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Sook Joung Lee,1,* Min Kyu Park,2,* Dong-Seong Shin,3 Min Ho Chun4 1Department of Physical Medicine and Rehabilitation, Dong-A University College of Medicine, Dong-A University Hospital, 2Department of Pharmacology and Clinical Pharmacology, Dong-A University College of Medicine, Dong-A University Hospital, Busan, 3Clinical Trials Center, Gachon University Gil Medical Center, Incheon, 4Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea *These authors contributed equally to this work Purpose: Cyclooxygenase (COX) is the main pharmacodynamic target of nonsteroidal anti-inflammatory drugs (NSAIDs). We investigated the inhibitory effects on COX-2 after NSAIDs administration using a lipopolysaccharide (LPS)-derived COX-2 induction model in whole blood, according to the genotypes of COX-2 single-nucleotide polymorphisms (SNPs). Patients and methods: Seven genotypes of COX-2 SNPs were selected from public databases and analyzed in 324 healthy subjects. Two genotypes showing a high percentage of variability were selected. A clinical trial examining pharmacodynamics according to the genotype of two SNPs (rs5275 and rs689466) was conducted. Twenty subjects were administered a single oral dose of 200 mg of celecoxib, and pharmacokinetic and pharmacodynamic analyses were performed. Results: In the analysis of the pharmacokinetic parameters, significant differences in drug exposure were not investigated for each SNP genotype. The pharmacodynamic analysis revealed that the maximum effect of COX-2 inhibition was achieved at 2.0 hours for all genotypes of COX-2 SNPs after a single oral administration of 200 mg celecoxib. The inhibitory effects according to the genotype of COX-2 SNPs were investigated, and the area under the effect curve of the rs689466 GG genotype was significantly lower than that for the AA or AG genotype. Conclusion: Our results demonstrated that inhibitory effects of celecoxib on COX-2 induction were different according to the genotype of COX-2 SNPs. In the present study, rs689466 is responsible for the variability of the response to celecoxib, suggesting that a subject with the GG genotype of rs689466 would be more responsive to celecoxib in terms of COX-2 inhibition. Keywords: nonsteroidal anti-inflammatory agent, cyclooxygenase-2, single-nucleotide polymorphism, drug response, pharmacodynamics, clinical trial

Three cell types including bovine pulmonary artery endothelium cells (CPAE), rat kangaroo kidney cells (PTK2), and human larynx epidermoid carcinoma cells (Hep-2) were used to study subcellular localisation and phototoxicity of Photofrin-II and lutetium texaphyrin (Lu Tex). Cells were examined for fluorescence after administration of the photosensitisers. Subcellular regions were exposed with a laser microbeam system that used an argon ion laser pumped dye laser generating a 630 nm for Photofrin-II and 730 nm for Lu Tex. Fluorescence detection suggests that the Photofrin-II is bound primarily to the mitochondria with some diffuse fluorescence in the rest of the cytoplasm. The fluorescence in Lu Tex treated cells appears to be localised to the lysosomes. The percentage of damaged cells following light exposure to the different subcellular regions after Photofrin-II or Lu Tex treatment demonstrates that the nuclear region was the most sensitive target followed by the perinuclear region and peripheral cytoplasm region.

Objective: To identify CT findings predictive of surgical management in non-emergency small bowel obstruction (SBO).Methods: Contrast-enhanced abdominal CT of 129 patients with non-emergency SBO were evaluated for small bowel luminal diameter, wall thickness, presence of the small bowel faeces sign (intraluminal particulate matter in a dilated small bowel) and length, transition point, submucosal oedema, mesenteric stranding, ascites and degree of obstruction (low grade partial, high grade partial and complete obstruction). Medical records were reviewed for age, gender, management and history of abdominal surgery, abdominal malignancy, or SBO. Statistical analyses were performed with Stata Release 9.2.Results: Degree of obstruction was the only predictor of need for surgery. Whereas 18.0% of patients with low-grade partial obstruction (n = 50) underwent surgery, 32.5% of patients with high-grade partial obstruction (n = 77) and 100% of patients with complete obstruction (n = 2) required surgery (P = 0.004). The small bowel faeces sign was inversely predictive of surgery (P = 0.018).Conclusion: In non-emergency SBO patients with contrast-enhanced CT imaging, grade of obstruction predicts surgery, while the small bowel faeces sign inversely predicts need for surgery. [ABSTRACT FROM AUTHOR]

Objective: Most of the current clinical data on the role of 2-[(18)F]fluoro-2-deoxy-D -glucose positron emission tomography ((18)F-FDG-PET) in musculoskeletal tumors come from patients studied with PET and less frequently with hardware fusion PET/computed tomography (CT). And the number of cases in each report is too small to clarify the exact clinical efficacy of PET or PET/CT. This prompted us to analyze our experience with (18)F-FDG-PET/CT in a relatively large group of patients with musculoskeletal tumors. Methods: (18)F-FDG-PET/CT was performed on 91 patients from May 2004 to June 2007. The final diagnosis was obtained from surgical biopsy in 83 patients (91%) and clinical follow-up in 8 (9%). We analyzed the characteristics and amount of (18)F-FDG uptake in soft tissue and bone tumors, and investigated the ability of (18)F-FDG-PET/CT to differentiate malignant from benign tumors. The cutoff maximum standardized uptake value (SUV(max)) was calculated using the receiver-operation characteristic curve method. Sensitivity, specificity, and diagnostic accuracy were calculated with cutoff SUV(max) and the final diagnosis. Unpaired t test was used for the statistical analysis. Results: Final diagnosis revealed 19 benign soft tissue tumors (mean SUV(max) 4.7), 27 benign bone tumors (5.1), 25 malignant soft tissue tumors (8.8), and 20 malignant bone tumors (10.8). There was a significant difference in SUV(max) between benign and malignant musculoskeletal tumors in total (P < 0.002), soft tissue tumors (P < 0.05), and bone tumors (P < 0.02). Sensitivity, specificity, and diagnostic accuracy were 80%, 65.2%, and 73% in total with cutoff SUV(max) 3.8, 80%, 68.4%, and 75% in the soft tissue tumors with cutoff SUV(max) 3.8, and 80%, 63%, and 70% in the bone tumors with cutoff SUV(max) 3.7. Conclusions: (18)F-FDG-PET/CT reliably differentiated malignant soft tissue and bone tumors from benign ones, although there were many false-positive and false negative lesions. Further studies with all kinds of musculoskeletal tumors in large numbers are needed to improve the diagnostic accuracy of (18)F-FDG-PET/CT. [ABSTRACT FROM AUTHOR]

Motile cilia are crucial for maintaining healthy bodily functions by facilitating fluid transport and removing foreign substances or debris from the body. The dysfunction of motile cilia leads to ciliopathy. In particular, damage to the motile cilia of the airways can cause or worsen respiratory disease, making it an attractive target for therapeutic interventions. However, there are no treatments to induce motile ciliogenesis. Forkhead box transcription factor J1 (FOXJ1), the master regulator, has been implicated in motile cilia formation. Mice lacking the Foxj1 gene show loss of axoneme, a key component of cilia, that further highlights the importance of FOXJ1 in motile cilia formation. This prompted us to identify new small molecules that could induce motile ciliogenesis. A phenotype-based high-throughput screening (HTS) in a Tg(foxj1a:eGFP) zebrafish model was performed and a novel hit compound was identified. Among the synthesized compounds, compound 16c effectively enhanced motile ciliogenesis in a transgenic zebrafish model. To further test the efficacy of compound 16c on a mammalian airway system consisting of multiciliated cells (MCCs), ex vivo mice tracheal epithelial cell culture was adopted under an air-liquid interface system (ALI). Compound 16c significantly increased the number of MCCs by enhancing motile ciliogenesis. In addition, compound 16c exhibited good liver microsomal stability, in vivo PK profiles with AUC, and oral bioavailability. There was no significant inhibition of CYP and hERG, and no cell cytotoxicity was shown. In an elastase-induced COPD (chronic obstructive pulmonary disease) mouse model, compound 16c effectively prevented the development and onset of COPD. Taken together, compound 16c has great promise as a therapeutic agent for treating and alleviating motile ciliopathies., 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 Masson SAS. All rights reserved.)

Hepatic dysregulation of lipid metabolism exacerbates inflammation and enhances the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). STAT3 has been linked to lipid metabolism and inflammation. Jolkinolide B (JB), derived from Euphorbia fischeriana , is known for its pharmacological anti-inflammatory and anti-tumor properties. Therefore, this study investigated whether JB affects MASLD prevention by regulating STAT3 signaling. JB attenuated steatosis and inflammatory responses in palmitic acid (PA)-treated hepatocytes. Additionally, JB treatment reduced the mRNA expression of de-novo lipogenic genes, such as acetyl-CoA carboxylase and stearoyl-CoA desaturase 1. Interestingly, JB-mediated reduction in inflammation and lipogenesis was dependent on STAT3 signaling. JB consistently modulated mitochondrial dysfunction and the mRNA expression of inflammatory cytokines by inhibiting PA-induced JAK/STAT3 activation. This study suggests that JB is a potential therapeutic agent to prevent major stages of MASLD through inhibition of JAK/STAT3 signaling in hepatocytes.

As chronic inflammation and oxidative stress cause various diseases in the human body, this study aimed to develop functional materials to prevent inflammation and oxidative stress. This study investigated the biological function and components of Terminalia catappa L. extract prepared using its leaves and branches (TCE). TCE was determined using ultraperformance liquid chromatography-quadrupole-time-of-flight mass spectrometry. Using RAW 264.7 mouse macrophages, inhibitory effects of the identified compounds on nitric oxide (NO) and reactive oxygen species (ROS) generation were analyzed. Therefore, α-punicalagin was selected as an active compound with the highest content (986.6 ± 68.4 μg/g) and physiological activity. TCE exhibited an inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory markers, including NO, inducible nitric oxide synthase, and inflammatory cytokines without exerting cytotoxicity. Moreover, TCE prevented excessive ROS production mediated by LPS and upregulated hemeoxygenase-1 expression via the nuclear translocation of nuclear factor erythroid 2-related factor 2. Interestingly, TCE prevented LPS-induced mitochondrial membrane potential loss, mitochondrial ROS production, and dynamin-related protein 1 phosphorylation (serine 616), a marker of abnormal mitochondrial fission. Furthermore, TCE considerably repressed the activation of LPS-induced mitogen-activated protein kinase pathway. Thus, TCE is a promising anti-inflammatory and antioxidant pharmaceutical or nutraceutical, as demonstrated via mitochondrial dysfunction and cellular signaling pathway regulation.

Purpose: The Protrieve Sheath (Inari Medical; Irvine, CA) is designed for embolic protection during venous thrombectomy. This report describes experience with its use., Materials and Methods: Between November 2022 and December 2023 (13 months), seventeen patients, including nine (52.9%) females and eight (47.1%) males (mean age 58.8 ± 13.3 years, range 37-81 years), underwent deep venous thrombectomy following the Protrieve Sheath placement for embolic protection. Gender, age, presenting symptoms, procedural indications, obstructed venous segments, the Protrieve Sheath access and deployment sites, thrombectomy devices utilized, need for stent reconstruction, technical success, clinical success, adverse events (the Protrieve Sheath maldeployment or clinically significant embolic events), removed thrombi analyses, and mortality were recorded. Technical success was defined as successful deployment of the Protrieve Sheath funnel central to the thrombectomy site. Clinical success was defined as improvement in presenting venous occlusive symptoms without procedure-related venous thromboembolism., Results: The most common presenting symptom was extremity swelling (n = 15; 88.2%). Nine (52.9%) patients had malignant and eight (47.1%) had benign etiologies of venous obstruction. Obstructed venous segments included the inferior vena cava (IVC) and lower extremity (n = 9; 52.9%), isolated lower extremity (n = 4; 23.5%), isolated IVC (n = 2; 11.8%), thoracic central veins and superior vena cava (n = 1; 5.9%), and isolated thoracic central vein (n = 1; 5.9%). The Protrieve Sheath access sites included the right internal jugular vein (n = 15; 88.2%) for IVC and lower extremity obstructions and the right common femoral vein (n = 2; 11.8%) for thoracic central vein and superior vena cava obstructions. The Protrieve sheath funnel deployment locations included intrahepatic IVC in 13 patients (n = 13; 76.5%), suprarenal IVC in two (n = 2; 11.8%), and inferior cavoatrial junction in two (n = 2; 11.8%). Thrombectomy devices used included the ClotTriever System (Inari Medical) (n = 15; 88.2%), the InThrill Thrombectomy System (Inari Medical) (n = 4; 23.5%), the FlowTriever System (Inari Medical) (n = 2; 11.8%), the Lightning Flash 16 Aspiration System (Penumbra; Salt Lake City, UT) (n = 2; 11.8%), the Cleaner Rotational Thrombectomy System (Argon; Plano, TX) (n = 1; 5.9%), and the RevCore Thrombectomy System (Inari Medical) (n = 1; 5.9%). Ten (58.8%) patients required stent reconstruction following thrombectomy. Technical success was achieved in all patients. Clinical success was achieved in 16 (94.1%) patients. No immediate adverse events, including the Protrieve Sheath maldeployment or clinically significant embolic events, occurred., Conclusion: Use of the Protrieve Sheath during large-bore venous mechanical thrombectomy resulted in favorable technical and clinical outcomes without device-related adverse events or clinically significant thromboembolic events., (© 2024. The Author(s).)

Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases., (© 2024. The Author(s).)

Background: There is a clinical need to omit axillary lymph node dissection (ALND) when residual disease in sentinel lymph nodes (SLNs) is low after neoadjuvant chemotherapy (NAC). This study aimed to clarify the relationship between micrometastasis in SLNs after NAC and additional non-SLN metastases by analyzing SLN biopsy results followed by ALND., Methods: This retrospective study reviewed clinical records of patients who underwent breast cancer surgery between January 2010 and June 2022 after NAC at Samsung Medical Center. Of 3944 patients, 806 underwent SLN biopsy followed by ALND. Intraoperative frozen SLN biopsy results were examined, including the number and size of metastases in SLNs, and further investigated the number of additional non-SLN metastases., Results: Among the 806 patients, 95 (11.8%) had micrometastasis on SLNs in frozen sections, of which 89 (93.7%) had clinically node-positive (cN1-3) breast cancer before NAC. Twenty-three patients (24.2%) exhibited positive additional non-SLNs after ALND. The presence of lymphovascular invasion (vs. absence; odds ratio [OR] = 4.02, p = .0151) and having two or more SLNs with micrometastasis (vs. a positive SLN; OR = 3.65, p = .0301) were significantly associated with additional non-SLN metastases. Tumor subtypes and breast pathological complete response after NAC showed no correlation with the additional non-SLN metastases., Conclusion: The study identified a 24.2% possibility of additional non-SLN metastasis if micrometastases was detected in the SLN after NAC. This rate is significant, indicating that ALND cannot be omitted if low volume residual disease, such as micrometastasis, is identified in the SLN after NAC., (© 2024 American Cancer Society.)

Purpose: To report antegrade transvenous obliteration, with or without concurrent portosystemic shunt creation, for the treatment of hemorrhagic rectal varices., Materials and Methods: Eight patients, including five (62.5%) females and three (37.5%) males, with mean age of 55.8 ± 13.8 years (range: 30-70 years), underwent transjugular-approach antegrade transvenous obliteration of rectal varices, with or without portosystemic shunt creation. Demographic data, procedural details, technical success of variceal obliteration, clinical success, adverse events, and follow-up outcomes were retrospectively recorded. Clinical success was defined as resolution of rectal hemorrhage., Results: Portal venous access was achieved via a transjugular intrahepatic approach in all patients. The inferior mesenteric vein was selected, and foamy sclerosant (1:2:3 mixture by volume of ethiodized oil: sodium tetradecyl sulfate: air) was injected into the rectal varices with antegrade balloon occlusion in seven (87.5%) and without balloon occlusion in one (12.5%). Five of eight (62.5%) patients underwent concomitant transjugular intrahepatic portosystemic shunt (TIPS) creation (mean diameter 8.4 ± 0.9-mm) immediately following transvenous obliteration. Technical success of variceal obliteration was achieved in all patients. There were no immediate post-procedural adverse events. There were no reported occurrences of rectal ischemia, perforation, or stricture following obliteration. Two (40%) of the patients who underwent concomitant TIPS creation developed hepatic encephalopathy within 30 days of the procedure, which was medically managed. Clinical resolution of hemorrhage was achieved in all patients with no recurrent rectal variceal hemorrhage during mean follow-up of 666 ± 396 days (range: 14 - 1,224 days)., Conclusion: Transvenous obliteration, with or without concurrent TIPS creation, is feasible with promising results for the management of rectal variceal hemorrhage., (© 2024. The Author(s).)

Glutathione peroxidase-1 (GPx1) and cAMP/Ca 2+ responsive element (CRE)-binding protein (CREB) regulate neuronal viability by maintaining the redox homeostasis. Since GPx1 and CREB reciprocally regulate each other, it is likely that GPx1-CREB interaction may play a neuroprotective role against oxidative stress, which are largely unknown. Thus, we investigated the underlying mechanisms of the reciprocal regulation between GPx1 and CREB in the male rat hippocampus. Under physiological condition, L-buthionine sulfoximine (BSO)-induced oxidative stress increased GPx1 expression, extracellular signal-regulated kinase 1/2 (ERK1/2) activity and CREB serine (S) 133 phosphorylation in CA1 neurons, but not dentate granule cells (DGC), which were diminished by GPx1 siRNA, U0126 or CREB knockdown. GPx1 knockdown inhibited ERK1/2 and CREB activations induced by BSO. CREB knockdown also decreased the efficacy of BSO on ERK1/2 activation. BSO facilitated dynamin-related protein 1 (DRP1)-mediated mitochondrial fission in CA1 neurons, which abrogated by GPx1 knockdown and U0126. CREB knockdown blunted BSO-induced DRP1 upregulation without affecting DRP1 S616 phosphorylation ratio. Following status epilepticus (SE), GPx1 expression was reduced in CA1 neurons and DGC. SE also decreased CREB activity CA1 neurons, but not DGC. SE degenerated CA1 neurons, but not DGC, accompanied by mitochondrial elongation. These post-SE events were ameliorated by N-acetylcysteine (NAC, an antioxidant), but deteriorated by GPx1 knockdown. These findings indicate that a transient GPx1-ERK1/2-CREB activation may be a defense mechanism to protect hippocampal neurons against oxidative stress via maintenance of proper mitochondrial dynamics., Competing Interests: Declaration of competing interest 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 Elsevier Ltd. All rights reserved.)

Spinocerebellar ataxias (SCAs) are a genetically heterogenous group of devastating neurodegenerative conditions for which clinical care currently focuses on managing symptoms. Across these diseases there is an unmet need for therapies that address underlying disease mechanisms. We utilised the shared CAG repeat expansion mutation causative for a large subgroup of SCAs, to develop a novel disease-gene independent and mechanism agnostic small molecule screening approach to identify compounds with therapeutic potential across multiple SCAs. Using this approach, we identified the FDA approved microtubule inhibitor Colchicine and a novel CAG-repeat binding compound that reduce expression of disease associated transcripts across SCA1, 3 and 7 patient derived fibroblast lines and the Atxn1 154Q/2Q SCA1 mouse model in a repeat selective manner. Furthermore, our lead candidate rescues dysregulated alternative splicing in Atxn1 154Q/2Q mice. This work provides the first example of small molecules capable of targeting the underlying mechanism of disease across multiple CAG SCAs.

Plant-parasitic nematodes constrain global food security. During parasitism, they secrete effectors into the host plant from two types of pharyngeal gland cells. These effectors elicit profound changes in host biology to suppress immunity and establish a unique feeding organ from which the nematode draws nutrition. Despite the importance of effectors in nematode parasitism, there has been no comprehensive identification and characterisation of the effector repertoire of any plant-parasitic nematode. To address this, we advance techniques for gland cell isolation and transcriptional analysis to define a stringent annotation of putative effectors for the cyst nematode Heterodera schachtii at three key life-stages. We define 717 effector gene loci: 269 "known" high-confidence homologs of plant-parasitic nematode effectors, and 448 "novel" effectors with high gland cell expression. In doing so we define the most comprehensive "effectorome" of a plant-parasitic nematode to date. Using this effector definition, we provide the first systems-level understanding of the origin, deployment and evolution of a plant-parasitic nematode effectorome. The robust identification of the effector repertoire of a plant-parasitic nematode will underpin our understanding of nematode pathology, and hence, inform strategies for crop protection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Molloy 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.)

Objective: We aimed to examine the effectiveness and safety of a novel torque-controlled catheter for cerebral angiography., Methods: A total of 417 patients who underwent routine transfemoral cerebral angiography were enrolled in a randomized controlled study to compare the new torque-controlled and control group catheters. Device success was assessed on parameters such as the assessment of the common carotid artery, device rotation force, and success rate with the crossover group after the failed procedure. Four neurointerventionalists investigated the degree of satisfaction of using the new device. Superiority and non-inferiority tests of satisfaction scores were estimated for the new torque-controlled and the control group catheters., Results: The new torque-controlled catheter showed improved performance in terms of technical device success (92.79 vs. 98.09 %, P  = 0.010), crossover after technical device failure (0 vs. 86.67 %, P  = 0.004), and common carotid artery access (92.79 vs. 98.56 %, P  = 0.004). The flexibility and rotational force of the new torque-controlled catheter were higher than those of the control group catheters (75.48 vs. 100 %, P  < 0.001). No marked adverse cerebrovascular accidents or vessel damage occurred in either group during the procedure. The differences between the two groups in terms of the device rotational force and operator satisfaction were 1.836 (1.765-1.907) and 2.092 (2.000-2.183), respectively. The new torque-controlled catheter showed superior device rotational force satisfaction, operator satisfaction, and manufacturer satisfaction, with statistical significance., Conclusion: The new torque-controlled catheter was effective, safe, and convenient compared to the control group catheters for diagnostic cerebrovascular angiography., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Ltd.)

The identification and characterization of antigen-specific T cells during health and disease remains a key to improving our understanding of immune pathophysiology. The technical challenges of tracking antigen-specific T cell populations within the endogenous T cell repertoire have been greatly advanced by the development of peptide:MHC tetramer reagents. These fluorescently labeled soluble multimers of MHC class I or class II molecules complexed to antigenic peptide epitopes bind directly to T cells with corresponding T cell receptor (TCR) specificity and can, therefore, identify antigen-specific T cell populations in their native state without a requirement for a functional response induced by ex vivo stimulation. For exceedingly rare populations, tetramer-bound T cells can be magnetically enriched to increase the sensitivity and reliability of detection. As the investigation of tissue-resident T cell immunity deepens, there is a pressing need to identify antigen-specific T cells that traffic to and reside in nonlymphoid tissues. In this protocol, we present a detailed set of instructions for the isolation and characterization of antigen-specific T cells present within mouse lungs. This involves the isolation of T cells from digested lung tissue followed by a general T cell magnetic enrichment step and tetramer staining for flow cytometry analysis and sorting. The steps highlighted in this protocol utilize common techniques and readily available reagents, making it accessible for nearly any researcher engaged in mouse T cell immunology, and are highly adaptable for a variety of downstream analyses of any low frequency antigen-specific T cell population residing within the lungs.

Interventional radiology (IR) is a unique specialty that incorporates a diverse set of skills ranging from imaging, procedures, consultation, and patient management. Understanding how IR generates value to the healthcare system is important to review from various perspectives. IR specialists need to understand how to meet demands from various stakeholders to expand their practice improving patient care. Thus, this review discusses the domains of value contributed to medical systems and outlines the parameters of success. IR benefits five distinct parties: patients, practitioners, payers, employers, and innovators. Value to patients and providers is delivered through a wide set of diagnostic and therapeutic interventions. Payers and hospital systems financially benefit from the reduced cost in medical management secondary to fast patient recovery, outpatient procedures, fewer complications, and the prestige of offering diverse expertise for complex patients. Lastly, IR is a field of rapid innovation implementing new procedural technology and techniques. Overall, IR must actively advocate for further growth and influence in the medical field as their value continues to expand in multiple domains. Despite being a nascent specialty, IR has become indispensable to modern medical practice., 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., (© 2024 Campbell IV, Chick, Shin and Makary.)

Patient-specific, human-based cellular models integrating a biomimetic blood-brain barrier (BBB), immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. By engineering a novel brain-mimicking 3D hydrogel and co-culturing all six major brain cell types derived from patient iPSCs, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model with in vivo- like hallmarks inclusive of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. We implemented the model to study Alzheimer's Disease pathologies associated with APOE4 genetic risk. APOE4 miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic GFAP. Unlike the co-emergent fate specification of glia and neurons in organoids, miBrains integrate independently differentiated cell types, a feature we harnessed to identify that APOE4 in astrocytes promotes neuronal tau pathogenesis and dysregulation through crosstalk with microglia.

Controlling stress and deformation induced by thermo-mechanical stimulation in high-precision mechanical systems can be achieved by mechanical metamaterials (MM) exhibiting negative thermal expansion (NTE) and negative Poisson's ratio (NPR). However, the inverse design of MM exhibiting a wide range of arbitrary target NTEs and NPRs is a challenging task due to the low design flexibility of analytical methods and parametric studies based on numerical simulation. In this study, we propose Bézier curve-based programmable chiral mechanical metamaterials (BPCMs) and a deep autoencoder-based inverse design model (DAIM) for the inverse design of BPCMs. Through iterative transfer learning with data augmentation, DAIM can generate BPCMs with a curved rib shape inaccessible with the Bézier curve, which improves the inverse design performance of the DAIM in the data sparse domain. This approach decreases the mean absolute error of NTE and NPR between the inverse design target and the numerical simulation results of inverse designed BPCMs on the data-sparse domain by 79.25% and 83.33% on average, respectively. A 3D-printed BPCM is validated experimentally and exhibits good coincidence with the target NTE and NPR. Our proposed BPCM and the corresponding inverse design framework enable the inverse design of BPCMs with NTE in the range of -1100 to 0 ppm K -1 and NPR in the range of -0.6 to -0.1. Furthermore, programmable thermal deformation modes with a fixed Poisson's ratio are realized by combining various inverse designed BPCM unit cells. BPCMs and the DAIM for their inverse design are expected to improve the mechanical robustness of high-precision mechanical systems through tunable modulation of thermo-mechanical stimulation.

Purpose: This study aims to evaluate the impact of South Korea's national insurance coverage (NIC) expansion and the addition of genetic counselors on BRCA1/2 mutation testing rates in breast cancer patients., Materials and Methods: A retrospective review was conducted at the Samsung Medical Center (SMC), dividing patients into three groups: pre-NIC expansion, post-NIC expansion, and post-extra genetic counselor involvement. The number of BRCA1/2 tests performed and the detection rates among newly diagnosed and follow-up patients, particularly focusing on triple-negative breast cancer (TNBC) cases, were analyzed., Results: Post-NIC expansion, there was a significant increase in BRCA1/2 testing rates, with a gradual rise in detection rates while maintaining statistical significance. TNBC patients under 60 experienced substantial increases in testing rates. The number of follow-up patients recalled for testing also rose significantly after the extra genetic counselor involvement. Additionally, NIC expansion increased insurance coverage for TNBC patients, enhancing accessibility to testing., Conclusion: The study highlights the positive impact of NIC expansion and genetic counselor involvement on BRCA1/2 mutation testing rates and subsequent patient management. Addressing financial barriers to testing and incorporating genetic counseling significantly improve patient outcomes. This model provides a potential strategy for enhancing early detection and personalized treatment for breast cancer patients with BRCA1/2 mutations, contributing to global cancer management efforts.

Background: A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG-157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG-157 and immune checkpoint inhibitors., Methods: CCL23, UM-SCC1 (human), and SCCVII (HPV-), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG-157, anti-PD-1, and anti-CTLA-4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi-color flow cytometry, immunohistochemistry, and RNA-seq analysis. Fecal microbiome was analyzed by 16S rRNA sequence., Results: Among the eight treatment groups, APG-157 + anti-CTLA-4 demonstrated the best tumor growth suppression (p = 0.0065 compared to the control), followed by anti-PD-1 + anti-CTLA-4 treatment group (p = 0.48 compared to the control). Immunophenotype showed over 30% of CD8+ T cells in APG-157 + anti-CTLA-4 group compared to 4%-5% of CD8+ T cells for the control group. Differential gene expression analysis revealed that APG-157 + anti-CTLA-4 group showed an enriched set of genes for inflammatory response and apoptotic signaling pathways. The fecal microbiome analysis showed a substantial difference of lactobacillus genus among groups, highest for APG-157 + anti-CTLA-4 treatment group. We were unable to perform correlative studies for MEER model as there was tumor growth suppression with all treatment conditions, except for the untreated control group., Conclusions: The results indicate that APG-157 and immune checkpoint inhibitor combination treatment could potentially lead to improved tumor control., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Delayed cerebral ischemia (DCI) is a factor contributing to poor outcome of aneurysmal subarachnoid hemorrhage (aSAH). Serial inflammatory response is known to affect the occurrence of DCI. The aim of this study was to evaluate associations of dynamic changes of various inflammatory markers with occurrence of DCI after aSAH., Methods: A total of 279 patients with interventional treatment for aSAH were enrolled, and dichotomized according to the occurrence of DCI. Various inflammatory markers, including systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and their dynamic changes were analyzed at four different time points. Receiver operating characteristic (ROC) curve analysis with area under the curve (AUC) and univariate, multivariate Cox regression analyses with hazard ratio (HR) and 95 % confidence interval (CI) were performed to identify predictors for DCI., Results: Differences of SII and SIRI values between DCI (+) and DCI (-) group were significantly higher at 5-7 days than at other time points (P < 0.001 and P < 0.001, respectively). SII and SIRI had higher predicting values for DCI occurrence than other inflammatory markers (AUC: 0.862, 95 % CI: 0.786-0.928; P < 0.001 and AUC: 0.851, 95 % CI: 0.769-0.913; P < 0.001, respectively). SII at 5-7 days (HR: 1.74, 95 % CI: 1.38-3.22, P = 0.020) and SIRI at 5-7 days (HR: 1.62, 95 % CI: 1.28-2.84, P = 0.035) were associated with occurrence of DCI., Conclusions: Dynamic changes of SII and SII might be predictors of DCI occurrence in patients with aSAH., Competing Interests: Declaration of competing interest The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a variety of in vitro methods to reduce the quantities of drug candidates needed in preclinical and clinical trials. Most prior studies have relied on animal or cell-culture models, which do not fully recapitulate the human BBB. The development of microfluidic models of human-derived BBB cells could address this issue. We analyzed a model for predicting BBB permeability using the Emulate BBB-on-a-chip machine. Ten compounds were evaluated, and their permeabilities were estimated. Our study demonstrated that the permeability trends of ten compounds in our microfluidic-based system resembled those observed in previous animal and cell-based experiments. Furthermore, we established a general correlation between the partition coefficient (Kp) and the apparent permeability (Papp). In conclusion, we introduced a new paradigm for predicting BBB permeability using microfluidic-based systems.

This study employs a bivariate EGARCH model to examine the Taiwan Futures Exchange's regular and after-hours trading, focusing on the critical aspects of spillover and expiration effects, as well as volatility clustering and asymmetry. The objective of this study is to observe the impact on the trading sessions in Taiwan by the influences of the European and American markets, focusing on the essential roles of the price discovery function and risk disclosure effectiveness of the regular hours trading. This research is imperative considering the increasing interconnectedness of global financial markets and the need for comprehensive risk assessment for investment strategies. It also examines the hedging behavior of after-hours traders, thereby aiming to contribute to pre-investment analysis by future investors. This examination is vital for understanding the dynamics of after-hours trading and its influence on market stability. Results indicate price continuity between both trading sessions, with regular trading often determining after-hours price ranges. Consequently, after-hours price changes can inform regular trading decisions. This finding highlights the importance of after-hours trading for shaping market expectations. Significant profit potential exists in after-hours trading open interest, which serves speculative and hedging purposes. While regular trading volatility influences after-hours trading, the reverse is not true. This suggests Taiwan market information poses a higher risk impact than European and American market data, emphasizing the unique position of the Taiwan market in the global financial ecosystem. After-hours trading volatility reflects the absorption of international market information and plays a crucial role in advance revelation of risks. This underscores the importance of after-hours trading in global risk management and strategy formulation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chiu 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.)

Gigaxonin is an E3 ubiquitin ligase that plays a role in cytoskeletal stability. Its role in cancer is not yet clearly understood. Our previous studies of head and neck cancer had identified gigaxonin interacting with p16 for NFκB ubiquitination. To explore its role in cancer cell growth suppression, we analyzed normal and tumor DNA from cervical and head and neck cancers. There was a higher frequency of exon 8 SNP (c.1293 C>T, rs2608555) in the tumor (46% vs. 25% normal, P = 0.011) pointing to a relationship to cancer. Comparison of primary tumor with recurrence and metastasis did not reveal a statistical significance. Two cervical cancer cell lines, ME180 and HT3 harboring exon 8 SNP and showing T allele expression correlated with higher gigaxonin expression, reduced in vitro cell growth and enhanced cisplatin sensitivity in comparison with C allele expressing cancer cell lines. Loss of gigaxonin expression in ME180 cells through CRISPR-Cas9 or siRNA led to aggressive cancer cell growth including increased migration and Matrigel invasion. The in vitro cell growth phenotypes were reversed with re-expression of gigaxonin. Suppression of cell growth correlated with reduced Snail and increased e-cadherin expression. Mouse tail vein injection studies showed increased lung metastasis of cells with low gigaxonin expression and reduced metastasis with reexpression of gigaxonin. We have found an association between C allele expression and RNA instability and absence of multimeric protein formation. From our results, we conclude that gigaxonin expression is associated with suppression of epithelial-mesenchymal transition through inhibition of Snail., Significance: Our results suggest that GAN gene exon 8 SNP T allele expression correlates with higher gigaxonin expression and suppression of aggressive cancer cell growth. There is downregulation of Snail and upregulation of e-cadherin through NFκB ubiquitination. We hypothesize that exon 8 T allele and gigaxonin expression could serve as diagnostic markers of suppression of aggressive growth of head and neck cancer., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Inflammatory reaction and immune dysregulation are known as components contributing to delayed cerebral ischemia (DCI) in patients with following aneurysmal subarachnoid hemorrhage (aSAH). The objective of this study was to investigate the role of pan-immune-inflammation value (PIV) as a novel comprehensive inflammatory marker in predicting the DCI development following aSAH. A total of 1028 participants with aSAH were enrolled. There were 296 patients with DCI and 732 patients without DCI. Various inflammatory markers were analyzed using peripheral blood sample obtained at admission. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff value of PIV for distinguishing DCI. Multivariate analysis was used to determine independent predictors for DCI. Mean PIV was significantly higher in the DCI (+) group than in the DCI (-) group (437.6 ± 214.7 vs 242.1 ± 154.7, P = 0.007). In ROC analysis, the optimal cutoff value of PIV was 356.7 for predicting DCI (area under the curve [AUC] 0.772, 95 % confidence interval [CI] 0.718-0.816; P < 0.001). Multivariate analysis showed that high Hunt-Hess grade (odds ratio [OR] 1.70, 95 % CI 1.38-2.22; P = 0.007), thick SAH (OR 1.82, 95 % CI 1.44-2.32; P = 0.005), and elevated PIV (≥356.7) (OR 1.42, 95 % CI 1.10-1.74; P = 0.013) were independent predictors of DCI after aSAH. PIV is a potent predictor of DCI in patients with aSAH. Elevated PIV is associated with more DCI development. Thus, PIV has predictive value for DCI development., 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 Ltd. All rights reserved.)

Rationale and Objectives: To evaluate wellness among interventional radiologists using a multidimensional survey., Materials and Methods: An anonymous 53-item survey, including 36 Perceived Wellness Survey (PWS) prompts, was created in Qualtrics (an online survey tool) to assess wellness among interventional radiology attendings and residents. The survey was open from June to September, 2022, 2 years into the COVID-19 Pandemic. The survey was distributed via Society of Interventional Radiology Forums, social media (Twitter, LinkedIn, and Facebook), and personal correspondence. PWS scores were categorized into Wellness Composite and subscores (physical, emotional, intellectual, psychological, social, and spiritual)., Results: 367 surveys were completed. 300 (81.7%) respondents were male and 67 (18.3%) were female. Respondents included attending physicians (297; 81.0%) and residents (70; 19.0%). Practice settings included academic (174; 47.4%), private (114; 31.0%), private-academic hybrid (62; 16.9%), and others (17; 4.7%). Mean Wellness Composite at academic centers (14.74 ± 3.16; range: 5.42-23.50) was significantly lower than at private (15.22 ± 3.37; range: 6.13-23.51) and hybrid (16.14 ± 2.47; range: 10.20-23.50) practices (p = 0.01). Respondents < 40 years old had significantly lower emotional wellness subscores compared to those ≥ 40 years old (4.34 ± 0.86 vs. 4.60 ± 0.87; p = 0.006). There were no significant differences between geographic regions in the United States, however, International respondents had significantly lower social and intellectual wellness (INT) subscores. Physical wellness subscore (4.00 ± 0.9) was significantly lower than the other subscores (4.59 ± 0.81) (p < .001). Overall mean Wellness Composite was 15.11 ± 3.13 (range: 5.42-23.51)., Conclusion: Overall self-reported wellness was lower among interventional radiologists practicing at academic centers. Interventional Radiologists < 40 years old and residents had lower emotional wellness, while international respondents had lower social and INT. Overall wellness scores were lower than prior PWS studies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Seetharam C. Chadalavada, MD, MS reports a relationship with Cook Medical Inc that includes: consulting or advisory. Seetharam C. Chadalavada, MD, MS reports a relationship with Philips that includes: consulting or advisory. Seetharam C. Chadalavada, MD, MS reports a relationship with Fortec Medical that includes: consulting or advisory and speaking and lecture fees. Jeffrey Forris Beecham Chick, MD, MPH reports a relationship with Inari Medical Inc that includes: consulting or advisory and speaking and lecture fees. Jeffrey Forris Beecham Chick, MD, MPH reports a relationship with Guerbet that includes: consulting or advisory and speaking and lecture fees. Jeffrey Forris Beecham Chick, MD, MPH reports a relationship with C R Bard Inc that includes: consulting or advisory and speaking and lecture fees. Jeffrey Forris Beecham Chick, MD, MPH reports a relationship with Argon Medical Devices Inc that includes: consulting or advisory and speaking and lecture fees. Jeffrey Forris Beecham Chick, MD, MPH reports a relationship with Boston Scientific Corp that includes: consulting or advisory and speaking and lecture fees. Jeffrey Forris Beecham Chick, MD, MPH reports a relationship with Medtronic Inc that includes: consulting or advisory and speaking and lecture fees. Jeffrey Forris Beecham Chick, MD, MPH reports a relationship with NXT Biomedical that includes: consulting or advisory and speaking and lecture fees. Anthony Hage, MD reports a relationship with Verdure Imaging that includes: consulting or advisory. Eric J Monroe MD reports a relationship with Biogen that includes:., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: To evaluate moral injury (MI) among interventional radiologists using validated assessment tools., Materials and Methods: An anonymous 29-question online survey was distributed to interventional radiologists using the Society of Interventional Radiology Connect Open Forum website, Twitter, Facebook, LinkedIn, and electronic mail. The survey consisted of demographic and practice environment questions, a global quality of life (QoL) scale (scored 1-100), the MI Symptom Scale‑Healthcare Professional (MISS-HP) (scored 1-100), and two open-ended questions. A MISS-HP score ≥ 36 was indicative of experiencing MI. P < .05 was considered statistically significant for all two-sided tests., Results: Beginning on March 30, 2023, 365 surveys were completed over 5 days. Of the respondents, 299 (81.9%) were male, 65 (17.8%) were female, and one preferred not to disclose gender. The respondents included practicing interventional radiologists (299; 81.9%) and interventional radiologists-in-training (66; 18.1%). Practice settings included academic (146; 40.0%), community (121; 33.2%), hybrid (84; 23.0%), or other (14; 3.8%) centers. Mean QoL was 71.1 ± 17.0 (range: 0-100) suggestive of "good" QoL. Mean QoL in the MI subgroup was significantly different from that for the rest of the group (67.6 ± 17.0 vs. 76.6 ± 16.0; P < 0.05). 223 (61.1%) respondents scored ≥ 36 on the MISS-HP, and thus were categorized as having profession-related MI. Mean MISS-HP was 39.9 ± 12.6 (range: 10-83). Mean MISS-HP in the MI subgroup was significantly different from that for the rest of the group (47.4 ± 9.6 vs. 28.0 ± 5.7; P < 0.05). There was a negative correlation between MI and QoL (r = -0.4; P < 0.001). Most common themes for greatest contribution to MI were ineffective leadership, barriers to patient care, corporatization of medicine, non-physician administration, performing futile procedures, turf battles, and reduced resources. Most common themes for ways to reduce MI were more autonomy, less bureaucracy, more administrative support, physician-directed leadership, adequate staffing, changes to the medical system, physician unionization, transparency with insurance companies, more time off, and leaving medicine/retirement., Conclusion: MI is prevalent among interventional radiologists, and it negatively correlates with QoL. Future work should investigate causative factors and mitigating solutions., 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 Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Lactiplantibacillus plantarum DSR330 (DSR330) has been examined for its antimicrobials production and probiotics. In this study, the hepatoprotective effects of DSR330 were examined against non-alcoholic fatty liver disease (NAFLD) in a high-fat diet (HFD)-fed C57BL/6 mouse model. To induce the development of fatty liver, a HFD was administered for five weeks, and then silymarin (positive control) or DSR330 (10 8 or 10 9 CFU/day) was administered along with the HFD for seven weeks. DSR330 significantly decreased body weight and altered serum and hepatic lipid profiles, including a reduction in triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels compared to those in the HFD group. DSR330 significantly alleviated HFD-related hepatic injury by inducing morphological changes and reducing the levels of biomarkers, including AST, ALT, and ALP. Additionally, DSR330 alleviated the expression of SREBP-1c, ACC1, FAS, ACO, PPARα, and CPT-1 in liver cells. Insulin and leptin levels were decreased by DSR330 compared to those observed in the HFD group. However, adiponectin levels were increased, similar to those observed in the ND group. These results demonstrate that L. plantarum DSR330 inhibited HFD-induced hepatic steatosis in mice with NAFLD by modulating various signaling pathways. Hence, the use of probiotics can lead to hepatoprotective effects.

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial., (© 2024. The Author(s).)

The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease. We sought to address these knowledge gaps through a comprehensive study of 29 publicly available RNA-sequencing datasets. We identified that dysregulation of alternative splicing is widespread across CAG expansion mouse models of SCAs 1, 3 and 7. These changes were detected presymptomatically, persisted throughout disease progression, were repeat length-dependent, and were present in brain regions implicated in SCA pathogenesis including the cerebellum, pons and medulla. Across disease progression, changes in alternative splicing occurred in genes that function in pathways and processes known to be impaired in SCAs, such as ion channels, synaptic signalling, transcriptional regulation and the cytoskeleton. We validated several key alternative splicing events with known functional consequences, including Trpc3 exon 9 and Kcnma1 exon 23b, in the Atxn1154Q/2Q mouse model. Finally, we demonstrated that alternative splicing dysregulation is responsive to therapeutic intervention in CAG expansion SCAs with Atxn1 targeting antisense oligonucleotide rescuing key splicing events. Taken together, these data demonstrate that widespread presymptomatic dysregulation of alternative splicing in CAG expansion SCAs may contribute to disease onset, early neuronal dysfunction and may represent novel biomarkers across this devastating group of neurodegenerative disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Despite the increasing use of immediate breast reconstruction (IBR), its oncologic safety in the setting of neoadjuvant chemotherapy (NACT) needs to be comprehensively clarified in breast cancer management. The objective of the present study was to analyze the oncologic safety of IBR following NACT., Methods: In total, 587 patients with breast cancer who underwent a total mastectomy (TM) with IBR after NACT between 2008 and 2017 at a single institution were retrospectively reviewed. The reviewed patients with IBR following skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) were matched 1:3 to patients who underwent TM alone after NACT. Matching variables included age, clinical T and N stages before NACT, response to NACT, pathologic T and N stages, and molecular subtypes., Results: After propensity score matching, 95 patients who underwent IBR following SSM/NSM after NACT (IBR group) and 228 patients who underwent TM alone after NACT (TM group) were selected. The median follow-up period was 73 (range, 5-181) months after matching. After matching, there were no significant differences between the two groups in 5-year locoregional recurrence-free survival (88.8% vs. 91.2%, p = 0.516), disease-free survival (67.3% vs. 76.6%, p = 0.099), distant metastasis-free survival (71.9% vs. 81.9%, p = 0.057), or overall survival (84.1% vs. 91.5, p = 0.061) rates. In multivariate analyses, conducting IBR was not associated with increased risks for locoregional recurrence, any recurrence, distant metastasis, or overall death., Conclusion: Our findings suggest that IBR following SSM/NSM elicits comparable long-term oncologic outcomes to those of TM alone in the setting of NACT., Competing Interests: The authors declare that they have no competing interests., (© 2024 Korean Breast Cancer Society.)

Depression is a common non-motor symptom in Parkinson's disease (PD) that includes anhedonia and impacts quality of life but is not effectively treated with conventional antidepressants clinically. Vagus nerve stimulation improves treatment-resistant depression in the general population, but research about its antidepressant efficacy in PD is limited. Here, we administered peripheral non-invasive focused ultrasound to hemiparkinsonian ('PD') and non-parkinsonian (sham) rats to mimic vagus nerve stimulation and assessed its antidepressant-like efficacy. Following 6-hydroxydopamine (6-OHDA) lesion, akinesia-like immobility was assessed in the limb-use asymmetry test, and despair- and anhedonic-like behaviors were evaluated in the forced swim test and sucrose preference test, respectively. After, tyrosine hydroxylase immuno-staining was employed to visualize and quantify dopaminergic degeneration in the substantia nigra pars compacta, ventral tegmental area, and striatum. We found that PD rats exhibited akinesia-like immobility and > 90% reduction in tyrosine hydroxylase immuno-staining ipsilateral to the lesioned side. PD rats also demonstrated anhedonic-like behavior in the sucrose preference test compared to sham rats. No 6-OHDA lesion effect on immobility in the forced swim test limited conclusions about the efficacy of ultrasound on despair-like behavior. However, ultrasound improved anhedonic-like behavior in PD rats and this efficacy was sustained through the end of the 1-week recovery period. The greatest number of animals demonstrating increased sucrose preference was in the PD group receiving ultrasound. Our findings here are the first to posit that peripheral non-invasive focused ultrasound to the celiac plexus may improve anhedonia in PD with further investigation needed to reveal its potential for clinical applicability., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To enhance articular cartilage healing, microfractures (Mfx) and bone marrow aspirate concentrate (BMAC) are commonly used, and some form of scaffold is often used together to increase its efficacy. Herein, we compared the efficacy of atelocollagen scaffold to that of collagen scaffold when used with Mfx or BMAC on osteochondral defect of animal., Methods: This experiment was designed in two stages, and therapeutic effects of Mfx and BMAC were respectively evaluated when used with atelocollagen or collagen scaffold. Femoral condyle defects were artificially created in male New Zealand White rabbits, and in each stage, 12 rabbits were randomly allocated into three treatment groups: test group with additional atelocollagen scaffold, the positive control group with collagen scaffold, and the negative control group. Then, for 12 weeks, macroscopic and histological evaluations were performed., Results: At 12 weeks, defects in the test group were fully regenerated with normal cartilage-like tissue, and were well integrated with the surrounding cartilage at both stages experiment, whereas defects in the control groups were not fully filled with regenerated tissue, and the tissue appeared as fibrous tissue. Histologically, the regenerated tissue in the test group showed a statistically significant improvement compared to the positive and negative control groups, achieving a similar structure as normal articular cartilage., Conclusion: The results showed that implantation of the atelocollagen scaffold enhanced cartilage regeneration following osteochondral defects in rabbits. This suggests that the atelocollagen scaffold can be used with Mfx or BMAC for effective regeneration of osteochondral defects., (© 2023. Korean Tissue Engineering and Regenerative Medicine Society.)

Introduction: A stent retriever (SR) is widely used in mechanical thrombectomy (MT) for M2 segment occlusion. However, the suitable size of SR in M2 occlusion remains unclear. Therefore, we aimed to compare 4 mm-sized SR with 3 mm-sized SR in M2 occlusion., Methods: Patients who underwent MT with SR for M2 occlusion were dichotomized into 4×20 mm SR and 3×20 mm SR groups. Then, 1:1 propensity score matching was performed. The M2 segment was divided into proximal and distal segments according to the occlusion site. Subgroup analysis was then performed for each cohort., Results: A total of 111 patients were enrolled, with 4×20 mm SR and 3×20 mm SR applied in 72 (64.9%) and 39 (35.1%) cases, respectively. In propensity score matching, mean number of stent passages for reperfusion was significantly lower in the 4×20 mm SR group than in the 3×20 mm SR group (1.5 ± 0.8 vs. 2.1 ± 1.1; p = 0.004). First-pass reperfusion (FPR) was more highly achieved in the 4×20 mm SR group than in the 3×20 mm SR group (52.6% vs. 42.1%; p = 0.007). In both proximal and distal occlusion cohorts, the 4 mm SR group showed lower mean number of SR passage (p = 0.004 and p = 0.003, respectively) and higher FPR rate than the 3 mm SR group (p = 0.003 and p = 0.007, respectively)., Conclusion: In MT for M2 occlusion, 4×20 mm SR enables an effective procedure with lesser SR passage for reperfusion and a higher rate of FPR than 3×20 mm SR., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Emboli commonly occurs in mechanical thrombectomy (MT). The objective of this study was to analyze predicting factors of emboli after MT., Methods: Patients who underwent MT with successful reperfusion for anterior circulation occlusion were enrolled. Emboli included distal emboli at digital subtraction angiography (DSA) and unexpected embolic infarct on diffusion-weighted image (DWI) without distal emboli at DSA. Baseline characteristics, procedural details, angiographic outcomes, and clinical outcomes were reviewed. Multivariable analyses were performed to evaluate predictive factors for the occurrence of emboli., Results: Of 601 patients, 149 (24.8%) patients had distal emboli at DSA, and 169 (28.1%) patients had unexpected embolic infarction on DWI even without distal emboli at DSA. A total of 318 (52.9%) patients were enrolled in the embolic group, and 283 (47.1%) patients were assigned to the non-embolic group. In multivariate analysis, larger microcatheter (OR 1.26, 95% CI 1.12-1.94; p = 0.047), clot passage (OR 1.33, 95% CI 1.07-1.87; p = 0.041), use of balloon guide catheter (BGC) (OR 0.70, 95% CI 0.52-0.92; p = 0.014), early ballooning of BGC (OR 0.68, 95% CI 0.50-0.90; p = 0.009), and longer stent retriever (OR 0.72, 95% CI 0.54-0.90; p = 0.029) were associated with occurrence of emboli., Conclusion: MT with only a stent retriever, use of a larger microcatheter, and clot passage might increase the risk of emboli. In contrast, contact aspiration thrombectomy, use of BGC, early ballooning of BGC, and use of longer stent retrievers could reduce the chance of emboli., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The initial cardiac rhythm in out-of-hospital cardiac arrest (OHCA) portends different prognoses and affects treatment decisions. Initial shockable rhythms are associated with good survival and neurological outcomes but there is conflicting evidence for those who initially present with non-shockable rhythms. The aim of this study is to evaluate if OHCA with conversion from non-shockable (i.e., asystole and pulseless electrical activity) rhythms to shockable rhythms compared to OHCA remaining in non-shockable rhythms is associated with better survival and neurological outcomes., Method: OHCA cases from the Pan-Asian Resuscitation Outcomes Study registry in 13 countries between January 2009 and February 2018 were retrospectively analyzed. Cases with missing initial rhythms, age <18 years, presumed non-medical cause of arrest, and not conveyed by emergency medical services were excluded. Multivariable logistic regression analysis was performed to evaluate the relationship between initial and subsequent shockable rhythm, survival to discharge, and survival with favorable neurological outcomes (cerebral performance category 1 or 2)., Results: Of the 116,387 cases included. 11,153 (9.6%) had initial shockable rhythms and 9,765 (8.4%) subsequently converted to shockable rhythms. Japan had the lowest proportion of OHCA patients with initial shockable rhythms (7.3%). For OHCA with initial shockable rhythm, the adjusted odds ratios (aOR) for survival and good neurological outcomes were 8.11 (95% confidence interval [CI] 7.62-8.63) and 15.4 (95%CI 14.1-16.8) respectively. For OHCA that converted from initial non-shockable to shockable rhythms, the aORs for survival and good neurological outcomes were 1.23 (95%CI 1.10-1.37) and 1.61 (95%CI 1.35-1.91) respectively. The aORs for survival and good neurological outcomes were 1.48 (95%CI 1.22-1.79) and 1.92 (95%CI 1.3 - 2.84) respectively for initial asystole, while the aOR for survival in initial pulseless electrical activity patients was 0.83 (95%CI 0.71-0.98). Prehospital adrenaline administration had the highest aOR (2.05, 95%CI 1.93-2.18) for conversion to shockable rhythm., Conclusion: In this ambidirectional cohort study, conversion from non-shockable to shockable rhythm was associated with improved survival and neurologic outcomes compared to rhythms that continued to be non-shockable. Continued advanced resuscitation may be beneficial for OHCA with subsequent conversion to shockable rhythms.

Infant femoral arterial access is an essential part of interventional procedures, hemodynamic monitoring, and support of critically ill patients. Due to small luminal diameter, superficial location, mobility, and increased risk of vasospasm, dissection, and thrombosis, femoral artery access in the infant is a technically demanding procedure. The purpose of this manuscript is to describe an approach to successful common femoral arterial access and arteriography in infants including common pearls and pitfalls., Competing Interests: Declaration of competing interest Author 5 is a scientific advisor and speaker for Biogen. Author 3 is a consultant and speaker for Inari Medical, Guerbet, C. R. Bard, Argon Medical Devices, Boston Scientific, and NXT Biomedical. None of the other authors have identified a conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: While large-bore mechanical thrombectomy provides effective venous thrombus removal, often with avoidance of thrombolytics, literature surrounding the application of these devices in pediatric patients is sparse., Objective: To report technical success and outcomes following large-bore thrombectomy systems in adolescent patients with deep venous thrombosis., Materials and Methods: A retrospective review identified all patients less than 18 years of age undergoing mechanical venous thrombectomy at a single institution between 2018 and 2022. No patients were excluded. Technical success was defined as extraction of thrombus sufficient to restore unimpeded flow in affected segments. Clinical success was defined as resolution of presenting symptoms., Results: Nine consecutive patients (6 females, 3 males; age range 15-17 years) underwent 10 thrombectomy procedures using ClotTriever (n=6; 60%), FlowTriever (n=2; 20%), or both (n=2; 20%). Chronicity of thrombus was categorized as acute (<2 weeks) in 6 (60%), subacute (2-6 weeks) in 1 (10%), and chronic (>6 weeks) in 3 (30%). Distribution of thrombus was lower extremity and/or inferior vena cava (IVC) in 9 (90%) and unilateral axillo-subclavian in 1 (10%). Technical success was achieved in 9 interventions (90%). Clinical success was achieved in 8 patients (88.9%). No patients received thrombolytics. There were no intraprocedural adverse events (AE). Minor complications (Society of Interventional Radiology mild adverse events) were observed in a delayed fashion following 2 interventions (20%)., Conclusions: This preliminary experience demonstrated high rates of technical and clinical success with large-bore deep venous thrombectomy in adolescent patients across a range of thrombus chronicity and locations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Zaluzanin C (ZC), a sesquiterpene lactone isolated from Laurus nobilis L., has been reported to have anti-inflammatory and antioxidant effects. However, the mechanistic role of ZC in its protective effects in Kupffer cells and hepatocytes has not been elucidated. The purpose of this study was to elucidate the efficacy and mechanism of action of ZC in Kupffer cells and hepatocytes. ZC inhibited LPS-induced mitochondrial ROS (mtROS) production and subsequent mtROS-mediated NF-κB activity in Kupffer cells (KCs). ZC reduced mRNA levels of pro-inflammatory cytokines (Il1b and Tnfa) and chemokines (Ccl2, Ccl3, Ccl4, Cxcl2 and Cxcl9). Tumor necrosis factor (TNF)-α-induced hepatocyte mtROS production was inhibited by ZC. ZC was effective in alleviating mtROS-mediated mitochondrial dysfunction. ZC enhanced mitophagy and increased mRNA levels of fatty acid oxidation genes (Pparα, Cpt1, Acadm and Hadha) and mitochondrial biosynthetic factors (Pgc1α, Tfam, Nrf1 and Nrf2) in hepatocytes. ZC has proven its anti-lipid effect by improving lipid accumulation in hepatocytes by enhancing mitochondrial function to facilitate lipid metabolism. Therefore, our study suggests that ZC may be an effective compound for hepatoprotection by suppressing inflammation and lipid accumulation through regulating mtROS.

Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain 1 . Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues 2-6 . The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development 7-10 . However, current approaches do not incorporate microglia or address their role in organoid maturation 11-21 . Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac) 22 . In organoid cocultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro) and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2 + lipid droplets that exported cholesterol and its esters, which were taken up by NPCs in the organoids. We also detected PLIN2 + lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leads to improved neurogenesis., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Safe drinking water sources are crucial for human health. Consequently, water quality management, including continuous monitoring of water quality and algae at sources, is critical to ensure the availability of safe water for local residents. This study aimed to construct statistical prediction models considering probability distributions relevant to cyanophyte cell counts and compare their prediction performance. In this study, water quality parameters at Juam Lake and Tamjin Lake, representative water sources in the Yeongsan and Seomjin rivers, South Korea, were investigated. We used a water quality monitoring network, algae alert system, and hydraulic and hydrological data measured every 7 days from January 2017 to December 2022 from the Water Environment Information System of the National Institute of Environmental Research. Using data for 2017-2021 as a training set and data for 2022 as a test set, the performances of seven models were compared for predicting cyanophyte cell counts. Environmental factors associated with algae in water sources were observed based on the monitoring data, and a prediction model appropriate for the cyanophyte distribution was generated, which also included the risk of toxicity. The extreme gradient boosting with the random forest model had the best predictive performance for cyanophyte cell counts. The study results are expected to facilitate water quality management in various water systems, including water sources., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Pathologic complete response (pCR) of breast cancer after neoadjuvant chemotherapy (NAC) is highly related to molecular subtypes. Patients who achieved tumor pCR after NAC have a better prognosis. However, despite of better prognosis, pCR patients have a potential for recurrence. There is little evidence of risk factors of recurrence in patients with pCR. We aim to analyze factors associated with tumor recurrence in patients who achieved pCR., Methods: This study retrospectively reviewed the data of patients diagnosed with breast cancer who achieved pCR after receiving NAC between January 2009 and December 2018 in Samsung Medical Center. pCR was defined as no residual invasive cancer in the breast and axillary nodes even if there is residual ductal carcinoma in situ (ypT0 or ypTis with ypN0). Breast cancers are classified into 4 subtypes based on hormone receptors (HR) and human epithelial growth factor receptor 2 (HER2) status. Patients who had bilateral breast cancer, ipsilateral supraclavicular or internal mammary lymph node metastasis, inflammatory breast cancer, distant metastasis, unknown subtype, and histologically unique case were excluded from the study., Results: In total 483 patients were included in this study except for patients who corresponded to the exclusion criteria. The median follow-up duration was 59.0 months (range, 0.5-153.3 months). Breast cancer recurred in 4.1% of patients (20 of 483). There was a significant difference in clinical T (P = 0.004) and clinical N (P = 0.034) stage in the Kaplan-Meier curve for disease-free survival. Molecular subtypes (P = 0.573), Ki67 (P = 1.000), and breast surgery type (P = 0.574) were not associated with tumor recurrence in patients who achieved pCR after NAC. In the clinical T stage and clinical N stage, there was a significant difference between recurrence and no-recurrence groups (clinical T stage; P = 0.045, clinical N stage; P = 0.002). Univariable Cox regression revealed statistical significance in the clinical T stage (P = 0.049) and clinical N stage (P = 0.010), while multivariable Cox regression demonstrated non-significance in the clinical T stage (P = 0.320) and clinical N stage (P = 0.073)., Conclusion: Results in this study showed that clinical T, clinical N stage, and molecular subtypes were not statistically significant predictors of recurrence in patients who achieved pCR after NAC. In spite of that, pCR after NAC may be more important than clinical staging and molecular subtype in early breast cancer. In addition, escalated treatments for patients with HER2 + or triple-negative tumors would be considered with a strict patient selection strategy to prevent over-treatment as well as achieve pCR., 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 © 2023 Choi, Woen, Jang, Lee, Shin, Kwak, Lee, Chae, Yu, Lee, Kim, Nam and Ryu.)