Active DNA damage eviction by HLTF stimulates nucleotide excision repair.

Nucleotide excision repair (NER) counteracts the onset of cancer and aging by removing helix-distorting DNA lesions via a "cut-and-patch"-type reaction. The regulatory mechanisms that drive NER through its successive damage recognition, verification, incision, and gap restoration reaction steps remain elusive. Here, we show that the RAD5-related translocase HLTF facilitates repair through active eviction of incised damaged DNA together with associated repair proteins. Our data show a dual-incision-dependent recruitment of HLTF to the NER incision complex, which is mediated by HLTF's HIRAN domain that binds 3'-OH single-stranded DNA ends. HLTF's translocase motor subsequently promotes the dissociation of the stably damage-bound incision complex together with the incised oligonucleotide, allowing for an efficient PCNA loading and initiation of repair synthesis. Our findings uncover HLTF as an important NER factor that actively evicts DNA damage, thereby providing additional quality control by coordinating the transition between the excision and DNA synthesis steps to safeguard genome integrity.

Differential processing of RNA polymerase II at DNA damage correlates with transcription-coupled repair syndrome severity.

DNA damage severely impedes gene transcription by RNA polymerase II (Pol II), causing cellular dysfunction. Transcription-Coupled Nucleotide Excision Repair (TC-NER) specifically removes such transcription-blocking damage. TC-NER initiation relies on the CSB, CSA and UVSSA proteins; loss of any results in complete TC-NER deficiency. Strikingly, UVSSA deficiency results in UV-Sensitive Syndrome (UVSS), with mild cutaneous symptoms, while loss of CSA or CSB activity results in the severe Cockayne Syndrome (CS), characterized by neurodegeneration and premature aging. Thus far the underlying mechanism for these contrasting phenotypes remains unclear. Live-cell imaging approaches reveal that in TC-NER proficient cells, lesion-stalled Pol II is swiftly resolved, while in CSA and CSB knockout (KO) cells, elongating Pol II remains damage-bound, likely obstructing other DNA transacting processes and shielding the damage from alternative repair pathways. In contrast, in UVSSA KO cells, Pol II is cleared from the damage via VCP-mediated proteasomal degradation which is fully dependent on the CRL4CSA ubiquitin ligase activity. This Pol II degradation might provide access for alternative repair mechanisms, such as GG-NER, to remove the damage. Collectively, our data indicate that the inability to clear lesion-stalled Pol II from the chromatin, rather than TC-NER deficiency, causes the severe phenotypes observed in CS.

Gender and age related brain structural and functional alterations in children with autism spectrum disorder.

To explore the effects of age and gender on the brain in children with autism spectrum disorder using magnetic resonance imaging. 185 patients with autism spectrum disorder and 110 typically developing children were enrolled. In terms of gender, boys with autism spectrum disorder had increased gray matter volumes in the insula and superior frontal gyrus and decreased gray matter volumes in the inferior frontal gyrus and thalamus. The brain regions with functional alterations are mainly distributed in the cerebellum, anterior cingulate gyrus, postcentral gyrus, and putamen. Girls with autism spectrum disorder only had increased gray matter volumes in the right cuneus and showed higher amplitude of low-frequency fluctuation in the paracentral lobule, higher regional homogeneity and degree centrality in the calcarine fissure, and greater right frontoparietal network-default mode network connectivity. In terms of age, preschool-aged children with autism spectrum disorder exhibited hypo-connectivity between and within auditory network, somatomotor network, and visual network. School-aged children with autism spectrum disorder showed increased gray matter volumes in the rectus gyrus, superior temporal gyrus, insula, and suboccipital gyrus, as well as increased amplitude of low-frequency fluctuation and regional homogeneity in the calcarine fissure and precentral gyrus and decreased in the cerebellum and anterior cingulate gyrus. The hyper-connectivity between somatomotor network and left frontoparietal network and within visual network was found. It is essential to consider the impact of age and gender on the neurophysiological alterations in autism spectrum disorder children when analyzing changes in brain structure and function.

Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome-scale CRISPR-Cas9 screening in myeloma cells.

Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.

Magnetic detection under high pressures using designed silicon vacancy centres in silicon carbide.

Pressure-induced magnetic phase transitions are attracting interest as a means to detect superconducting behaviour at high pressures in diamond anvil cells, but determining the local magnetic properties of samples is a challenge due to the small volumes of sample chambers. Optically detected magnetic resonance of nitrogen vacancy centres in diamond has recently been used for the in situ detection of pressure-induced phase transitions. However, owing to their four orientation axes and temperature-dependent zero-field splitting, interpreting these optically detected magnetic resonance spectra remains challenging. Here we study the optical and spin properties of implanted silicon vacancy defects in 4H-silicon carbide that exhibit single-axis and temperature-independent zero-field splitting. Using this technique, we observe the magnetic phase transition of Nd2Fe14B at about 7 GPa and map the critical temperature-pressure phase diagram of the superconductor YBa2Cu3O6.6. These results highlight the potential of silicon vacancy-based quantum sensors for in situ magnetic detection at high pressures.

Programmable photoacoustic manipulation of microparticles in liquid.

Particle manipulation through the transfer of light or sound momentum has emerged as a powerful technique with immense potential in various fields, including cell biology, microparticle assembly, and lab-on-chip technology. Here, we present a novel method called Programmable Photoacoustic Manipulation (PPAM) of microparticles in liquid, which enables rapid and precise arrangement and controllable transport of numerous silica particles in water. Our approach leverages the modulation of pulsed laser using digital micromirror devices (DMD) to generate localized Lamb waves in a stainless steel membrane and acoustic waves in water. The particles undergo a mechanical force of about several µN due to membrane vibrations and an acoustic radiation force of about tens of nN from the surrounding water. Consequently, this approach surpasses the efficiency of optical tweezers by effectively countering the viscous drag imposed by water and can be used to move thousands of particles on the membrane. The high power of the pulsed laser and the programmability of the DMD enhance the flexibility in particle manipulation. By integrating the benefits of optical and acoustic manipulation, this technique holds great promise for advancing large-scale manipulation, cell assembly, and drug delivery.

Programmable spin and transport of a living shrimp egg through photoacoustic pressure.

In the fields of biomedicine and microfluidics, the non-contact capture, manipulation, and spin of micro-particles hold great importance. In this study, we propose a programmable non-contact manipulation technique that utilizes photoacoustic effect to spin and transport living shrimp eggs. By directing a modulated pulsed laser toward a liquid-covered stainless-steel membrane, we can excite patterned Lamb waves within the membrane. These Lamb waves occur at the interface between the membrane and the liquid, enabling the manipulation of nearby particles. Experimental results demonstrate the successful capture, spin, and transport of shrimp eggs in diameter of 220 µm over a distance of about 5 mm. Calculations indicate that the acoustic radiation force and torque generated by our photoacoustic manipulation system are more than 299.5 nN and 41.0 nN·mm, respectively. The system surpasses traditional optical tweezers in terms of force and traditional acoustic tweezers in terms of flexibility. Consequently, this non-contact manipulation system significantly expands the possibilities for applications in various fields, including embryo screening, cell manipulation, and microfluidics.

Fully Polarized Topological Isostatic Metamaterials in Three Dimensions.

Topological surface states are unique to topological materials and are immune to disturbances. In isostatic lattices, mechanical topological floppy modes exhibit softness depending on the polarization relative to the terminating surface. However, in three dimensions, the polarization of topological floppy modes is disrupted by the ubiquitous mechanical Weyl lines. Here, we demonstrate, both theoretically and experimentally, the fully polarized topological mechanical phases free of Weyl lines. Floppy modes emerge exclusively on a particular surface of the three-dimensional isostatic structure, leading to the strongly asymmetric stiffness between opposing boundaries. Additionally, uniform soft strains can reversibly shift the lattice configuration to Weyl phases, switching the stiffness contrast to a trivially comparable level. Our work demonstrates the fully polarized topological mechanical phases in three dimensions, and paves the way towards engineering soft and adaptive metamaterials.

Long-term outcomes prediction in diabetic heart failure with preserved ejection fraction by cardiac MRI.

OBJECTIVES: We aimed to explore imaging features including tissue characterization and myocardial deformation in diabetic heart failure with preserved ejection fraction (HFpEF) patients by magnetic resonance imaging (MRI) and investigate its prognostic value for adverse outcomes. MATERIALS AND METHODS: Patients with HFpEF who underwent cardiac MRI between January 2010 and December 2016 were enrolled. Feature-tracking (FT) analysis and myocardial fibrosis were assessed by cardiac MRI. Cox proportional regression analysis was performed to determine the association between MRI variables and primary outcomes. Primary outcomes were all-cause death or heart failure hospitalization during the follow-up period. RESULTS: Of the 335 enrolled patients with HFpEF, 191 had diabetes mellitus (DM) (mean age: 58.7 years ± 10.8; 137 men). During a median follow-up of 10.2 years, 91 diabetic HFpEF and 56 non-diabetic HFpEF patients experienced primary outcomes. DM was a significant predictor of worse prognosis in HFpEF. In diabetic HFpEF, the addition of conventional imaging variables (left ventricular ejection fraction, left atrial volume index, extent of late gadolinium enhancement (LGE)) and global longitudinal strain (GLS) resulted in a significant increase in the area under the receiver operating characteristic curve (from 0.693 to 0.760, p < 0.05). After adjustment for multiple clinical and imaging variables, each 1% worsening in GLS was associated with a 9.8% increased risk of adverse events (p = 0.004). CONCLUSIONS: Diabetic HFpEF is characterized by more severely impaired strains and myocardial fibrosis, which is identified as a high-risk HFpEF phenotype. In diabetic HFpEF, comprehensive cardiac MRI provides incremental value in predicting prognosis. Particularly, MRI-FT measurement of GLS is an independent predictor of adverse outcome in diabetic HFpEF. CLINICAL RELEVANCE STATEMENT: Our findings suggested that MRI-derived variables, especially global longitudinal strain, played a crucial role in risk stratification and predicting worse prognosis in diabetic heart failure with preserved ejection fraction, which could assist in identifying high-risk patients and guiding therapeutic decision-making. KEY POINTS: • Limited data are available on the cardiac MRI features of diabetic heart failure with preserved ejection fraction, including myocardial deformation and tissue characterization, as well as their incremental prognostic value. • Diabetic heart failure with preserved ejection fraction patients was characterized by more impaired strains and myocardial fibrosis. Comprehensive MRI, including tissue characterization and global longitudinal strain, provided incremental value for risk prediction. • MRI served as a valuable tool for identifying high-risk patients and guiding clinical management in diabetic heart failure with preserved ejection fraction.

Poly(N,N-diethylacrylamide)-endowed spontaneous emulsification during the breath figure process and the formation of membranes with hierarchical pores.

The spontaneous emulsification for the formation of water-in-oil (W/O) or oil-in-water (O/W) emulsions needs the help of at least one kind of the third component (surfactant or cosolvent) to stabilize the oil-water interface. Herein, with the water/CS2-soluble polymer poly(N,N-diethylacrylamide) (PDEAM) as a surfactant, the spontaneous formation of water-in-PDEAM/CS2 emulsions is reported for the first time. The strong affinity between PDEAM and water or the increase of PDEAM concentration will accelerate the emulsification process with high dispersed phase content. It is demonstrated that the spontaneous emulsification of condensed water droplets into the PDEAM/CS2 solution occurs during the breath figure process, resulting in porous films with two levels of pore sizes (i.e., micron and submicron). The emulsification degree and the amounts of submicron-sized pores increase with PDEAM concentration and solidifying time of the solution. This work brings about incremental interest in spontaneous emulsification that may happen during the breath figure process. The combination of these two simultaneous processes provides us with an option to build hierarchically porous structures with condensed and emulsified water droplets as templates. Such porous membranes may have great potential in fields such as separation, cell culture, and biosensing.

Effect of oral administration of microcin Y on growth performance, intestinal barrier function and gut microbiota of chicks challenged with Salmonella Pullorum.

The lasso peptide microcin Y (MccY) effectively inhibits various serotypes of Salmonella in vitro, but the antibacterial effect against S. Pullorum in poultry is still unclear. This study was the first to evaluate the safety and anti-S. Pullorum infection of MccY in specific pathogen-free (SPF) chicks. The safety test showed that the body weight, IgA and IgM levels of serum, and cecal microbiota structure of 3 groups of chicks orally administrated with different doses of MccY (5 mg/kg, 10 mg/kg, 20 mg/kg) for 14 days were not significantly different from those of the control group. Then, the chicks were randomized into 3 groups for the experiment of anti-S. Pullorum infection: (I) negative control group (NC), (II) S. Pullorum-challenged group (SP, 5 × 108 CFU/bird), (III) MccY-treated group (MccY, 20 mg/kg). The results indicated that compared to the SP group, treatment of MccY increased body weight and average daily gain (P < 0.05), reduced S. Pullorum burden in feces, liver, and cecum (P < 0.05), enhanced the thymus, and decreased the spleen and liver index (P < 0.05). Additionally, MccY increased the jejunal villus height, lowered the jejunal and ileal crypt depth (P < 0.05), and upregulated the expression of IL-4, IL-10, ZO-1 in the jejunum and ileum, as well as CLDN-1 in the jejunum (P < 0.05) compared to the SP group. Furthermore, MccY increased probiotic flora (Barnesiella, etc.), while decreasing (P < 0.05) the relative abundance of pathogenic flora (Escherichia and Salmonella, etc.) compared to the SP group.

Active Left Atrial Ejection Fraction as a Non-Invasive Marker in Pulmonary Hypertension Secondary to Heart Failure.

BACKGROUND: Patients with pulmonary hypertension (PH) secondary to left heart failure (HF) exhibit a complex pathophysiological profile and poor prognosis. Left atrial function is pivotal in the progression of this disease, yet its predictive significance remains exclusive. This study aimed to explore the predictive capability of LA metrics in this population and compare them with other common predictors. METHODS: In this retrospective study, consecutive patients with PH secondary to HF who underwent cardiac magnetic resonance (CMR) imaging between December 2010 and December 2021 were enrolled. The composite endpoint was defined as all-cause death, heart-lung transplantation, or left ventricular assist device implantation. Survival analyses were performed using Kaplan-Meier curves and Cox regression analyses. RESULTS: A total of 174 patients with PH secondary to HF, with a mean age of 53.2 ± 14.9 years, including 90 men, were included in the final analysis. During a median follow-up of 31.9 months, 58 patients (33.3%) with PH reached the endpoints. There was a fair correlation between active left atrial ejection fraction (LAEF) and pulmonary artery wedge pressure (r = -0.397, p = 0.044). Active LAEF had a strong correlation with oxygen consumption at anaerobic threshold (r = 0.769, p < 0.001) and peak oxygen consumption (r = 0.754, p < 0.001). Active LAEF demonstrated comparable prognostic performance to other variables measured by echocardiography or CMR. After adjusting for clinical variables and left ventricular ejection fraction, active LAEF was still an independent predictor for adverse events (C-statistic: 0.784). Subgroup analysis among HF patients with preserved ejection fraction demonstrated that those with active LAEF ≤ 8.6% had a 7.05-fold higher risk of experiencing the composite endpoint compared to those with active LAEF > 8.6%. CONCLUSION: Although active LAEF does not demonstrate statistical improvement in outcome discrimination compared to established metrics, it may still merit consideration for assessing disease severity and prognosis in patients with PH secondary to HF. The integration of active LAEF and HF subtypes may stratify individuals at different levels of risk.

Natural anti-neuroinflammatory inhibitors in vitro and in vivo from Aglaia odorata.

Fifty compounds including seven undescribed (1, 13, 18-20, 30, 31) and forty-three known (2-12, 14-17, 21-29, 32-50) ones were isolated from the extract of the twigs and leaves of Aglaia odorata with anti-neuroinflammatory activities. Their structures were determined by a combination of spectral analysis and calculated spectra (ECD and NMR). Among them, compounds 13-25 were found to possess tertiary amide bonds, with compounds 16, 17, and 19-21 existing detectable cis/trans mixtures in 1H NMR spectrum measured in CDCl3. Specifically, the analysis of the cis-trans isomerization equilibrium of tertiary amides in compounds 19-24 was conducted using NMR spectroscopy and quantum chemical calculations. Bioactivity evaluation showed that the cyclopenta[b]benzofuran derivatives (2-6, 8, 10, 12) could inhibit nitric oxide production at the nanomolar concentration (IC50 values ranging from 2 to 100 nM) in lipopolysaccharide-induced BV-2 cells, which were 413-20670 times greater than that of the positive drug (minocycline, IC50 = 41.34 µM). The cyclopenta[bc]benzopyran derivatives (13-16), diterpenoids (30-35), lignan (40), and flavonoids (45, 47, 49, 50) also demonstrated significant inhibitory activities with IC50 values ranging from 1.74 to 38.44 µM. Furthermore, the in vivo anti-neuroinflammatory effect of rocaglaol (12) was evaluated via immunofluorescence, qRT-PCR, and western blot assays in the LPS-treated mice model. The results showed that rocaglaol (12) attenuated the activation of microglia and decreased the mRNA expression of iNOS, TNF-α, IL-1ß, and IL-6 in the cortex and hippocampus of mice. The mechanistic study suggested that rocaglaol might inhibit the activation of the NF-κB signaling pathway to relieve the neuroinflammatory response.

Characteristic terpenylated coumarins from Ferula ferulaeoides as potential inhibitors on overactivation of microglia.

A total of 37 characteristic terpenylated coumarins (1-25), including 17 undescribed compounds (1-5, 6a/6b, 7-10, 11a/11b-13a/13b), have been isolated from the root of Ferula ferulaeoides. Meanwhile, twelve pairs of enantiomers (6a/6b, 11a/11b-15a/15b, 17a/17b, 18a/18b, 20a/20b-22a/22b, and 25a/25b) were chirally purified. The structures of these new compounds were elucidated using HRESIMS, UV, NMR, and calculated 13C NMR with a custom DP4 + analysis. The absolute configurations of all the compounds were determined for the first time using electronic circular dichroism (ECD). Then, their inhibitory effects on nitric oxide (NO) production were evaluated with LPS-induced BV-2 microglia. Compared with the positive control minocycline (IC50 = 59.3 µM), ferulaferone B (2) exhibited stronger inhibitory potency with an IC50 value of 12.4 µM. The immunofluorescence investigation indicated that ferulaferone B (2) could inhibit Iba-1 expression in LPS-stimulated BV-2 microglia.

Axially chiral dihydrophenanthrene dimers from Pholidota yunnanensis with anti-neuroinflammatory activities.

Axially chiral compounds are well known in medicinal chemistry of natural products, but their absolute configurations and bioactivities are rarely reported and studied. In this study, eleven undescribed axially chiral dihydrophenanthrene dimers, as well as twenty-five known dihydrophenanthrenes, were isolated from the entire plant of Pholidota yunnanensis. Their structures were elucidated by comprehensive spectroscopic analysis. A method for determining the absolute configurations of enantiomers was developed based on the rotational barriers and calculated ECD spectra. Additionally, the activities of all isolated compounds were assessed in LPS-induced BV-2 microglial cells. Most dihydrophenanthrenes exhibited significant NO inhibitory activities, and compound 7 showed the most potent inhibitory effect with an IC50 value of 1.5 µM, compared to the positive control minocycline. The immunofluorescence and western blot results revealed that compound 7 suppressed the expression of Iba-1, iNOS and COX-2 in LPS-stimulated BV-2 microglial cells.

Characteristic alkaloids from Stemona sessilifolia with lung protective effects.

In the research on lung protective effects from the roots of Stemona sessilifolia, twenty-five Stemona alkaloids have been isolated, including four undescribed components (1, 3-5), a new natural product (2) and 20 known alkaloids (6-25). Their structures were analyzed by NMR spectra, high-resolution mass spectrum data, and other chemical methods. UPLC-QTOF/MS method was used to identify the Stemona alkaloids and summarize the fragmentation patterns of mass spectrometry. The lung-protective effects of these compounds were evaluated using MLE-12 cells induced by NNK and nm SiO2. The results showed that compounds 3, 5, 8, 10-11, 17-21 and 23 exhibited protective effects on NNK-induced cell injury. Compounds 2, 8-11, 14, 17-19 and 22 showed improvement in nm SiO2-induced lung epithelial cell injury. Compound 10 (tuberostemonine D), a representative alkaloid with a high content in Stemona sessilifolia, significantly protected C57BL/6 lung injury mice induced by nm SiO2, suggesting it a key component of Stemona alkaloids that play a protective role in lung injury. The results of in vivo activity showed that compound 10 could improve the lung injury of mice, reduce ROS content, and recover the levels of SOD and MDA in serum. Its protective effect on lung injury might be related to Nrf2 activation.

Macrophage-specific FGFR1 deletion alleviates high-fat-diet-induced liver inflammation by inhibiting the MAPKs/TNF pathways.

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease that is substantially associated with obesity-induced chronic inflammation. Macrophage activation and macrophage-medicated inflammation play crucial roles in the development and progression of NAFLD. Furthermore, fibroblast growth factor receptor 1 (FGFR1) has been shown to be essentially involved in macrophage activation. This study investigated the role of FGFR1 in the NAFLD pathogenesis and indicated that a high-fat diet (HFD) increased p-FGFR1 levels in the mouse liver, which is associated with increased macrophage infiltration. In addition, macrophage-specific FGFR1 knockout or administration of FGFR1 inhibitor markedly protected the liver from HFD-induced lipid accumulation, fibrosis, and inflammatory responses. The mechanistic study showed that macrophage-specific FGFR1 knockout alleviated HFD-induced liver inflammation by suppressing the activation of MAPKs and TNF signaling pathways and reduced fat deposition in hepatocytes, thereby inhibiting the activation of hepatic stellate cells. In conclusion, the results of this research revealed that FGFR1 could protect the liver of HFD-fed mice by inhibiting MAPKs/TNF-mediated inflammatory responses in macrophages. Therefore, FGFR1 can be employed as a target to prevent the development and progression of NAFLD.

Targeting RNA oxidation by ISG20-mediated degradation is a potential therapeutic strategy for acute kidney injury.

Oxidative stress plays a central role in the pathophysiology of acute kidney injury (AKI). Although RNA is one of the most vulnerable cell components to oxidative damage, it is unclear whether RNA oxidation is involved in the pathogenesis of AKI. In this study, we found that the level of RNA oxidation was significantly enhanced in kidneys of patients with acute tubular necrosis (ATN) and in the renal tubular epithelial cells (TECs) of mice with AKI, and oxidized RNA overload resulted in TEC injury. We further identified interferon-stimulated gene 20 (ISG20) as a novel regulator of RNA oxidation in AKI. Tubule-specific deficiency of ISG20 significantly aggravated renal injury and RNA oxidation in the ischemia/reperfusion-induced AKI mouse model and ISG20 restricted RNA oxidation in an exoribonuclease activity-dependent manner. Importantly, overexpression of ISG20 protected against oxidized RNA overproduction and renal ischemia/reperfusion injury in mice and ameliorated subsequent protein aggresome accumulation, endoplasmic reticulum stress, and unfolded protein response. Thus, our findings provide direct evidence that RNA oxidation contributes to the pathogenesis of AKI and that ISG20 importantly participates in the degradation of oxidized RNA, suggesting that targeting ISG20-handled RNA oxidation may be an innovative therapeutic strategy for AKI.

Diagnostic performance of coronary computed tomography angiography stenosis score for coronary stenosis.

BACKGROUND: Coronary computed tomography angiography stenosis score (CCTA-SS) is a proposed diagnosis score that considers the plaque characteristics, myocardial function, and the diameter reduction rate of the lesions. This study aimed to evaluate the diagnostic performance of the CCTA-SS in seeking coronary artery disease (CAD). METHODS: The 228 patients with suspected CAD who underwent CCTA and invasive coronary angiography (ICA) procedures were under examination. The diagnostic performance was evaluated with the receiver operating curve (ROC) for CCTA-SS in detecting CAD (defined as a diameter reduction of ≥ 50%) and severe CAD (defined as a diameter reduction of ≥ 70%). RESULTS: The area under ROC (AUC) of CCTA-SS was 0.909 (95% CI: 0.864-0.943), which was significantly higher than that of CCTA (AUC: 0.826; 95% CI: 0.771-0.873; P = 0.0352) in diagnosing of CAD with a threshold of 50%. The optimal cutoff point of CCTA-SS was 51% with a sensitivity of 90.66%, specificity of 95.65%, positive predictive value of 98.80%, negative predictive value of 72.13%, and accuracy of 91.67%, whereas the optimal cutoff point of CCTA was 55%, and the corresponding values were 87.36%, 93.48%, 98.15%, 65.15%, and 88.60%, respectively. With a threshold of 70%, the performance of CCTA-SS with an AUC of 0.927 (95% CI: 0.885-0.957) was significantly higher than that of CCTA with an AUC of 0.521 (95% CI: 0.454-0.587) (P < 0.0001). CONCLUSIONS: CCTA-SS significantly improved the diagnostic accuracy of coronary stenosis, including CAD and severe CAD, compared with CCTA.

BRAF V600E mutation in thyroid carcinoma: a large-scale study in Han Chinese population.

BACKGROUND: The prevalence of genetic mutations in thyroid cancer varies significantly among different ethnic backgrounds. The present study aimed to investigate the clinical potential of BRAF V600E in a large group of homogenous Han Chinese patients. METHODS: From 2018 to 2021, 6232 thyroid disease patients who underwent thyroidectomy at our hospital were enrolled. We measured the diagnostic value of BRAF and plotted ROC curves. Patients with full clinical-pathological data were selected and divided into the BRAF mutation and wild type groups. We conducted univariate and multivariate analyses to quantify the differences in potential predictive factors of papillary thyroid carcinoma (PTC) patients between the groups. Kaplan-Meier survival analysis was used to estimate overall recurrence and recurrence rate. RESULTS: The prevalence of BRAF V600E mutation was 86.0% in PTCs. The sensitivity and specificity of BRAF mutation for diagnosing PTC from suspicious lesions were 85.5% and 100%, respectively. The sensitivity and specificity of BRAF analysis in the indeterminate cytology group were 72.5% and 100%, respectively. BRAF mutation showed an independent association with older age, negative HT, larger tumor size, extrathyroidal extension, and multifocality in PTCs. In micro-PTCs (tumor size ≤ 1), the mutation was also positively correlated with progressive phenotypes of extrathyroidal extension and multifocality. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analysis. CONCLUSIONS: This large single-center study reveals that BRAF V600E is highly prevalent in the Han Chinese population and demonstrates BRAF V600E mutation testing has high diagnostic accuracy and its strong association with the progress of aggressiveness in PTCs and a higher probability of recurrence. BRAF mutation can serve as an accurate marker for diagnosis and decision-making with great value.