzed through flow cytometry. In the experiments with SKG mice, MYp or vehicle was administered and inflammation was evaluated through immunohistochemistry and enzyme-linked immunosorbent assay. The results showed that MYp did not decrease cell viability of PBMCs even after 48 h. Additionally, the frequencies of IFN-γ and IL-17A producing cells were significantly reduced after MYp treatment in the PBMC cultures. Furthermore, MYp treatment significantly suppressed arthritis and enthesitis in the SKG mouse model. The results suggest the first evidence that MYp can effectively alleviate clinical symptoms and restore cytokine balance in patients with AS., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Childhood trauma and interpersonal sensitivity impact the development of mood disorders. In this study, we investigate the association between childhood trauma and interpersonal sensitivity in patients with mood disorders. A total 775 patients (major depressive disorder [MDD, n = 241], bipolar I disorder [BD I, n = 119], and bipolar II disorder [BD II, n = 415]) and 734 controls. For evaluation, we used the Childhood Trauma Questionnaire-Short Form (CTQ) and Interpersonal Sensitivity Measure (IPSM). We examined between-group differences for each subscale in the CTQ and IPSM. Patients with BD II had significantly higher IPSM total scores than patients with MDD, BD I, or controls. The CTQ total score was related to the IPSM total score in all participants and subgroups. Among the CTQ subscales, emotional abuse showed the highest correlation with the IPSM total score, while separation anxiety and fragile inner self showed higher positive correlations with CTQ than the other subscales of IPSM in all patient groups and the control group, respectively. The findings reveal that childhood trauma and interpersonal sensitivity are positively correlated among patients with MDD, BD I, and BD II, and that interpersonal sensitivity is higher in patients with BD II than those with BD I or MDD. Childhood trauma is associated with interpersonal sensitivity, and each trauma type has a different impact on mood disorders. We expect that this study will encourage future research on interpersonal sensitivity and childhood trauma in mood disorders to improve treatment approaches., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

LMTK3 is a brain-specific transmembrane serine/threonine protein kinase that acts as a scaffold for protein phosphatase-1 (PP1). Although LMKT3 has been identified as a risk factor for autism and epilepsy, its physiological significance is unknown. Here, we demonstrate that LMTK3 copurifies and binds to KCC2, a neuron-specific K + /Cl - transporter. KCC2 activity is essential for Cl - -mediated hyperpolarizing GABA A R receptor currents, the unitary events that underpin fast synaptic inhibition. LMTK3 acts to promote the association of KCC2 with PP1 to promote the dephosphorylation of S940 within its C-terminal cytoplasmic domain, a process the diminishes KCC2 activity. Accordingly, acute inhibition of LMTK3 increases KCC2 activity dependent upon S940 and increases neuronal Cl - extrusion. Consistent with this, LMTK3 inhibition reduced intrinsic neuronal excitability and the severity of seizure-like events in vitro . Thus, LMTK3 may have profound effects on neuronal excitability as an endogenous modulator of KCC2 activity., Competing Interests: The authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Inc.)

Conducting precise electronic-vibrational dynamics simulations of molecular systems poses significant challenges when dealing with realistic environments composed of numerous vibrational modes. Here, we introduce a technique for the construction of effective phonon spectral densities that capture accurately open-system dynamics over a finite time interval of interest. When combined with existing nonperturbative simulation tools, our approach can reduce significantly the computational costs associated with many-body open-system dynamics.

Dichlorvos (2,2-Dichlorovinyl dimethyl phosphate, [DDVP]) belongs to the class of organophosphates and is widely used as an insecticide in agriculture farming and post-harvest storage units. Extensive research has been conducted to assess the factors responsible for the presence of DDVP in terrestrial and aquatic ecosystems, as well as the entire food chain. Numerous studies have demonstrated the presence of DDVP metabolites in the food chain and their toxicity to mammals. These studies emphasize that both immediate and chronic exposure to DDVP can disrupt the host's homeostasis, leading to multi-organ damage. Furthermore, as a potent carcinogen, DDVP can harm aquatic systems. Therefore, understanding the contamination of DDVP and its toxicological effects on both plants and mammals is vital for minimizing potential risks and enhancing safety in the future. This review aimed to comprehensively consolidate information about the distribution, ecological effects, and health impacts of DDVP, as well as its metabolism, detection, prevention, and remediation strategies. In summary, this study observes the distribution of DDVP contaminations in vegetables and fruits, resulting in significant toxicity to humans. Although several detection and bioremediation strategies are emerging, the improper application of DDVP and the alarming level of DDVP contamination in foods lead to human toxicity that requires attention., 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 © 2023. Published by Elsevier Inc.)

Purpose: Advances in chemotherapeutic and targeted agents have increased pathologic complete response (pCR) rates after neoadjuvant systemic therapy (NST). Vacuum-assisted biopsy (VAB) has been suggested to accurately evaluate pCR. This study aims to confirm the non-inferiority of the 5-year disease-free survival of patients who omitted breast surgery when predicted to have a pCR based on breast magnetic resonance imaging (MRI) and VAB after NST, compared with patients with a pCR who had undergone breast surgery in previous studies., Methods: The Omission of breast surgery for PredicTed pCR patients wIth MRI and vacuum-assisted bIopsy in breaST cancer after neoadjuvant systemic therapy (OPTIMIST) trial is a prospective, multicenter, single-arm, non-inferiority study enrolling in 17 tertiary care hospitals in the Republic of Korea. Eligible patients must have a clip marker placed in the tumor and meet the MRI criteria suggesting complete clinical response (post-NST MRI size ≤ 1 cm and lesion-to-background signal enhancement ratio ≤ 1.6) after NST. Patients will undergo VAB, and breast surgery will be omitted for those with no residual tumor. Axillary surgery can also be omitted if the patient was clinically node-negative before and after NST and met the stringent criteria of MRI size ≤ 0.5 cm. Survival and efficacy outcomes are evaluated over five years., Discussion: This study seeks to establish evidence for the safe omission of breast surgery in exceptional responders to NST while minimizing patient burden. The trial will address concerns about potential undertreatment due to false-negative results and recurrence as well as improved patient-reported quality of life issues from the omission of surgery. Successful completion of this trial may reshape clinical practice for certain breast cancer subtypes and lead to a safe and less invasive approach for selected patients., Trial Registration: ClinicalTrials.gov Identifier: NCT05505357. Registered on August 17, 2022. Clinical Research Information Service Identifier: KCT0007638. Registered on July 25, 2022., Competing Interests: Jiwon Koh reported receiving consultation fees from DCGen. Co., Ltd., outside the submitted work. Hee-Chul Shin, Wonshik Han, and Han-Byoel Lee reported being member of the board of directors of and holding stock and ownership interests at DCGen, Co, Ltd., outside the submitted work. Han-Byoel Lee reported receiving grants in the form of Mammotome® Elite needles from Devicor Medical Products, Inc. for this work. The grant source had no part in the design and preparation of the protocol. No other disclosures were reported., (© 2024 Korean Breast Cancer Society.)

Ethnopharmacological Relevance: Naringenin (NGN) is a widely distributed flavonoid with potent antioxidant and neuroprotective properties. Neuroprotective agents play a crucial role in the treatment of hypoxic-ischemic encephalopathy (HIE). It has shown potential therapeutic effects for neurological disorders. However, its efficacy on HIE is yet to be investigated., Aim of the Study: This study aims to investigate the potential neuroprotective effect of naringenin and its underlying molecular mechanisms in reducing oxidative stress, apoptosis, and improving brain outcomes following HIE. Additionally, the study aims to identify the potential targets, mechanisms, and functions of naringenin using network pharmacology analysis., Materials and Methods: Neonatal mice were exposed to the hypoxic-ischemic brain damage (HIBD) model to determine brain water content, and brain tissue was subjected to hematoxylin and eosin (HE), immunohistochemistry (IHC), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and Nissl staining to investigate its neuroprotective effects. Furthermore, the neonatal mouse primary neuron oxygen-glucose deprivation (OGD) model to measure reactive oxygen species (ROS) production in vitro. The protein levels were characterized by Western Blot, and mRNA levels were evaluated by a real-time quantitative PCR detecting system (qPCR). Transmission electron microscopy (TEM) and mitochondrial fluorescent staining were used to observe mitochondrial morphology. Neuronal nuclei (NeuN) and microtubule-associated protein 2 (MAP2) were detected by Immunofluorescence (IF). Finally, network pharmacology was employed to determine the common target of naringenin and HIE. The core genes were obtained via protein-protein interaction networks (PPI) analysis and molecular docking was examined, and the mechanism of action was explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, small interfering RNA (siRNA) was constructed for verification., Results: Naringenin has a neuroprotective effect in HIBD by modulating Vegfa expression and activating the PI3K/AKT pathway to inhibit apoptosis. Furthermore, molecular docking results suggest that Vegfa is a potential binding target of naringenin, and silencing Vegfa partially reverses the pharmacological effects of NGN., Conclusion: Our findings suggest that naringenin demonstrates potential clinical application for treating HIE as a novel neuroprotective agent., 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 © 2023 Elsevier B.V. All rights reserved.)

Phosphodiesterase 4 (PDE4) inhibitors are expected to exhibit efficacy against inflammatory diseases due to their broad pharmacological activity. The launched PDE4 inhibitors apremilast, crisaborole, and roflumilast have not exhibited sufficient inhibitory potential due to poor margins of effectiveness and tolerability. In this report, we describe the non-clinical efficacy, brain translocation, and vomit-inducing effects of ME3183 compared with apremilast. ME3183 showed extensive cytokine suppression in vitro studies using human peripheral blood mononuclear cells and T cells. ME3183 also significantly suppressed skin inflammation in a chronic oxazolone-induced dermatitis model and showed antipruritic effects in a substance P-induced mouse pruritus model. In these in vitro and in vivo studies, ME3183 also significantly suppressed cytokines, and focusing on tumor necrosis factor-α as a psoriasis-related cytokine and interleukin-4 as an atopic dermatitis-related cytokine, ME3183 potently inhibited both cytokines. ME3183 showed in vivo efficacy at lower doses than apremilast. The brain distribution of ME3183 was sufficiently low in mice and rats. The effective dose of ME3183 for emesis was similar to that of apremilast in ferrets. Given its high-potency inhibitory effects, ME3183 would have a wide margin of efficacy and tolerability. These wide margins demonstrate the effectiveness of ME3183 in treating many inflammatory diseases, such as psoriasis and atopic dermatitis. An on-going phase 2 trial is expected to further demonstrate the efficacy and safety of ME3183., Competing Interests: Declaration of competing interest All authors are employees of Meiji Seika Pharma Co., Ltd., (Copyright © 2023 Meiji Seika Pharma Co., Ltd. Published by Elsevier B.V. All rights reserved.)