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Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-ß without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.
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Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.
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Mutación con Ganancia de Función , Lupus Eritematoso Sistémico , Receptor Toll-Like 7 , Animales , Autoinmunidad/genética , Linfocitos B , GMP Cíclico/análogos & derivados , Guanosina , Humanos , Lupus Eritematoso Sistémico/genética , Ratones , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismoRESUMEN
Intracellular sensors detect changes in levels of essential metals to initiate homeostatic responses. But, a mammalian manganese (Mn) sensor is unknown, representing a major gap in understanding of Mn homeostasis. Using human-relevant models, we recently reported that: 1) the primary homeostatic response to elevated Mn is upregulation of hypoxia-inducible factors (HIFs), which increases expression of the Mn efflux transporter SLC30A10; and 2) elevated Mn blocks the prolyl hydroxylation of HIFs by prolyl hydroxylase domain (PHD) enzymes, which otherwise targets HIFs for degradation. Thus, the mammalian mechanism for sensing elevated Mn likely relates to PHD inhibition. Moreover, 1) Mn substitutes for a catalytic iron (Fe) in PHD structures; and 2) exchangeable cellular levels of Fe and Mn are comparable. Therefore, we hypothesized that elevated Mn directly inhibits PHD by replacing its catalytic Fe. In vitro assays using catalytically active PHD2, the primary PHD isoform, revealed that Mn inhibited, and Fe supplementation rescued, PHD2 activity. However, a mutation in PHD2 (D315E) that selectively reduced Mn binding without substantially impacting Fe binding or enzymatic activity resulted in complete insensitivity of PHD2 to Mn in vitro. Additionally, hepatic cells expressing full-length PHD2D315E were less sensitive to Mn-induced HIF activation and SLC30A10 upregulation than PHD2wild-type. These results: 1) define a fundamental Mn sensing mechanism for controlling Mn homeostasis-elevated Mn inhibits PHD2, which functions as a Mn sensor, by outcompeting its catalytic Fe, and PHD2 inhibition activates HIF signaling to up-regulate SLC30A10; and 2) identify a unique mode of metal sensing that may have wide applicability.
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Homeostasis , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Manganeso , Humanos , Manganeso/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Células HEK293 , Hierro/metabolismoRESUMEN
Here we report SUPPORT (statistically unbiased prediction utilizing spatiotemporal information in imaging data), a self-supervised learning method for removing Poisson-Gaussian noise in voltage imaging data. SUPPORT is based on the insight that a pixel value in voltage imaging data is highly dependent on its spatiotemporal neighboring pixels, even when its temporally adjacent frames alone do not provide useful information for statistical prediction. Such dependency is captured and used by a convolutional neural network with a spatiotemporal blind spot to accurately denoise voltage imaging data in which the existence of the action potential in a time frame cannot be inferred by the information in other frames. Through simulations and experiments, we show that SUPPORT enables precise denoising of voltage imaging data and other types of microscopy image while preserving the underlying dynamics within the scene.
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Microscopía , Redes Neurales de la Computación , Relación Señal-Ruido , Distribución Normal , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
BACKGROUND AND AIMS: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. APPROACH AND RESULTS: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. CONCLUSIONS: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.
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In this in vivo study on hairless mice, we examined the effects of light-emitting diode (LED) treatment applied prior to ultraviolet B (UVB) irradiation. We found that pre-treating with LED improved skin morphological and histopathological conditions compared to those only exposed to UVB irradiation. In our study, histological evaluation of collagen and elastic fibers after LED treatment prior to UVB irradiation showed that this pretreatment significantly enhanced the quality of fibers, which were otherwise poor in density and irregularly arranged due to UV exposure alone. This suggests that LED treatment promotes collagen and elastin production, leading to improved skin properties. Additionally, we observed an increase in Claudin-1 expression and a reduction in nuclear factor-erythroid 2-related factor 2 (Nrf-2) and heme-oxygenase 1 (HO-1) expression within the LED-treated skin tissues, suggesting that LED therapy may modulate key skin barrier proteins and oxidative stress markers. These results demonstrate that pretreatment with LED light can enhance the skin's resistance to UVB-induced damage by modulating gene regulation associated with skin protection. Further investigations are needed to explore the broader biological effects of LED therapy on other tissues such as blood vessels. This study underscores the potential of LED therapy as a non-invasive approach to enhance skin repair and counteract the effects of photoaging caused by UV exposure.
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BACKGROUND: Gut microbial dysbiosis is implicated in chronic liver disease and hepatocellular carcinoma (HCC), but the role of microbiomes from various body sites remains unexplored. We assessed disease-specific alterations in the urinary microbiome in HCC patients, investigating their potential as diagnostic biomarkers. METHODS: We performed cross-sectional analyses of urine samples from 471 HCC patients and 397 healthy controls and validated the results in an independent cohort of 164 HCC patients and 164 healthy controls. Urinary microbiomes were analyzed by 16S rRNA gene sequencing. A microbial marker-based model distinguishing HCC from controls was built based on logistic regression, and its performance was tested. RESULTS: Microbial diversity was significantly reduced in the HCC patients compared with the controls. There were significant differences in the abundances of various bacteria correlated with HCC, thus defining a urinary microbiome-derived signature of HCC. We developed nine HCC-associated genera-based models with robust diagnostic accuracy (area under the curve [AUC], 0.89; balanced accuracy, 81.2%). In the validation, this model detected HCC with an AUC of 0.94 and an accuracy of 88.4%. CONCLUSIONS: The urinary microbiome might be a potential biomarker for the detection of HCC. Further clinical testing and validation of these results are needed in prospective studies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Microbiota , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Estudios Prospectivos , Estudios Transversales , ARN Ribosómico 16S/genética , Microbiota/genéticaRESUMEN
BACKGROUND: Several PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies. RESULTS: To overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the "FG loop" of hPD-1, distinct from those of Keytruda® ("C'D loop") and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201's binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME. CONCLUSIONS: In summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.
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Reacciones Cruzadas , Inmunoterapia , Receptor de Muerte Celular Programada 1 , Animales , Humanos , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ratones , Reacciones Cruzadas/inmunología , Inmunoterapia/métodos , Concentración de Iones de Hidrógeno , Neoplasias/inmunología , Neoplasias/terapia , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Línea Celular Tumoral , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Epítopos/inmunología , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Ratones Endogámicos C57BL , FemeninoRESUMEN
BACKGROUND: Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863). METHODS: We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise. FINDINGS: Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months). INTERPRETATION: Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Furanos , Cetonas , Nivolumab , Receptor ErbB-2 , Transcriptoma , Humanos , Femenino , Cetonas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Furanos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Nivolumab/uso terapéutico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Persona de Mediana Edad , Genómica/métodos , Anciano , Biomarcadores de Tumor/genética , Adulto , Mutación , Metástasis de la Neoplasia , Perfilación de la Expresión Génica , Policétidos PoliéteresRESUMEN
Background Chimeric antigen receptor (CAR) T cells are a promising cancer therapy; however, reliable and repeatable methods for tracking and monitoring CAR T cells in vivo remain underexplored. Purpose To investigate direct and indirect imaging strategies for tracking the biodistribution of CAR T cells and monitoring their therapeutic effect in target tumors. Materials and Methods CAR T cells co-expressing a tumor-targeting gene (anti-CD19 CAR) and a human somatostatin receptor subtype 2 (hSSTr2) reporter gene were generated from human peripheral blood mononuclear cells. After direct labeling with zirconium 89 (89Zr)-p-isothiocyanatobenzyl-desferrioxamine (DFO), CAR T cells were intravenously injected into immunodeficient mice with a CD19-positive and CD19-negative human tumor xenograft on the left and right flank, respectively. PET/MRI was used for direct in vivo imaging of 89Zr-DFO-labeled CAR T cells on days 0, 1, 3, and 7 and for indirect cell imaging with the radiolabeled somatostatin receptor-targeted ligand gallium 68 (68Ga)-DOTA-Tyr3-octreotide (DOTATOC) on days 6, 9, and 13. On day 13, mice were euthanized, and tissues and tumors were excised. Results The 89Zr-DFO-labeled CAR T cells were observed on PET/MRI scans in the liver and lungs of mice (n = 4) at all time points assessed. However, they were not visualized in CD19-positive or CD19-negative tumors, even on day 7. Serial 68Ga-DOTATOC PET/MRI showed CAR T cell accumulation in CD19-positive tumors but not in CD19-negative tumors from days 6 to 13. Notably, 68Ga-DOTATOC accumulation in CD19-positive tumors was highest on day 9 (mean percentage injected dose [%ID], 3.7% ± 1.0 [SD]) and decreased on day 13 (mean %ID, 2.6% ± 0.7) in parallel with a decrease in tumor volume (day 9: mean, 195 mm3 ± 27; day 13: mean, 127 mm3 ± 43) in the group with tumor growth inhibition. Enhanced immunohistochemistry staining of cluster of differentiation 3 (CD3) and hSSTr2 was also observed in excised CD19-positive tumor tissues. Conclusion Direct and indirect cell imaging with PET/MRI enabled in vivo tracking and monitoring of CAR T cells in an animal model. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bulte in this issue.
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Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Animales , Ratones , Xenoinjertos , Radioisótopos de Galio , Receptores de Somatostatina , Leucocitos Mononucleares , Distribución Tisular , Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Modelos Animales de Enfermedad , Linfocitos TRESUMEN
Different antiviral treatments for chronic hepatitis B (CHB) have been known to have different metabolic effects. This study aimed to reveal whether tenofovir alafenamide (TAF)-induced dyslipidemia and its associated outcomes are significant. This study utilized 15-year historical cohort including patients with CHB in Korea and consisted of two parts: the single-antiviral and switch-antiviral cohorts. In the single-antiviral cohort, patients were divided into four groups (entecavir [ETV]-only, tenofovir disoproxil fumarate [TDF]-only, TAF-only, and non-antiviral). Propensity score matching (PSM) and linear regression model were sequentially applied to compare metabolic profiles and estimated atherosclerotic cardiovascular disease (ASCVD) risks longitudinally. In the switch-antiviral cohort, pairwise analyses were conducted in patients who switched NAs to TAF or from TAF. In the single-antiviral cohort, body weight and statin use showed significant differences between groups before PSM, but well-balanced after PSM. Changes in total cholesterol were significantly different between groups (-2.57 mg/dL/year in the TDF-only group and +2.88 mg/dL/year in the TAF-only group; p = 0.002 and p = 0.02, respectively). In the TDF-only group, HDL cholesterol decreased as well (-0.55 mg/dL/year; p < 0.001). The TAF-only group had the greatest increase in ASCVD risk, followed by the TDF-only group and the non-antiviral group. In the switch-antiviral cohort, patients who switched from TDF to TAF had a higher total cholesterol after switching (+9.4 mg/dL/year) than before switching (-1.0 mg/dL/year; p = 0.047). Sensitivity analysis on data with an observation period set to a maximum of 3 years for NA treatment showed consistent results on total cholesterol (-2.96 mg/dL/year in the TDF-only group and +3.09 mg/dL/year in the TAF-only group; p = 0.001 and p = 0.005, respectively). Another sensitivity analysis conducted on statin-treated patients revealed no significant change in cholesterol and ASCVD risk. TAF was associated with increased total cholesterol, whereas TDF was associated with decreased total and HDL cholesterol. Both TAF and TDF were associated with increased ASCVD risks, and statin use might mitigate these risks.
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Antivirales , Enfermedades Cardiovasculares , Hepatitis B Crónica , Tenofovir , Humanos , Masculino , Hepatitis B Crónica/tratamiento farmacológico , Femenino , Antivirales/uso terapéutico , Antivirales/efectos adversos , Tenofovir/uso terapéutico , Tenofovir/efectos adversos , Tenofovir/análogos & derivados , Persona de Mediana Edad , Adulto , República de Corea/epidemiología , Dislipidemias/inducido químicamente , Dislipidemias/epidemiología , Estudios de Cohortes , Guanina/análogos & derivados , Guanina/uso terapéutico , Guanina/efectos adversos , AlaninaRESUMEN
BACKGROUND: Bipolar disorder (BD) shows heterogeneous illness presentation both cross-sectionally and longitudinally. This phenotypic heterogeneity might reflect underlying genetic heterogeneity. At the same time, overlapping characteristics between BD and other psychiatric illnesses are observed at clinical and biomarker levels, which implies a shared biological mechanism between them. Incorporating these two issues in a single study design, this study investigated whether phenotypically heterogeneous subtypes of BD have a distinct polygenic basis shared with other psychiatric illnesses. METHODS: Six lifetime phenotype dimensions of BD identified in our previous study were used as target phenotypes. Associations between these phenotype dimensions and polygenic risk scores (PRSs) of major psychiatric illnesses from East Asian (EA) and other available populations were analyzed. RESULTS: Each phenotype dimension showed a different association pattern with PRSs of mental illnesses. PRS for EA schizophrenia showed a significant negative association with the cyclicity dimension (p = 0.044) but a significant positive association with the psychotic/irritable mania dimension (p = 0.001). PRS of EA major depressive disorder demonstrated a significant negative association with the elation dimension (p = 0.003) but a significant positive association with the comorbidity dimension (p = 0.028). CONCLUSION: This study demonstrates that well-defined phenotype dimensions of lifetime-basis in BD have distinct genetic risks shared with other major mental illnesses. This finding supports genetic heterogeneity in BD and suggests a pleiotropy among BD subtypes and other psychiatric disorders beyond BD. Further genomic analyses adopting deep phenotyping across mental illnesses in ancestrally diverse populations are warranted to clarify intra-diagnosis heterogeneity and inter-diagnoses commonality issues in psychiatry.
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BACKGROUND: We investigated the risks of depression/anxiety in patients with multiple sclerosis (pwMS) or patients with neuromyelitis optica spectrum disorder (pwNMOSD). OBJECTIVES: MS/NMOSD cohorts were collected from Korean National Health Insurance Service, using the International Classification of Diseases-10th and information on Rare Intractable Disease program. Patients who were younger than 20 years, had a previous depression/anxiety, or died in the index year were excluded. METHODS: Hazard ratios (HRs) of depression/anxiety in pwMS and pwNMOSD from controls matched 1:5 for age, sex, hypertension, diabetes, and dyslipidemia were calculated using Cox regressions with a 1-year lag period and estimated over time. RESULTS: During a mean follow-up of 4.1 years, adjusted hazard ratios (aHR) for depression were 3.25 (95% confidence interval (CI) = 2.59-4.07) in MS and 2.17 (1.70-2.76) in NMOSD, and aHRs for anxiety were 1.83 (1.49-2.23) in MS and 1.56 (1.26-1.91) in NMOSD. The risks of anxiety/depression did not differ between MS and NMOSD and were highest in the second year after diagnosis of MS/NMOSD. The relative risk of depression was higher in younger pwMS/pwNMOSD, and the relative risk of anxiety was higher in pwMS who was male, had low income, or lived in a non-urban area. CONCLUSION: The risk of depression and anxiety was increased in pwMS/pwNMOSD.
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Ansiedad , Depresión , Esclerosis Múltiple , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/epidemiología , República de Corea/epidemiología , Masculino , Femenino , Adulto , Esclerosis Múltiple/epidemiología , Persona de Mediana Edad , Ansiedad/epidemiología , Depresión/epidemiología , Estudios de Cohortes , Adulto Joven , Factores de RiesgoRESUMEN
INTRODUCTION: Although the relationship between migraine and multiple sclerosis (MS) has been reported, the risk of migraine in MS and neuromyelitis optica spectrum disorder (NMOSD) is unclear. Therefore, this study investigated the risk of migraine in the Korean MS and NMOSD populations. METHODS: This study analyzed claims data from 1,492 patients with MS and 1,551 patients with NMOSD based on diagnostic codes in the Korean National Health Insurance Service. Migraine risk was compared with a control group (matched 1:5 for age, sex, and comorbidities) using Cox proportional hazards analysis. Patients aged <20 years and with previous migraine were excluded. RESULTS: Migraine risk was higher in patients with MS (adjusted hazard ratio [aHR] 1.37; 95% confidence interval [CI]: 1.15-1.62) but did not differ significantly in patients with NMOSD (aHR 1.05; 95% CI: 0.87-1.27) compared to controls. No significant sex-based differences in migraine risk were observed. Patients with NMOSD showed decreasing risk with age (p for interaction = 0.040). Comorbidities like hypertension, diabetes, or dyslipidemia did not significantly alter migraine risk in either group. CONCLUSION: The study results revealed an increased risk of migraines in patients with MS but not in patients with NMSOD compared with matched controls.
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BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses heterogeneous fatty liver diseases associated with metabolic disorders. We aimed to evaluate the association between MAFLD and extrahepatic malignancies based on MAFLD subtypes. METHODS: This nationwide cohort study included 9 298 497 patients who participated in a health-screening programme of the National Health Insurance Service of Korea in 2009. Patients were further classified into four subgroups: non-MAFLD, diabetes mellitus (DM)-MAFLD, overweight/obese-MAFLD and lean-MAFLD. The primary outcome was the development of any primary extrahepatic malignancy, while death, decompensated liver cirrhosis and liver transplantation were considered competing events. The secondary outcomes included all-cause and extrahepatic malignancy-related mortality. RESULTS: In total, 2 500 080 patients were diagnosed with MAFLD. During a median follow-up of 10.3 years, 447 880 patients (6.0%) with extrahepatic malignancies were identified. The DM-MAFLD (adjusted subdistribution hazard ratio [aSHR] = 1.13; 95% confidence interval [CI] = 1.11-1.14; p < .001) and the lean-MAFLD (aSHR = 1.12; 95% CI = 1.10-1.14; p < .001) groups were associated with higher risks of extrahepatic malignancy than the non-MAFLD group. However, the overweight/obese-MAFLD group exhibited a similar risk of extrahepatic malignancy compared to the non-MAFLD group (aSHR = 1.00; 95% CI = .99-1.00; p = .42). These findings were reproduced in several sensitivity analyses. The DM-MAFLD was an independent risk factor for all-cause mortality (adjusted hazard ratio [aHR] = 1.41; 95% CI = 1.40-1.43; p < .001) and extrahepatic malignancy-related mortality (aHR = 1.20; 95% CI = 1.17-1.23; p < .001). CONCLUSION: The diabetic or lean subtype of MAFLD was associated with a higher risk of extrahepatic malignancy than non-MAFLD. As MAFLD comprises a heterogeneous population, appropriate risk stratification and management based on the MAFLD subtypes are required.
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Neoplasias , Enfermedad del Hígado Graso no Alcohólico , Humanos , Estudios de Cohortes , Sobrepeso , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Obesidad/complicaciones , Obesidad/epidemiologíaRESUMEN
OBJECTIVES: To evaluate the performance of the Academia-Government Collaboration for Laboratory Medicine Standardization in Korea (KR-STDZN) based on data from KR-STDZN proficiency testing (KR-STDZN-PT) for creatinine over eight years (2015-2022). METHODS: We used KR-STDZN-PT data of creatinine tests from 2015 to 2022. Acceptance of the participating institutions' test results was assessed by calculating the acceptance performance as absolute bias (absBias%), total coefficient of variance (tCV%), and total error (TE%) for each sample using six measurements from each institution and true values of each reference material. The test result was considered acceptable when absBias%, tCV%, and TE% were <5.10, <3.20, and <11.40â¯%, respectively. The proportion of acceptable institutions among all participating institutions in each round was defined as the acceptance rate. Improvements in absBias%, tCV%, and TE% were analyzed using creatinine concentration ranges in samples. RESULTS: The number of participating institutions increased from 2015 to 2017 but remained consistent since 2018. The acceptance rates for absBias% and TE% increased from 52.2 and 77.6â¯%, in 2015 and to 90.7 and 96.3â¯%, in 2022, respectively. The acceptance rate for tCV% remained in the 90â¯% range for eight years. When creatinine <3â¯mg/dL, mean absBias%, and mean TE% improved significantly in 2021-2022 compared to 2015-2016 (p<0.05). When creatinine >3â¯mg/dL, acceptance performance did not improve. Mean tCV% remained consistent annually regardless of creatinine concentration. No significant variations in test methods were observed. CONCLUSIONS: The collaboration between academia and the government improved creatinine testing quality. Nevertheless, KR-STDZN must be expanded and refined.
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Academia , Ensayos de Aptitud de Laboratorios , Humanos , Creatinina , Estándares de Referencia , GobiernoRESUMEN
AIM: Antiviral treatment reduces the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. However, there is a lack of high-quality evidence regarding the preventive effects of tenofovir alafenamide (TAF) on HCC. We evaluated the impact of TAF use after curative treatment on HCC recurrence. METHODS: Patients who underwent surgery or radiofrequency ablation as a curative treatment for HCC were selected. Those patients who continued antiviral treatment with nucleos(t)ide analogs (NAs; entecavir [ETV] or tenofovir disoproxil fumarate [TDF]) or switched to TAF were included. The primary outcome was HCC recurrence, and the time-varying effect of NA use on HCC recurrence was analyzed using various statistical methods. RESULTS: Among 2794 consecutive patients with chronic hepatitis B who received curative treatment for HCC, 199 subsequently switched from ETV or TDF to TAF. After a median of 3.0 years, 1303 patients (46.6%) experienced HCC recurrence. After propensity score matching (ratio 1:10), switching to TAF was not associated with an increased HCC recurrence (HR 1.00, 95% CI 0.68-1.47; p = 1.00) by time-varying Cox analysis. Switching to TAF was not associated with HCC recurrence in subgroups of NA (HR 1.06, 95% CI 0.67-1.67; p = 0.81 for TDF, and HR 1.09, 95% CI 0.51-2.33; p = 0.82 for ETV). Kaplan-Meier analysis showed comparable HCC recurrence-free survival between patients who switched to TAF and those who continued with their NA (p = 0.08). Time-varying Cox analyses in various subgroups confirmed the primary findings. CONCLUSIONS: TAF is as effective as TDF and ETV in preventing HCC recurrence after curative treatment.
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Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure-activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the ß-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the ß-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC.
Asunto(s)
Antineoplásicos , Carcinoma de Células Renales , Neoplasias Renales , Proteína Glutamina Gamma Glutamiltransferasa 2 , Animales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Imidazoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Simulación del Acoplamiento Molecular , Proteína Glutamina Gamma Glutamiltransferasa 2/antagonistas & inhibidores , Transglutaminasas/antagonistas & inhibidores , Transglutaminasas/metabolismo , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
This study investigated the effects of pregabalin on microglial differentiation in rats with neuropathic pain (NP) induced by sciatic nerve ligation and transection. After confirming NP, the rats were randomly allocated to either a pregabalin or control group. The pregabalin group received intraperitoneal injections of 10 mg/kg pregabalin, while the control group received an equivalent volume of normal saline following surgery. On postoperative day 28, neuronal damage, microglial activity, and microglial differentiation were assessed. The pregabalin group exhibited significantly less neuronal damage compared to the control group, along with a significant decrease in activated microglial expression in both the brain and spinal cord. Pregabalin treatment also significantly altered the microglial phenotype expression, with a decrease in the M1 phenotype percentage and an increase in the M2 phenotype percentage in both the brain (M1 phenotype: 43.52 ± 12.16% and 18.00 ± 8.57% in the control and pregabalin groups, respectively; difference: 27.26 [15.18-42.10], p = 0.002; M2 phenotype: 16.88 ± 6.47% and 39.63 ± 5.82% in the control and pregabalin groups, respectively; difference 22.04 [17.17-32.70], p < 0.001) and the spinal cord ipsilateral to nerve injury (M1 phenotype: 44.35 ± 12.12% and 13.78 ± 5.39% in the control and pregabalin groups, respectively; difference 30.46 [21.73-44.45], p < 0.001; M2 phenotype: 7.64 ± 3.91% and 33.66 ± 7.95% in the control and pregabalin groups, respectively; difference 27.41 [21.21-36.30], p < 0.001). Overall, pregabalin treatment significantly decreased the microglial M1 phenotype while increasing the microglial M2 phenotype in NP rats.
Asunto(s)
Diferenciación Celular , Microglía , Neuralgia , Pregabalina , Animales , Pregabalina/farmacología , Pregabalina/uso terapéutico , Microglía/efectos de los fármacos , Microglía/patología , Neuralgia/tratamiento farmacológico , Neuralgia/patología , Neuralgia/etiología , Ratas , Diferenciación Celular/efectos de los fármacos , Masculino , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Modelos Animales de Enfermedad , Analgésicos/farmacología , Analgésicos/uso terapéutico , Nervio Ciático/efectos de los fármacos , Nervio Ciático/patología , Ratas Sprague-Dawley , Humanos , Encéfalo/efectos de los fármacos , Encéfalo/patologíaRESUMEN
Glycated albumin (GA) reflects glycemic status for the past three weeks. GA level demonstrates a strong correlation with HbA1c level and is used as an adjunctive biomarker for diagnosis and monitoring of type 2 diabetes mellitus (T2DM). In this study, we validated the predictive performance of baseline GA for development of T2DM in healthy individuals in Korea. From August 2013 to September 2014, the medical records of 3,771 healthy Koreans were retrospectively reviewed. Each participant was categorized into tertiles based on initial GA level. During the follow-up period through May 2020, study participants were evaluated for T2DM using HbA1c, fasting glucose level, and a self-reported diagnosis history. Baseline GA level by tertile (T1 to T3) was 10.4 ± 0.8% (mean ± SD), 12.1 ± 0.3%, and 13.7 ± 0.9%, respectively. The median follow-up was 5.97 years, during which 4.9% (186 of 3,771) of the participants developed T2DM. After adjusting for confounding factors, the hazard ratio for the development of T2DM in the highest GA level group (T3) compared to the reference group (T1) was 2.46 (95% CI, 1.7 to 3.58, p < 0.001 for trend) with a Harrell's C index of 0.80 (95% CI, 0.76 to 0.83). Also, within highest group of baseline HbA1c and FG levels, higher GA levels were associated with an increased HRs for T2DM. In conclusion, Our study confirms that the risk of T2DM increases with baseline GA level. Additional follow-up of the cohort is warranted to investigate the correlations between GA and other clinical indicators including diabetic complications.