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The structural dynamics of artificial assemblies, in aspects such as molecular recognition and structural transformation, provide us with a blueprint to achieve bioinspired applications. Here, we describe the assembly of redox-switchable chiral metal-organic cages Λ8/Δ8-[Pd6(CoIIL3)8]28+ and Λ8/Δ8-[Pd6(CoIIIL3)8]36+. These isomeric cages demonstrate an on-off chirality logic gate controlled by their chemical and stereostructural dynamics tunable through redox transitions between the labile CoII-state and static CoIII-state with a distinct Cotton effect. The transition between different states is enabled by a reversible redox process and chiral recognition originating in the tris-chelate Co-centers. All cages in two states are thoroughly characterized by NMR, ESI-MS, CV, CD, and X-ray crystallographic analysis, which clarify their redox-switching behaviors upon chemical reduction/oxidation. The stereochemical lability of the CoII-center endows the Λ8/Δ8-CoII-cages with efficient chiral-induction by enantiomeric guests, leading to enantiomeric isomerization to switch between Λ8/Δ8-CoII-cages, which can be stabilized by oxidation to their chemically inert forms of Λ8/Δ8-CoIII-cages. Kinetic studies reveal that the isomerization rate of the Δ8-CoIII-cage is at least an order of magnitude slower than that of the Δ8-CoII-cage even at an elevated temperature, while its activation energy is 16 kcal mol-1 higher than that of the CoII-cage.
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Atherosclerosis (AS) is a common cause of coronary heart disease and stroke. The delivery of exogenous H2S and in situ production of O2 within atherosclerotic plaques can help suppress inflammatory cell infiltration and alleviate disease progression. However, the uncontrolled release of gas donors hinders achieving effective drug concentrations and causes toxic effects. Herein, diallyl trisulfide (DATS)-loaded metal-organic cage (MOC)-68-doped MnO2 nanoparticles are developed as a microenvironment-responsive nanodrug with the capacity for the in situ co-delivery of H2S and O2 to inflammatory cells within plaques. This nanomedicine exhibited excellent monodispersity and stability and protected DATS from degradation in the circulation. In vitro studies showed that the nanomedicine reduced macrophage polarization toward an inflammatory phenotype and inhibited the formation of foam cells, while suppressing the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin-1ß. In a mouse model of ApoE-/- genotype, the nanomedicine reduces the plaque burden, inflammatory infiltration, and hypoxic conditions within the plaques. Furthermore, the treatment process and therapeutic effects can be monitored by magnetic resonance image (MRI), in real time upon Mn2+ release from the acidic- and H2O2- microenvironment-responsive MnO2 nanoparticles. The DATS-loaded MOC-68-doped MnO2-based nanodrug holds great promise as a novel theranostic platform for AS.
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In the present study, the environment-friendly visible-light-promoted strategy is used to perform an efficient, simple, and straightforward photocatalytic succinimide derivative synthesis from the reaction of 1,6-enynes and aryl sulfonyl bromide at room temperature under air ambient conditions. This method features mild conditions, broad substrate scope, high yields, and excellent configurational selectivity. In addition, all the atoms of the substrates involved in the reaction converge in the product structures, showing a high atomic economy. Moreover, the most important characteristic of this study is that no photocatalyst and additives are used, while the key factor that triggers the reaction is visible light, indicating that this study has an important practical value.
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BACKGROUND: The long-term effectiveness of cognitive behavioural therapy (CBT) in medicated attention-deficit/hyperactivity disorder (ADHD) adults with residual symptoms needs to be verified across multiple dimensions, especially with respect to maladaptive cognitions and psychological quality of life (QoL). An exploration of the mechanisms underlying the additive benefits of CBT on QoL in clinical samples may be helpful for a better understanding of the CBT conceptual model and how CBT works in medicated ADHD. METHODS: We conducted a secondary analysis of a randomised controlled trial including 98 medicated ADHD adults with residual symptoms who were randomly allocated to the CBT combined with medication (CBT + M) group or the medication (M)-only group. Outcomes included ADHD-core symptoms (ADHD Rating Scale), depression symptoms (Self-rating Depression Scale), maladaptive cognitions (Automatic Thoughts Questionnaire and Dysfunctional Attitude Scale), and psychological QoL (World Health Organization Quality of Life-Brief Version-psychological domain). Mixed linear models (MLMs) were used to analyse the long-term effectiveness at one-year follow-up, and structural equation modeling (SEM) was performed to explore the potential mechanisms of CBT on psychological QoL. RESULTS: ADHD patients in the CBT + M group outperformed the M-only group in reduction of ADHD core symptoms (d = 0.491), depression symptoms (d = 0.570), a trend of reduction of maladaptive cognitions (d = 0.387 and 0.395, respectively), and improvement of psychological QoL (d = - 0.433). The changes in above dimensions correlated with each other (r = 0.201 ~ 0.636). The influence of CBT on QoL was mediated through the following four pathways: 1) changes in ADHD core symptoms; 2) changes in depressive symptoms; 3) changes in depressive symptoms and then maladaptive cognitions; and 4) changes firstly in depressive symptoms, maladaptive cognitions, and then ADHD core symptoms. CONCLUSIONS: The long-term effectiveness of CBT in medicated ADHD adults with residual symptoms was further confirmed. The CBT conceptual model was verified in clinical samples, which would be helpful for a deeper understanding of how CBT works for a better psychological QoL outcome. TRIAL REGISTRATION: ChiCTR1900021705 (2019-03-05).
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Transtorno do Deficit de Atenção com Hiperatividade , Terapia Cognitivo-Comportamental , Adulto , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Qualidade de Vida , Seguimentos , Resultado do Tratamento , Terapia Cognitivo-Comportamental/métodosRESUMO
Type III redundancy of the foramen ovale flap (RFOF) mimics hemodynamic changes of mitral stenosis(MS), which has not been particularly highlighted in previous literature but carries a favorable prognosis.
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Hemodinâmica , Estenose da Valva Mitral , Humanos , Estenose da Valva Mitral/fisiopatologia , Estenose da Valva Mitral/cirurgia , Hemodinâmica/fisiologia , Diagnóstico Diferencial , Feminino , Forame Oval/fisiopatologia , Forame Oval/diagnóstico por imagem , Ecocardiografia Transesofagiana/métodosRESUMO
Morphology and function in a fetal heart with severe tricuspid regurgitation remains challenging. The aim of this study was to assess cardiac morphology and function in fetuses with severe tricuspid regurgitation by fetal heart quantification (HQ) and to assess the practical value of fetal HQ. Clinical information was analyzed for 63 pregnant women who underwent fetal cardiac ultrasonography. The women were divided into those who had a fetus with severe tricuspid regurgitation (n = 20) and those with a normal fetus (n = 40). The global sphericity index (GSI), fractional area change (FAC), and global longitudinal strain (GLS) of both ventricles and the sphericity index (SI) and fractional shortening (FS) of 24 segments were quantified by fetal HQ using speckle tracking imaging. Fetuses with severe tricuspid regurgitation had a significantly lower GSI (1.14 ± 0.10 vs. 1.26 ± 0.08, p < 0.001) and a higher GSI Z-score (-0.98 ± 1.01 vs. 0.25 ± 0.87, p < 0.001) as well as a significantly lower right ventricular FAC (36.50 ± 7.34% vs. 45.19 ± 3.39%, p < 0.001), FAC Z-score (-1.02 ± 1.41 vs. 0.49 ± 0.74, p < 0.001), and GLS (-21.01 ± 5.66% vs. 45.19 ± 3.49%, p < 0.001). The SI and SI Z-score were significantly lower in segments 1-18 of the right ventricle in fetuses with severe tricuspid regurgitation (p < 0.05); furthermore, FS of segments 1-12 and 19-24 and the FS Z-score of segments 18-24 were significantly lower in fetuses with severe tricuspid regurgitation (p < 0.05). Fetal HQ is useful for evaluation of cardiac morphology and function in fetuses with severe tricuspid regurgitation and can provide important reference information for both clinical diagnosis and treatment.
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Insuficiência da Valva Tricúspide , Humanos , Feminino , Gravidez , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Coração Fetal/diagnóstico por imagem , Ventrículos do Coração , Ultrassonografia Pré-Natal/métodosRESUMO
PURPOSE: This study was designed to investigate the application value of the atrial septum excursion index (ASEI) in fetuses with isolated restrictive foramen ovale (RFO) or redundant foramen ovale flap (RFOF) and the outcomes of these fetuses. METHODS: This was a retrospective study. Healthy pregnant women who were examined by antenatal fetal echocardiography from January 1, 2019 to December 31, 2021, at Sir Run Run Shaw Hospital were enrolled. One hundred seventy-seven (177) fetuses were categorized into three groups by diagnosis: (1) RFOF (n = 33), (2) RFO (n = 21), and (3) normal (n = 123). Fetal echocardiographic features and postnatal outcomes were collected. RESULTS: The median ASEIs were 0.50 (range, 0.41-0.65) in the control group, 0.76 (range, 0.67-0.88) in the RFOF group and 0.31 (range, 0.14-0.35) in the RFO group, and the differences were significant (p < 0.001). The ratios of right atrium/left atrium, right ventricle/left ventricle, and pulmonary artery diameter to aorta diameter (PA/AO) and the pulmonary annulus Z-scores were greater in fetuses with RFOF and RFO than in the controls (p < 0.05). Twenty-seven of 33 fetuses (87.9%) with RFOF and 19 of 21 fetuses (90.5%) with RFO had good outcomes after birth. CONCLUSION: The ASEI may be a new tool for quantitatively assessing the mobility of foramen ovale flaps in fetuses with isolated RFOF or RFO.
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Ecocardiografia , Forame Oval , Ultrassonografia Pré-Natal , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Ultrassonografia Pré-Natal/métodos , Adulto , Ecocardiografia/métodos , Forame Oval/diagnóstico por imagem , Forame Oval/embriologia , Forame Oval/cirurgia , Comunicação Interatrial/cirurgia , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/embriologia , Coração Fetal/diagnóstico por imagem , Coração Fetal/fisiopatologia , Septo Interatrial/diagnóstico por imagem , Septo Interatrial/embriologia , Septo Interatrial/cirurgiaRESUMO
Gastrointestinal (GI) cancers are some of the main public health threats to the world. Even though surgery, chemotherapy, and targeted therapy are available for their treatments, these approaches provide limited success in reducing mortality, making the identification of additional therapeutic targets mandatory. Chromatin remodeling in cancer has long been studied and related therapeutics are widely used, although less is known about factors with prognostic and therapeutic potential in such areas as gastrointestinal cancers. Through applying systematic bioinformatic analysis, we determined that out of 31 chromatin remodeling factors in six gastrointestinal cancers, only PR/SET domain 1 (PRDM1) showed both expression alteration and prognosis prediction. Analyses on pathways, therapies, and mediators showed that cell cycle, bromodomain inhibitor IBET151, and BET protein BRD4 were, respectively involved in PRDM1-high stomach cancer, while cell line experiments validated that PRDM1 knockdown in human stomach cancer cell line SNU-1 decreased its proliferation, BRD4 expression, and responsiveness to IBET151; accordingly, these results indicate the contribution by PRDM1 in stomach cancer formation and its association with BRD4 modulation as well as BET inhibitor treatment.
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Photoluminescent metal-organic frameworks (MOFs) have been a subject of considerable interest for many years. However, the regulation of excited states of MOFs at the single crystal level remains restricted due to a lack of control methods. The singlet-triplet emissive property can be significantly influenced by crystal conformational distortions. This review introduces an intelligent responsive MOF material, denoted as LIFM-SHL-3a, characterized by flexible C-S-C bonds. LIFM-SHL-3a integrates elastic structural dynamics with fluorescence and room temperature phosphorescence (RTP) modulation under heating conditions. The deformable carbon-sulfur bond essentially propels the distortion of molecular conformation and alters the stacking mode, as illustrated by single-crystal-to-single-crystal transformation detection. The deformation of flexible C-S-C bonds leads to different noncovalent interactions in the crystal system, thereby achieving modulation of the fluorescence (F) and RTP bands. In the final state structure, the ratio of fluorescence is 66.7%, and the ratio of RTP is 32.6%. This stands as a successful demonstration of modulating F/RTP within the dynamic MOF, unlocking potential applications in optical sensing and beyond. Especially, a PL thermometer with a relative sensitivity of 0.096-0.104%·K-1 in the range of 300-380 K and a H2S probe with a remarkably low LOD of 125.80 nM can be obtained using this responsive MOF material of LIFM-SHL-3a.
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Purpose: To evaluate and compare the diagnostic value of contrast-enhanced transcranial Doppler (c-TCD) and contrast-enhanced transthoracic echocardiography (c-TTE) for right to left shunt (RLS) in patent foramen ovale (PFO) by meta-analysis. Methods: The literature included in the Cochrane Library, PubMed, and Embase were searched by using "contrast-enhanced transcranial Doppler (c-TCD), contrast-enhanced transthoracic echocardiography (c-TTE), patent foramen ovale (PFO), and right to left shunt (RLS)" as the keywords from inception through April 30, 2024. The diagnostic accuracy research quality assessment tool (QUADAS-2) was used to evaluate the quality of the included literature. The combined sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and Diagnostic odds ratio (DOR) were pooled, and a comprehensive ROC curve analysis was performed. Statistical software StataSE 12.0 and Meta-Disc 1.4 were used for data analysis. Results: A total of 8,536 articles were retrieved, and 9 articles that met all inclusion criteria were included in this meta-analysis. The meta-analysis results show that the combined sensitivity, specificity, PLR, NLR, DOR, and area under the SROC curve of c-TCD for the diagnose of PFO-RLS were 0.91 (95% CI, 0.88-0.93), 0.87 (95% CI: 0.84-0.91), 6.0 (95% CI, 2.78-12.96), 0.10 (95% CI, 0.06-0.18), 91.61 (95% CI, 26.55-316.10), and 0.9681, respectively; the corresponding values of c-TTE were 0.86 (95% CI, 0.84-0.89), 0.88 (95% CI, 0.84-0.91), 5.21 (95% CI, 2.55-10.63), 0.16 (95% CI, 0.09-0.31), 71.43 (95% CI, 22.85-223.23), and 0.9532. The ROC curve shows that c-TCD has slightly higher diagnostic value for PFO than c-TTE, but there is no significant statistical difference (Z = 0.622, p > 0.05). Deek funnel pattern showed no significant publication bias. Conclusion: Both c-TCD and c-TTE have high diagnostic values for PFO-RLS. However, c-TCD has slightly higher sensitivity and lower specificity in diagnosing PFO-RLS compared to c-TTE.Systematic review registration: identifier [CRD42024544169].
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Early detection of cancer recurrence using specific biomarkers remains a clinically unmet need, although methodologies for monitoring tumor markers, cell-free DNA, and circulating tumor cells have been established for decades. Tumor recurrence develops in metastatic or dormant cancer cells under continuous immune surveillance. Alterations in the population and function of immune cells may contribute to cancer recurrence. Here, we utilized an animal model to imitate breast tumor recurrence after surgical resection and investigated the abundance and gene expression profiles of immune cells using NanoString analysis. Bioinformatic analysis of a published single-cell RNA sequencing database of myeloid-derived suppressor cells (MDSCs) was performed to identify common targets between the two studies. Identified biomarkers were validated using human peripheral blood mononuclear cell (PBMC) datasets. The inhibitory effect of MDSCs on T-cell proliferation was assessed in vitro. Our data demonstrated that the number of MDSCs significantly increased during recurrence. Comparison of our NanoString data with a single-cell RNA sequencing dataset of MDSCs in another spontaneous breast cancer model identified colony-stimulating factor 3 receptor (Csf3r)-positive MDSCs as a potential marker for predicting tumor relapse. We validated our findings using two previously published PBMC databases of patients with breast cancer with or without recurrence and confirmed the elevated MDSC gene signature and CSF3R expression in patients with tumor recurrence. 35 patients with breast cancer were also included in our study, that patients with higher levels of CSF3R had worse survival. In vitro experiments demonstrated that Csf3r + MDSCs exhibited enhanced reactive oxygen species (ROS) levels and robust T-cell suppression ability. We conclude that an increase in CSF3R + MDSCs is a potential biomarker for early detection of tumor recurrence in patients with breast cancer.
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By integrating a tailor-made donor-acceptor (D-A) ligand in a metal-organic framework (MOF), a material with unprecedented features emerges. The ligand combines a pair of cyano groups as acceptors with four sulfanylphenyls as donors, which expose each a carboxylic acid as coordination sites. Upon treatment with zinc nitrate in a solvothermal synthesis, the MOF is obtained. The new material combines temperature-assisted reverse intersystem crossing (RISC) and intersystem crossing (ISC). As these two mechanisms are active in different temperature windows, thermal switching between their characteristic emission wavelengths is observed for this material. The two mechanisms can be activated by both, one-photon absorption (OPA) and two-photon absorption (TPA) resulting in a large excitement window ranging from ultraviolet (UV) over visible light (VL) to near infrared (NIR). Furthermore, the emission features of the material are pH sensitive, such that its application potential is demonstrated in a first ammonia sensor.
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Coarctation of the aorta (CoA) ranks among the most prevalent congenital heart defects and poses a life-threatening risk if left undiagnosed. Herein, we utilized fetal heart quantification (HQ) technology to improve the prenatal prediction of CoA. A retrospective analysis was conducted on 64 fetal cases with suspected aortic arch constriction, identified through prenatal ultrasound findings between November 2020 and March 2022 at the Department of Ultrasound, Sir Run Run Shaw Hospital, Zhejiang University. According to the follow-up results, these cases were divided into two groups: 35 cases confirmed as CoA by postpartum surgery or induction, and 29 cases initially suspected of CoA prenatally but subsequently ruled out postnatally. Additionally, 88 cases of normal fetuses were randomly selected as the control group. Both conventional M-mode ultrasound techniques and Fetal HQ software were utilized for fetal analysis across all groups. Parameters related to the heart were measured, including fetal 4-CV length, width, Global Spherical Index (GSI), Mitral Annular Plane Systolic Excursion (MAPSE), areas and ratios of the left and right ventricles, as well as lengths and ratios of the left and right ventricles. Functional measurements of the left and right ventricles included ejection fraction (EF), fractional area change (FAC), global longitudinal strain (GLS), fractional shortening (FS), end-diastolic diameter (ED), and sphericity index (SI). Left ventricular (LV)-GLS, LV-FAC, LV-EF, and LV-EF Z-score could potentially differentiate between true CoA and false CoA or normal groups and serve as potential indicators for the clinical diagnosis of CoA. The receiver operating characteristic (ROC) curves indicated that LV-GLS and LV-EF Z-score have the greatest predictive power for CoA diagnosis. The segments 6-12 of FS in the confirmed CoA group were significantly lower than those in the false CoA and normal groups. Fetal HQ technology, by assessing changes in the size and shape of the heart, can provide relatively reliable parameter support for the prenatal diagnosis of fetal aortic coarctation.
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Here we report for the first time the phenomenon of continuously color-tunable electrochemiluminescence (ECL) from individual gold nanoclusters (Au NCs) confined in a porous hydrogel matrix by adjusting the concentration of the co-reactant. Specifically, the hydrogel-confined Au NCs exhibit strong dual-color ECL in an aqueous solution with triethylamine (TEA) as a co-reactant, with a record-breaking quantum yield of 95%. Unlike previously reported Au NCs, the ECL origin of the hydrogel-confined Au NCs is related to both the Au(0) kernel and the Au(i)-S surface. Surprisingly, the surface-related ECL of Au NCs exhibits a wide color-tunable range of 625-829 nm, but the core-related ECL remains constant at 489 nm. Theoretical and experimental studies demonstrate that the color-tunable ECL is caused by the dynamic surface reconstruction of Au NCs and TEA radicals. This work opens up new avenues for dynamically manipulating the ECL spectra of core-shell emitters in biosensing and imaging research.
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BACKGROUND/AIM: Following the National Comprehensive Cancer Network guidelines, radiotherapy is administered after breast-conserving surgery (BCS) in patients with more than four positive lymph nodes. Four positive lymph nodes are typically considered an indicator to assess disease spread and patient prognosis. However, the subjective counting of positive axillary lymph nodes underscores the need for biomarkers to improve diagnostic precision and reduce the risk of unnecessary treatments. Loss of E-cadherin expression is associated with cancer metastasis, but its potential as a predictive marker for cancer treatment remains uncertain. This study aimed to investigate the validity of E-cadherin as a reference for adjuvant radiotherapy in breast cancer patients with positive lymph nodes post-mastectomy. MATERIALS AND METHODS: Immunohistochemistry was performed on 60 clinical tissue specimens to assess these implications. RESULTS: Although no significant result was found in a single E-cadherin subgroup (low, medium, and high subgroups according to the X-tile algorithm), the proposed multivariate model, including the E-cadherin category, breast cancer subtype, and tumor size, yielded satisfactory recurrence risk estimation results for patients undergoing BCS. Patients with a low E-cadherin category, triple-negative breast cancers, and tumor size over 5 cm could have an increased risk of recurrence. CONCLUSION: Our study proposed a multivariate model that serves as a candidate prognostic factor for recurrence-free survival in patients undergoing BCS and radiotherapy. Utilizing this model for patient stratification in high-risk diseases and as a standard for assessing postoperative intensified therapy can potentially improve patient outcomes.
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Biomarcadores Tumorais , Neoplasias da Mama , Caderinas , Mastectomia Segmentar , Recidiva Local de Neoplasia , Humanos , Feminino , Caderinas/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/metabolismo , Pessoa de Meia-Idade , Prognóstico , Idoso , Adulto , Imuno-Histoquímica , Metástase Linfática , Estadiamento de NeoplasiasRESUMO
BACKGROUND: High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. METHOD: HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. RESULTS: A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). CONCLUSION: Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.
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Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Adulto , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/genética , Hepatite B Crônica/epidemiologia , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , DNA Viral/genética , Vírus da Hepatite B/genéticaRESUMO
OBJECTIVES: This study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population. METHODS: Patients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE. RESULTS: In the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p<0.01), higher Systemic Lupus Erythematosus Disease Activity Index scores (3.00 vs 2.37, p=0.04), elevated risks of renal involvement within the first year of SLE diagnosis, including WHO class III-IV lupus nephritis (OR 2.36, 95% CI 1.47 to 3.80, p<0.01), estimated glomerular filtration rate <60 mL/min/1.73m2 (OR 1.49, 95% CI 1.18 to 1.89, p<0.01) and urine protein-to-creatinine ratio >150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p<0.01), along with increased seropositivity risks, compared with those in the lowest quartile. Furthermore, among patients with SLE with onset before 50 years, the highest PRS quartile was significantly associated with more serious renal diseases within the first year of SLE diagnosis. CONCLUSIONS: PRS of SLE is associated with earlier onset, renal involvement within the first year of SLE diagnosis and seropositivity in Taiwanese patients. Integrating PRS with clinical decision-making may enhance lupus nephritis screening and early treatment to improve renal outcomes in patients with SLE.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Adulto , Humanos , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/epidemiologia , Nefrite Lúpica/genética , Estratificação de Risco Genético , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Rim , GenótipoRESUMO
BACKGROUND: Links have been reported between the airflow limitation and both metabolic syndrome (MetS) and fatty liver (FL). Additionally, associations between genetic factors and risks of MetS, FL, and airflow limitation have been identified separately in different studies. Our study aims to simultaneously explore the association between specific single nucleotide polymorphisms (SNPs) of certain genes and the risk of the three associated diseases. METHODS: In this retrospective cross-sectional nationwide study, 150,709 participants from the Taiwan Biobank (TWB) were enrolled. We conducted a genotype-phenotype association analysis of nine SNPs on seven genes (ApoE-rs429358, MBOAT7-rs641738, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, TM6SF2-rs58542926, and IFNL4-rs368234815) using data from the TWB1.0 and TWB2.0 genotype dataset. Participants underwent a series of assessments including questionnaires, blood examinations, abdominal ultrasounds, and spirometry examinations. RESULTS: MetS was associated with FL and airflow limitation. ApoE-rs429358, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, and TM6SF2-rs58542926 were significantly associated with the risk of MetS. The cumulative impact of T alleles of ApoE-rs429358 and TM6SF2-rs58542926 on the risk of FL was observed (p-value for trend < 0.001). Individuals without MetS and airflow limitation carrying LEPR-rs1805096 G_G genotype exhibited a reduction in the forced expiratory volume in 1 s percentage prediction (Coefficient -35, 95 % confidence interval (CI) -69.7- -0.4), low forced vital capacity percentage prediction (Coefficient -41.6, 95 % CI -82.6- -0.6), and low vital capacity percentage prediction (Coefficient -42.2, 95 % CI -84.2- -0.1). CONCLUSIONS: MetS significantly correlated with FL and airflow limitation. Multiple SNPs were notably associated with MetS. Specifically, T alleles of ApoE-rs429358 and TM6SF2-rs58542926 cumulatively increased the risk of FL. LEPR-rs1805096 shows a trend-wise association with pulmonary function, which is significant in patients without MetS or airflow limitation.
Assuntos
Fígado Gorduroso , Predisposição Genética para Doença , Síndrome Metabólica , Polimorfismo de Nucleotídeo Único , Humanos , Síndrome Metabólica/genética , Masculino , Taiwan/epidemiologia , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Estudos Retrospectivos , Idoso , Fígado Gorduroso/genética , Estudos de Associação Genética , Adulto , Receptores para Leptina/genética , Bancos de Espécimes Biológicos , Apolipoproteínas E/genética , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas de Membrana/genética , Fatores de RiscoRESUMO
The beneficial effect of social interaction in mitigating the incidence of post-stroke depression (PSD) and ameliorating depressive symptoms has been consistently demonstrated through preclinical and clinical studies. However, the underlying relationship with oxytocin requires further investigation. In light of this, the present study aimed to explore the protective effect of pair housing on the development of PSD and the potential relationship with oxytocin receptors. The PSD model was induced by middle cerebral artery occlusion (MCAO) for 50 min, followed by 4-week isolated housing and restrained stress. Subsequently, each mouse in the pair-housing group (PH) was pair-housed with an isosexual healthy partner. Another group was continuously administrated fluoxetine (10 mg/Kg, i.p, once a day) for 3 weeks. To elucidate the potential role of oxytocin, we subjected pair-housed PSD mice to treatment with an oxytocin receptor (OXTR) antagonist (L368,889) (5 mg/Kg, i.p, once a day) for 3 weeks. At 31 to 32 days after MCAO, anxiety- and depressive-like behaviors were assessed using sucrose consumption, forced swim test, and tail-suspension test. The results showed that pair housing significantly improved post-stroke depression to an extent comparable to that of fluoxetine treatment. Furthermore, pair housing significantly decreased corticosterone in serum, increasing OXT mRNA expression in the hypothalamus. Treatment with L368,889 essentially reversed the effect of pair housing, with no discernible sex differences apart from changes in body weight. Pair housing increased hippocampal serotonin (5-HT), but treatment with L368,889 had no significant impact. Additionally, pair housing effectively reduced the number of reactive astrocytes and increased Nissl's body in the cortex and hippocampal CA3 regions. Correspondingly, treatment with L368,889 significantly reversed the changes in the Nissl's body and reactive astrocytes. Moreover, pair housing downregulated mRNA levels of TNF-α, IL-1ß, and IL-6 in the cortex caused by PSD, which was also reversed by treatment with L368,889. In conclusion, pair housing protects against the development of PSD depending on OXT and OXTR in the brain, with no significant divergence based on sex. These findings provide valuable insights into the potential of social interaction and oxytocin as therapeutic targets for PSD. Further research into the underlying mechanisms of these effects may contribute to the development of novel treatments for PSD.
Assuntos
Canfanos , Depressão , Modelos Animais de Doenças , Fluoxetina , Piperazinas , Receptores de Ocitocina , Animais , Receptores de Ocitocina/metabolismo , Masculino , Depressão/etiologia , Depressão/metabolismo , Camundongos , Fluoxetina/farmacologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/psicologia , Abrigo para Animais , Ocitocina/farmacologia , Ocitocina/metabolismo , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/psicologia , Comportamento Animal/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacosRESUMO
AIMS: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer. MAIN METHODS: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan. KEY FINDINGS: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan. SIGNIFICANCE: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.