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1.
Eur Radiol ; 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38980412

RESUMO

OBJECTIVES: To investigate the diagnostic performance and interobserver agreement of quantitative CT parameters indicating strong lymph node (LN) enhancement in differentiated thyroid cancer (DTC), comparing them with qualitative analysis by radiologists of varying experience. MATERIALS AND METHODS: This study included 463 LNs from 399 patients with DTC. Three radiologists independently analyzed strong LN enhancement on CT. Qualitative analysis of strong enhancement was defined as LN cortex showing greater enhancement than adjacent muscles on the arterial phase. Quantitative analysis included the mean attenuation value (MAV) of LN on arterial phase (LNA) and venous phase (LNV), LNA normalized to the common carotid artery (NAVCCA), internal jugular vein (NAVIJV), and sternocleidomastoid muscle (NAVSCM), attenuation difference [AD; (LNA - MAVSCM)], and relative washout ratio [((LNA - LNV)/LNA) × 100]. The interobserver agreement and diagnostic performance of the quantitative and qualitative analyses were evaluated. RESULTS: Interobserver agreement was excellent for all quantitative CT parameters (ICC, 0.83-0.94) and substantial for qualitative assessment (κ = 0.61). All CT parameters except for LNV showed good diagnostic performance for metastatic LNs (AUC, 0.81-0.85). NAVCCA (0.85, 95% CI: 0.8-0.9) and AD (0.85, 95% CI: 0.81-0.89) had the highest AUCs. All quantitative parameters except for NAVIJV had significantly higher AUCs than qualitative assessments by inexperienced radiologists, with no significant difference from assessments by an experienced radiologist. CONCLUSION: Quantitative assessment of LN enhancement on arterial phase CT showed higher interobserver agreement and AUC values than qualitative analysis by inexperienced radiologists, supporting the need for a standardized quantitative CT parameter-based model for determining strong LN enhancement. CLINICAL RELEVANCE STATEMENT: When assessing strong LN enhancement in DTC, quantitative CT parameters indicating strong enhancement can improve interobserver agreement, regardless of experience level. Therefore, the development of a standardized diagnostic model based on quantitative CT parameters might be necessary. KEY POINTS: Accurate preoperative assessment of LN metastasis in thyroid cancer is crucial. Quantitative CT parameters indicating strong LN enhancement demonstrated excellent interobserver agreement and good diagnostic performance. Quantitative assessment of contrast enhancement offers a more objective model for the identification of metastatic LNs.

2.
Anticancer Res ; 44(7): 2909-2919, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38925848

RESUMO

BACKGROUND/AIM: NUAK family kinase 2 (NUAK2) is a promising target for cancer therapeutics due to its reported role in protein phosphorylation, a critical process in cancer cell survival, proliferation, invasion, and senescence. This study aimed to identify novel inhibitors that disrupt NUAK2 activity. We have already identified two KRICT Hippo kinase inhibitor (KHKI) compounds, such as KHKI-01128 and KHKI-01215. Our aim was to evaluate the impact of KHKI-01128 and KHKI-01215 on NUAK2 activity and elucidate its mechanism in colorectal cancer cells. MATERIALS AND METHODS: To evaluate anticancer properties of these inhibitors, four in vitro assays in the SW480 cell line (time-resolved fluorescence resonance energy transfer assay, KINOMEscan kinase profiling, viability, and apoptosis assays) and two pharmacological mechanism analyses (Gene Set Enrichment Analysis and western blotting) were performed. RESULTS: KHKI-01128 and KHKI-01215 exhibited potent inhibitory activity against NUAK2 (half-maximal inhibitory concentration=0.024±0.015 µM and 0.052±0.011 µM, respectively). These inhibitors suppressed cell proliferation, with half-maximal inhibitory concentrations of 1.26±0.17 µM and 3.16±0.30 µM, respectively, and induced apoptosis of SW480 cells. Gene Set Enrichment Analysis revealed negative enrichment scores of -0.84 for KHKI-01128 (false-discovery rate=0.70) and 1.37 for KHKI-01215 (false-discovery rate=0.18), indicating that both effectively suppressed the expression of YES1-associated transcriptional regulator (YAP) target genes. CONCLUSION: These results suggest that KHKI-01128 and KHKI-01215 are potent NUAK2 inhibitors with promising potential for pharmaceutical applications.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Neoplasias Colorretais , Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteínas Quinases/metabolismo
4.
Sci Transl Med ; 16(748): eadn0223, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38753806

RESUMO

A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.


Assuntos
Vacinas contra a AIDS , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Animais , Humanos , Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Camundongos , Vacinação , Imunização Secundária , HIV-1/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Anticorpos Amplamente Neutralizantes/imunologia
5.
Nat Immunol ; 25(6): 1073-1082, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38816615

RESUMO

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.


Assuntos
Vacinas contra a AIDS , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Proteína gp41 do Envelope de HIV , Infecções por HIV , HIV-1 , Macaca mulatta , Animais , Humanos , Proteína gp41 do Envelope de HIV/imunologia , Anticorpos Anti-HIV/imunologia , Camundongos , Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , HIV-1/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Vacinação , Anticorpos Amplamente Neutralizantes/imunologia , Linfócitos B/imunologia , Nanopartículas/química , Feminino , Regiões Determinantes de Complementaridade/imunologia , Epitopos/imunologia
6.
Eur J Radiol ; 176: 111505, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38796886

RESUMO

PURPOSE: To identify high-risk computed tomography (CT) features for predicting gallbladder (GB) cancer in patients presenting with localized GB wall thickening. METHODS: This retrospective analysis included 120 patients (mean age: 63.9 ± 10.0 years; 51 men) exhibiting localized GB wall thickening on CT scans obtained between January 2008 and May 2017. Two radiologists independently evaluated CT imaging features for predicting GB cancer. The diagnostic performance of significant imaging features and their combinations was evaluated. High-risk CT features ranked by accuracy were delineated for predicting GB cancer. RESULTS: This study included 55 patients with GB cancer and 65 with benign GB conditions. The top-four most accurate CT imaging features for predicting GB cancer were identified: heterogeneously enhancing single layer or strongly enhancing thick inner layer; GB wall thickness > 6.5 mm; hyperenhancement on arterial phase; and absence of intramural small cystic lesions (accuracies of 90.0 %, 88.3 %, 85.0 %, and 85.0 %, respectively). The combination of any three high-risk features exhibited the highest accuracy (94.2 %). The presence of any high-risk feature yielded a sensitivity of 100 %, whereas that of all high-risk features indicated a specificity of 100 %. CONCLUSION: CT imaging features, whether alone or in combination, could effectively and accurately predict GB cancer among patients with localized GB wall thickening. This finding holds significance in guiding decisions regarding further diagnostic tests and treatment planning.


Assuntos
Neoplasias da Vesícula Biliar , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X , Humanos , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Idoso , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/patologia , Reprodutibilidade dos Testes , Diagnóstico Diferencial , Idoso de 80 Anos ou mais , Adulto
7.
JAMA Otolaryngol Head Neck Surg ; 150(6): 502-508, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38696210

RESUMO

Importance: Ethanol ablation (EA) was shown to be safe and effective for treating ranula, but few studies have assessed long-term outcomes and recurrence of ranula after EA. Objective: To evaluate the long-term outcomes and the risk factors for recurrence and receipt of subsequent surgery in patients who underwent treatment with EA for ranula. Design, Setting, and Participants: This case-series study was conducted at a single tertiary hospital and assessed patients who were treated with EA between July 2009 and March 2021. Among 70 consecutive patients, those with follow-up loss or who were followed up for less than 24 months were excluded. Exposures: EA for ranula. Main Outcomes and Measures: The primary outcome was recurrence at last follow-up after single or multiple EA sessions. Secondary outcomes included receipt of subsequent surgery and the recurrence-free survival (RFS) rate after initial EA. Factors possibly associated with outcomes included patient age and sex; ranula site, type, diameter, volume, and echogenicity; the presentation-to-EA interval; parapharyngeal space extension; and sublingual gland herniation. Risk factors were identified on logistic regression analyses. Two-year RFS rates were analyzed for the initial cohort using the Kaplan-Meier method and compared by log-rank tests. Results: A total of 57 patients (mean [SD] age, 26.4 [12.1] years; 24 female individuals [42%]) who were followed up for a median of 57 months (range, 24-167 months) were included. The recurrence rate was 33% (n = 19), and 11 (19%) underwent subsequent surgery. Among patients with recurrence, 86% (31 of 36) experienced first recurrence within 12 months after initial EA. A presentation-to-EA interval of 12 months or longer was associated with an increased risk of recurrence (adjusted odds ratio [OR], 3.74; 95% CI, 1.01-13.82). No risk factors were significantly associated with subsequent surgery (highest OR in parapharyngeal space extension: adjusted OR, 4.96; 95% CI, 0.94-26.35). Among the initial cohort of 70 patients, 2-year RFS was lower in a maximum diameter of ranula of 5 cm or greater than less than 5 cm (24% [95% CI, 7%-41%] vs 50% [95% CI, 34%-66%]; difference, 26% [95% CI, -4% to 56%]; log-rank test, P = .02). Conclusions and Relevance: This case-series study found that the recurrence rate of ranula after EA was 33%. A presentation-to-EA interval of 12 months or longer may be a risk factor for recurrence, suggesting that early intervention with EA might minimize recurrence. Most first recurrences occurred within 12 months after EA, with a maximum diameter of ranula of 5 cm or greater being a possible risk factor.


Assuntos
Etanol , Rânula , Recidiva , Humanos , Feminino , Masculino , Fatores de Risco , Rânula/cirurgia , Etanol/uso terapêutico , Técnicas de Ablação/métodos , Adolescente , Adulto , Criança , Estudos Retrospectivos , Resultado do Tratamento , Pessoa de Meia-Idade , Adulto Jovem
8.
Science ; 384(6697): eadj8321, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38753769

RESUMO

Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.


Assuntos
Vacinas contra a AIDS , Anticorpos Amplamente Neutralizantes , Regiões Determinantes de Complementaridade , Centro Germinativo , Anticorpos Anti-HIV , Animais , Humanos , Vacinas contra a AIDS/imunologia , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Regiões Determinantes de Complementaridade/imunologia , Microscopia Crioeletrônica , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Centro Germinativo/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Macaca mulatta , Células B de Memória/imunologia
9.
Science ; 384(6697): eadk0582, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38753770

RESUMO

Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody-induced epitope masking, driving further B cell receptor (BCR) modification in GC-experienced B cells after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors to the V3-glycan-targeted bnAb BG18 and that B cells primed by N332-GT5 were effectively boosted by either of two novel protein immunogens designed to have minimum cross-reactivity with the off-target V1-binding responses. The delivery of the prime and boost immunogens as messenger RNA lipid nanoparticles (mRNA-LNPs) generated long-lasting GCs, somatic hypermutation, and affinity maturation and may be an effective tool in HIV vaccine development.


Assuntos
Vacinas contra a AIDS , Anticorpos Amplamente Neutralizantes , Centro Germinativo , Anticorpos Anti-HIV , HIV-1 , Imunização Secundária , Nanopartículas , Vacinas de mRNA , Animais , Humanos , Camundongos , Vacinas contra a AIDS/imunologia , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Reações Cruzadas , Técnicas de Introdução de Genes , Centro Germinativo/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , HIV-1/genética , Lipossomos , Células B de Memória/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/genética , Hipermutação Somática de Imunoglobulina , Vacinas de mRNA/imunologia , Feminino , Camundongos Endogâmicos C57BL
10.
Eur Radiol ; 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38767659

RESUMO

OBJECTIVE: To assess the prognostic impact of preoperative MRI features on outcomes for single large hepatocellular carcinoma (HCC) (≥ 8 cm) after surgical resection. MATERIAL AND METHODS: This retrospective study included 151 patients (mean age: 59.2 years; 126 men) with a single large HCC who underwent gadoxetic acid-enhanced MRI and surgical resection between 2008 and 2020. Clinical variables, including tumor markers and MRI features (tumor size, tumor margin, and the proportion of hypovascular component on hepatic arterial phase (AP) (≥ 50% vs. < 50% tumor volume) were evaluated. Cox proportional hazards model analyzed overall survival (OS), recurrence-free survival (RFS), and associated factors. RESULTS: Among 151 HCCs, 37.8% and 62.2% HCCs were classified as ≥ 50% and < 50% AP hypovascular groups, respectively. The 5- and 10-year OS and RFS rates in all patients were 62.0%, 52.6% and 41.4%, 38.5%, respectively. Multivariable analysis revealed that ≥ 50% AP hypovascular group (hazard ratio [HR] 1.7, p = 0.048), tumor size (HR 1.1, p = 0.006), and alpha-fetoprotein ≥ 400 ng/mL (HR 2.6, p = 0.001) correlated with poorer OS. ≥ 50% AP hypovascular group (HR 1.9, p = 0.003), tumor size (HR 1.1, p = 0.023), and non-smooth tumor margin (HR 2.1, p = 0.009) were linked to poorer RFS. One-year RFS rates were lower in the ≥ 50% AP hypovascular group than in the < 50% AP hypovascular group (47.4% vs 66.9%, p = 0.019). CONCLUSION: MRI with ≥ 50% AP hypovascular component and larger tumor size were significant factors associated with poorer OS and RFS after resection of single large HCC (≥ 8 cm). These patients require careful multidisciplinary management to determine optimal treatment strategies. CLINICAL RELEVANCE STATEMENT: Preoperative MRI showing a ≥ 50% arterial phase hypovascular component and larger tumor size can predict worse outcomes after resection of single large hepatocellular carcinomas (≥ 8 cm), underscoring the need for tailored, multidisciplinary treatment strategies. KEY POINTS: MRI features offer insights into the postoperative prognosis for large hepatocellular carcinoma. Hypovascular component on arterial phase ≥ 50% and tumor size predicted poorer overall survival and recurrence-free survival. These findings can assist in prioritizing aggressive and multidisciplinary approaches for patients at risk for poor outcomes.

11.
Clin Orthop Surg ; 16(2): 275-285, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38562624

RESUMO

Background: To date, the efficiency of collagen meniscal scaffold implantation in Asian patients with partial meniscal defects has not been evaluated. In addition, no study has quantitatively analyzed meniscal regeneration using three-dimensional (3D) volume analysis after collagen scaffold implantation. We aimed to compare meniscal regeneration using 3D volume analysis between Asian patients undergoing collagen-based meniscal scaffold implantation after partial meniscectomy and those undergoing only partial meniscectomy. Methods: Nineteen patients who underwent collagen-based meniscal scaffold implantation and 14 who underwent partial meniscectomy were analyzed with a prospective randomized control design for 12 months postoperatively. The demographic characteristics, Kellgren-Lawrence grade, and location of the injury lesion (medial or lateral meniscus) were not significantly different between the groups. Using 3D volume analysis with magnetic resonance imaging (MRI), the meniscus-removing ratio during the operative procedure and the meniscus defect-filling ratio were measured during the 12-month postoperative period. Clinically, the visual analog scale, International Knee Documentation Committee score, and Knee Injury and Osteoarthritis Outcome Score were evaluated. The Whole-Organ Magnetic Resonance Imaging Score (WORMS) and Genovese grade were also evaluated using MRI. Results: In the 3D volume analysis, the average meniscus-removing ratio during surgery was not significantly different between the groups (-9.3% vs. -9.2%, p = 0.984). The average meniscus defect-filling ratio during the postoperative 12-month period was 7.5% in the scaffold group and -0.4% in the meniscectomy group (p < 0.001). None of the clinical results were significantly different between the scaffold and meniscectomy groups at 12 months postoperatively. The average change in the total WORMS score was not significantly different between the groups (0 vs. 1.9, p = 0.399). The Genovese grade of the implanted collagen scaffold did not significantly change during the follow-up period in terms of morphology and size (p = 0.063); however, the grade significantly improved in terms of signal intensity (p = 0.001). Conclusions: Definite meniscal regeneration and stable scaffold incorporation were observed after collagen-based meniscal scaffold implantation in Asian patients during 12 months of follow-up. A long-term follow-up study with a larger cohort is required to determine the advantages of collagenous meniscal scaffold implantation in Asian patients.


Assuntos
Meniscos Tibiais , Alicerces Teciduais , Humanos , Seguimentos , Resultado do Tratamento , Estudos Prospectivos , Meniscos Tibiais/diagnóstico por imagem , Meniscos Tibiais/cirurgia , Colágeno , Regeneração
12.
J Pers Med ; 14(4)2024 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-38673042

RESUMO

The nasal cavity constitutes the foremost portion of the respiratory system, composed of the anterior nasal aperture, nostrils, and choanae. It has an intricate anatomical structure since it has various functions, such as heat exchange, humidification, and filtration. Accordingly, clinical symptoms related to the nose, such as nasal congestion, snoring, and nasal septal deviation, are closely linked to the complex anatomical structure of the nasal cavity. Thus, the nasal cavity stands as a paramount structure in both forensic and clinical contexts. The majority of relevant studies have performed comparisons between sexes, with studies making comparisons according to the FI and NI only and examining relative percentages. Furthermore, the nasal cavity was measured in 2D, and not 3D, in most cases. In this study, we conducted a 3D modeling and anthropometric assessment of the nasal cavity using a 3D analysis software. Furthermore, we aimed to investigate whether the size of the nasal cavity differs according to sex, facial index (FI), and nasal index (NI). We retrospectively reviewed the cone-beam computed tomography (CBCT) data of 100 participants (50 males, 50 females) aged 20-29 years who visited the dental hospital of Dankook University (IRB approval no. DKUDH IRB 2020-01-007). Our findings showed that nasal cavity sizes generally differed according to sex, FI, and NI. These findings provide implications for performing patient-tailored surgeries in clinical practice and conducting further research on the nasal cavity. Therefore, we believe that our study makes a significant contribution to the literature.

13.
Stroke ; 55(5): 1370-1380, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38572656

RESUMO

BACKGROUND: Mild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However, the lack of chemicals that can safely inhibit mitochondrial respiration has impeded the clinical translation of the preconditioning concept. We previously showed that meclizine, an over-the-counter antivertigo drug, can toggle metabolism from mitochondrial respiration toward glycolysis and protect against ischemia-reperfusion injury in the brain, heart, and kidney. Here, we examine the mechanism of action of meclizine and report the efficacy and improved safety of the (S) enantiomer. METHODS: We determined the anoxic depolarization latency, tissue and neurological outcomes, and glucose uptake using micro-positron emission tomography after transient middle cerebral artery occlusion in mice pretreated (-17 and -3 hours) with either vehicle or meclizine. To exclude a direct effect on tissue excitability, we also examined spreading depression susceptibility. Furthermore, we accomplished the chiral synthesis of (R)- and (S)-meclizine and compared their effects on oxygen consumption and histamine H1 receptor binding along with their brain concentrations. RESULTS: Micro-positron emission tomography showed meclizine increases glucose uptake in the ischemic penumbra, providing the first in vivo evidence that the neuroprotective effect of meclizine indeed stems from its ability to toggle metabolism toward glycolysis. Consistent with reduced reliance on oxidative phosphorylation to sustain the metabolism, meclizine delayed anoxic depolarization onset after middle cerebral artery occlusion. Moreover, the (S) enantiomer showed reduced H1 receptor binding, a dose-limiting side effect for the racemate, but retained its effect on mitochondrial respiration. (S)-meclizine was at least as efficacious as the racemate in delaying anoxic depolarization onset and decreasing infarct volumes after middle cerebral artery occlusion. CONCLUSIONS: Our data identify (S)-meclizine as a promising new drug candidate with high translational potential as a chemical preconditioning agent for preemptive prophylaxis in patients with high imminent stroke or myocardial infarction risk.

14.
Liver Int ; 44(7): 1578-1587, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38651924

RESUMO

BACKGROUND AND AIMS: The Liver Imaging Reporting and Data System (LI-RADS) offers a standardized approach for imaging hepatocellular carcinoma. However, the diverse styles and structures of radiology reports complicate automatic data extraction. Large language models hold the potential for structured data extraction from free-text reports. Our objective was to evaluate the performance of Generative Pre-trained Transformer (GPT)-4 in extracting LI-RADS features and categories from free-text liver magnetic resonance imaging (MRI) reports. METHODS: Three radiologists generated 160 fictitious free-text liver MRI reports written in Korean and English, simulating real-world practice. Of these, 20 were used for prompt engineering, and 140 formed the internal test cohort. Seventy-two genuine reports, authored by 17 radiologists were collected and de-identified for the external test cohort. LI-RADS features were extracted using GPT-4, with a Python script calculating categories. Accuracies in each test cohort were compared. RESULTS: On the external test, the accuracy for the extraction of major LI-RADS features, which encompass size, nonrim arterial phase hyperenhancement, nonperipheral 'washout', enhancing 'capsule' and threshold growth, ranged from .92 to .99. For the rest of the LI-RADS features, the accuracy ranged from .86 to .97. For the LI-RADS category, the model showed an accuracy of .85 (95% CI: .76, .93). CONCLUSIONS: GPT-4 shows promise in extracting LI-RADS features, yet further refinement of its prompting strategy and advancements in its neural network architecture are crucial for reliable use in processing complex real-world MRI reports.


Assuntos
Neoplasias Hepáticas , Imageamento por Ressonância Magnética , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Carcinoma Hepatocelular/diagnóstico por imagem , Processamento de Linguagem Natural , Sistemas de Informação em Radiologia , República da Coreia , Mineração de Dados , Fígado/diagnóstico por imagem
15.
Eur Radiol ; 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38625610

RESUMO

PURPOSE: To determine whether switching to contrast media based on the sharing of N-(2,3-dihydroxypropyl) carbamoyl side chain reduces the recurrence of iodinated contrast media (ICM)-associated adverse drug reactions (ADRs). MATERIALS AND METHODS: This single-center retrospective study included 2133 consecutive patients (mean age ± SD, 56.1 ± 11.4 years; male, 1052 [49.3%]) who had a history of ICM-associated ADRs and underwent contrast-enhanced CT examinations. The per-patient and per-exam-based recurrence ADR rates were compared between cases of switching and non-switching the ICM from ICMs that caused the previous ADRs, and between cases that used ICMs with common and different carbamoyl side chains from ICMs that caused the previous ADRs. Downgrade rates (no recurrence or the occurrence of ADR less severe than index ADRs) were also compared. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were additionally performed. RESULTS: In per-patient analysis, switching of ICM showed a lower recurrence rate (switching, 10.4% [100/965] vs. non-switching, 28.4% [332/1168]), with the adjusted odds ratio (OR) of 0.27 (95% CI: 0.21, 0.34; p < 0.001). The result was consistent in PSM (OR, 0.29 [95% CI: 0.22, 0.39]; p < 0.001), IPTW (OR, 0.28 [95% CI: 0.22, 0.36]; p < 0.001), and in per-exam analysis (5.5% vs. 13.8%; OR, 0.32 [95% CI: 0.27, 0.37]; p < 0.001). There was lower per-exam recurrence (5.0% [195/3938] vs. 7.8% [79/1017]; OR, 0.63 [95% CI: 0.47, 0.83]; p = 0.001) and higher downgrade rates (95.6% [3764/3938] vs. 93.3% [949/1017]; OR, 1.51 [95% CI: 1.12, 2.03]; p = 0.006) when using different side chain groups. CONCLUSION: Switching to an ICM with a different carbamoyl side chain reduced the recurrent ADRs and their severity during subsequent examinations. CLINICAL RELEVANCE STATEMENT: Switching to an iodinated contrast media with a different carbamoyl side chain reduced the recurrent adverse drug reactions and their severity during subsequent examinations.

16.
J Plast Reconstr Aesthet Surg ; 92: 244-251, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38574571

RESUMO

BACKGROUND: Thickened nerve cross-sectional areas (CSA) have been investigated in compressive neuropathy, but the longitudinal extent of nerve swelling has yet to be evaluated. We did a volumetric assessment of the ulnar nerve in cubital tunnel syndrome (CuTS) with three-dimensional (3D) magnetic resonance imaging (MRI) modeling and investigated this relationship with clinical and electrodiagnostic parameters. METHODS: We compared 40 CuTS patient elbow MRIs to 46 patient elbow MRIs with lateral elbow epicondylitis as controls. The ulnar nerve was modeled with Mimics software and was assessed qualitatively and quantitatively. The CSA and ulnar nerve volumes were recorded, and the area under the receiver operating characteristic (ROC) curve was calculated for diagnostic performance. We analyzed clinical and electrodiagnostic parameters to investigate their relationship with the 3D ulnar nerve parameters. RESULTS: For the diagnosis of CuTS, the area under the curve value was 0.915 for the largest CSA and 0.910 for the volume in the ROC curve. The optimal cut-off was 14.53 mm2 and 529 mm3 respectively. When electrodiagnostic parameters were investigated, the 3D ulnar nerve volume was significantly inversely associated with motor conduction velocity, although there was no association between the largest CSA and any of the electrodiagnostic parameters. CONCLUSIONS: The 3D ulnar nerve volume, which is an integration or multilevel measurement of CSAs, showed diagnostic usefulness similar to CSA, but it correlated better with conduction velocity, indicating demyelination or early-to-moderate nerve damage in CuTS.


Assuntos
Síndrome do Túnel Ulnar , Eletrodiagnóstico , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Nervo Ulnar , Humanos , Síndrome do Túnel Ulnar/diagnóstico , Síndrome do Túnel Ulnar/diagnóstico por imagem , Nervo Ulnar/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Eletrodiagnóstico/métodos , Adulto , Idoso , Curva ROC
18.
Magn Reson Imaging ; 109: 127-133, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38513784

RESUMO

PURPOSE: Magnetic resonance elastography (MRE) is a noninvasive tool for diagnosing hepatic fibrosis with high accuracy. We investigated the preoperative clinical and imaging predictors of intrahepatic recurrence after curative resection of hepatocellular carcinoma (HCC), and evaluated MRE as a predictor of intrahepatic recurrence. METHODS: We retrospectively evaluated 80 patients who underwent preoperative contrast-enhanced magnetic resonance imaging (MRI) with two-dimensional MRE and curative resection for treatment-naïve HCC between May 2019 and December 2021. Liver stiffness (LS) was measured on the elastograms, and the optimal cutoff of LS for predicting intrahepatic recurrence was obtained using receiver operating characteristic (ROC) analysis. An LS above this cutoff was defined as MRE-recurrence. Preoperative imaging features of the tumor were assessed on MRI, including features in the Liver Imaging Reporting and Data System and microvascular invasion (MVI). Recurrence-free survival (RFS) rates were estimated using the Kaplan-Meier method, and differences were compared using the log-rank test. Using a Cox proportional hazards model, we conducted a multivariable analysis to investigate the factors affecting recurrence-free survival. RESULTS: During a median follow-up period of 32 months (range, 4-52 months), thirteen patients (16.3%) developed intrahepatic recurrence. ROC analysis determined an LS cutoff of ≥4.35 kPa to define MRE-recurrence. The 4-year RFS rate was significantly higher in patients without MRE-recurrence than in those with MRE-recurrence (93.4% vs. 48.9%; p = 0.001). In multivariable analysis, MRE-recurrence (Hazard ratio [HR], 5.9; 95% confidence interval [CI], 1.5-23.1) and MVI (HR, 3.4; 95% CI, 1.0-11.3) were independent predictors of intrahepatic recurrence. CONCLUSIONS: Patients without MRE-recurrence had significantly higher RFS rates than those with MRE-recurrence. MRE-recurrence and MVI were independent predictors of intrahepatic recurrence in patients after curative resection for HCC.


Assuntos
Carcinoma Hepatocelular , Técnicas de Imagem por Elasticidade , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Técnicas de Imagem por Elasticidade/métodos , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos
19.
J Med Virol ; 96(3): e29536, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38488495

RESUMO

Following the worldwide surge in mpox (monkeypox) in 2022, cases have persisted in Asia, including South Korea, and sexual contact is presumed as the predominant mode of transmission, with a discernible surge in prevalence among immunocompromised patients. Drugs such as tecovirimat can result in drug-resistant mutations, presenting obstacles to treatment. This study aimed to ascertain the presence of tecovirimat-related resistant mutations through genomic analysis of the monkeypox virus isolated from a reported case involving prolonged viral shedding in South Korea. Here, tecovirimat-resistant mutations, previously identified in the B.1 clade, were observed in the B.1.3 clade, predominant in South Korea. These mutations exhibited diverse patterns across different samples from the same patient and reflected the varied distribution of viral subpopulations in different anatomical regions. The A290V and A288P mutant strains we isolated hold promise for elucidating these mechanisms, enabling a comprehensive analysis of viral pathogenesis, replication strategies, and host interactions. Our findings imply that acquired drug-resistant mutations, may present a challenge to individual patient treatment. Moreover, they have the potential to give rise to transmitted drug-resistant mutations, thereby imposing a burden on the public health system. Consequently, the meticulous genomic surveillance among immunocompromised patients, conducted in this research, assumes paramount importance.


Assuntos
Benzamidas , Hospedeiro Imunocomprometido , Humanos , Eliminação de Partículas Virais , Isoindóis , Mutação , República da Coreia
20.
Ultrasonography ; 43(2): 141-150, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38369737

RESUMO

PURPOSE: This study investigated the clinical and ultrasonographic (US) findings of suture granulomas and recurrent tumors, and aimed to identify specific characteristics of suture granulomas through an experimental study. METHODS: This retrospective study included 20 pathologically confirmed suture granulomas and 40 recurrent tumors between January 2010 and December 2020. The clinical findings included suture material, surgery, and initial TNM stage. The US findings included shape, size, margin, echogenicity, heterogeneity, vascularity, and internal echogenic foci. The distribution, paired appearance, and "knot-and-ear" appearance of internal echogenic foci were assessed. An experiment using pork meat investigated the US configuration of suture knots. RESULTS: Eighteen patients with 20 suture granulomas (15 women; mean age, 52±13 years) and 37 patients with 40 recurrent tumors (24 women; 54±18 years) were included. Patients with suture granulomas exhibited earlier initial T and N stages than those with recurrent tumors. The knot-and-ear appearance, defined as an echogenic dot accompanied by two adjacent echogenic dots or lines based on experimental findings, was observed in 50% of suture granulomas, but not in recurrent tumors (P<0.001). Central internal echogenic foci (68.8%, P=0.023) and paired appearance (75.0%, P<0.001) were more frequent in suture granulomas. During follow-up, 94.1% of suture granulomas shrunk. CONCLUSION: The knot-and-ear appearance is a potential pathognomonic finding of suture granuloma, and central internal echogenic foci with paired appearance were typical US features. Clinically, suture granulomas showed early T and N stages and size reduction during follow-up. Understanding these features can prevent unnecessary biopsy or diagnostic surgery.

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