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Abstract Myocardial infarction (MI) is a leading cause of death globally. Stem cell therapy is considered a potential strategy for MI treatment. Transplantation of classic stem cells including embryonic, induced pluripotent and cardiac stem cells exhibited certain repairing effect on MI via supplementing cardiomyocytes, however, their clinical applications were blocked by problems of cell survival, differentiation, functional activity and also biosafety and ethical concerns. Here, we introduced human amniotic epithelial stem cells (hAESCs) featured with immunomodulatory activities, immune-privilege and biosafety, for constructing a stem cell cardiac patch based on porous antioxidant polyurethane (PUR), which demonstrated decent hAESCs compatibility. In rats, the administration of PUR-hAESC patch significantly reduced fibrosis and facilitated vascularization in myocardium after MI and consequently improved cardiac remodeling and function. Mechanistically, the patch provides a beneficial microenvironment for cardiac repair by facilitating a desirable immune response, paracrine modulation and limited oxidative milieu. Our findings may provide a potential therapeutic strategy for MI.

Abstract Purpose To investigate whether the body composition parameters can be employed as potential biomarkers for predicting the progression risk of chronic kidney disease (CKD). Materials and methods Four hundred sixteen patients diagnosed with CKD were included in this retrospective study. Patients with a greater than 50% decline in estimated glomerular filtration rate or progression to end-stage kidney disease were in the high-risk group, otherwise, they were in a low-risk group. Body composition area, the index, and radiodensities in the Hounsfield unit (HU), which reflect the degree of X-ray absorption, were measured on abdominal CT images. Risk factors in body composition and clinical parameters of CKD were identified by Cox regression and utilized to construct the nomogram. The performance of the nomogram was assessed using time receiver operating characteristics curves, calibration curves, and decision curve analysis. Results There were 254 patients in low-risk group and 162 in high-risk group (268 males, 148 females, mean age: 55.89 years). Urea, diabetes, 24 h-urinary protein, mean arterial pressure, and subcutaneous adipose tissue radiodensity (SATd) were valuable indicators for predicting the high-risk group. The area under curve values for the nomogram of training/validation set at 1 year, 2 years, and 3 years were 0.805/0.753, 0.784/0.783, and 0.846/0.754, respectively. For diabetic CKD patients, extra attention needs to be paid to visceral to subcutaneous fat ratio and renal sinus fat radiodensity. Conclusion SATd was the most valuable noninvasive indicator of all body composition parameters for predicting high-risk populations with CKD. The nomogram we constructed has generalization with easily obtainable indicators, good performance, differentiation, and clinical practicability. Critical relevance statement Radiodensity rather than an area of adipose tissue can be used as a new biomarker of prognosis for CKD patients, providing new insights into risk assessment, stratified management, and treatment for CKD patients. Key Points Obesity is an independent risk factor for the development and prognosis of CKD. Adipose tissue radiodensity is more valuable than fat area in prognosticating for kidney disease. Parameters that prognosticate in diabetic CKD patients are different from those in other CKD patients. Graphical Abstract

Non-invasive or minutely invasive and wireless brain stimulation that can target any region of the brain is an open problem in engineering and neuroscience with serious implications for the treatment of numerous neurological diseases. Despite significant recent progress in advancing new methods of neuromodulation, none has successfully replicated the efficacy of traditional wired stimulation and improved on its downsides without introducing new complications. Due to the capability to convert magnetic fields into local electric fields, MagnetoElectric NanoParticle (MENP) neuromodulation is a recently proposed framework based on new materials that can locally sensitize neurons to specific, low-strength alternating current (AC) magnetic fields (50Hz 1.7 kOe field). However, the current research into this neuromodulation concept is at a very early stage, and the theoretically feasible game-changing advantages remain to be proven experimentally. To break this stalemate phase, this study leveraged understanding of the non-linear properties of MENPs and the nanoparticles' field interaction with the cellular microenvironment. Particularly, the applied magnetic field's strength and frequency were tailored to the M − H hysteresis loop of the nanoparticles. Furthermore, rectangular prisms instead of the more traditional “spherical” nanoparticle shapes were used to: (i) maximize the magnetoelectric effect and (ii) improve the nanoparticle-cell-membrane surface interface. Neuromodulation performance was evaluated in a series of exploratory in vitro experiments on 2446 rat hippocampus neurons. Linear mixed effect models were used to ensure the independence of samples by accounting for fixed adjacency effects in synchronized firing. Neural activity was measured over repeated 4-min segments, containing 90 s of baseline measurements, 90 s of stimulation measurements, and 60 s of post stimulation measurements. 87.5 % of stimulation attempts produced statistically significant (P 0.05 and P > 0.15 respectively). Furthermore, an exploratory analysis of a direct current (DC) magnetic field indicated that the DC field could be used with MENPs to inhibit neuron activity (P

Abstract Mutations in the nuclear envelope (NE) protein lamin A/C (encoded by LMNA), cause a severe form of dilated cardiomyopathy (DCM) with early-onset life-threatening arrhythmias. However, molecular mechanisms underlying increased arrhythmogenesis in LMNA-related DCM (LMNA-DCM) remain largely unknown. Here we show that a frameshift mutation in LMNA causes abnormal Ca2+ handling, arrhythmias and disformed NE in LMNA-DCM patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Mechanistically, lamin A interacts with sirtuin 1 (SIRT1) where mutant lamin A/C accelerates degradation of SIRT1, leading to mitochondrial dysfunction and oxidative stress. Elevated reactive oxygen species (ROS) then activates the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-ryanodine receptor 2 (RYR2) pathway and aggravates the accumulation of SUN1 in mutant iPSC-CMs, contributing to arrhythmias and NE deformation, respectively. Taken together, the lamin A/C deficiency-mediated ROS disorder is revealed as central to LMNA-DCM development. Manipulation of impaired SIRT1 activity and excessive oxidative stress is a potential future therapeutic strategy for LMNA-DCM.

Abstract Background Acute thrombotic events play a major role in various cardiovascular diseases. Therefore, direct thrombus imaging can be proved beneficial for early diagnosis and prompt therapy of thrombosis. Our study investigated targeted dual‐modality cyclic arginine‐glycine‐aspartic micro bubbles (cRGD‐MBs) for direct imaging of thrombi by fluorescence and ultrasound. Methods cRGD‐MBs were prepared by mechanical vibration and chemical chelation methods. Results Coulter counter analysis demonstrated that the cRGD‐MBs were well dispersed, with diameters ranging from 1 to 3 μm. They emitted bright red fluorescence under an excitation wavelength of 660 nm. In vivo fluorescence and ultrasound imaging revealed that cRGD‐MBs accumulated at the site of thrombus in the carotid artery with significant fluorescence and ultrasonic signal. Conclusions This study showed that novel microbubble cRGD‐MBs were successfully synthesized, and that these could potentially be used as contrast agents for immediate diagnosis of acute thrombus in vivo.

Brugada syndrome (BrS) is a hereditary arrhythmia syndrome characterized by right bundle branch block on an electrocardiogram and persistent ST-segment elevation in the right precordial leads. In this study, we describe the establishment of an induced pluripotent stem cell (iPSC) line derived from a BrS patient carrying the novel heterogeneous missense mutation (c.3118G>C; p.G1040R) in the sodium channel protein type 5 subunit alpha (SCN5A) gene. Skin fibroblasts underwent reprogramming using a non-integrated Sendai viral method. Generated iPSC line exhibited embryonic stem cell-like morphology, maintained a normal karyotype, expressed pluripotency markers, and demonstrated the capacity to differentiate into three germ layers.

Abstract The crucial role of ribonucleotide reductase M2 (RRM2) enzyme in cancer occurrence and progression has been well‐established, but its specific function and significance in medulloblastoma (MB) remains largely unknown. First, we conducted a bioinformatics analysis of public genomic databases and observed highly expressed RRM2 in MB and an association of high RRM2 expression with adverse outcomes. In addition, by collecting clinical MB specimens for polymerase chain reaction (PCR), western blotting (WB), and immunohistochemistry (IHC), RRM2 was confirmed to be highly expressed in tumor tissues. Furthermore, immunohistochemical analysis linked adverse prognosis to high RRM2 expression. Moreover, knocking down RRM2 significantly inhibited MB cell proliferation, migration, and invasion in vitro. This report is the first to demonstrate the oncogenic role of RRM2 in MB, associated with adverse patient outcomes. Knocking down RRM2 contributes to weakened proliferating, migrating, and invading potentials of MB cells. RRM2 is expected to be a novel prognostic biomarker and therapeutic target for MB.

Abstract Elevated levels of tumor‐associated macrophages and microglia in the immune microenvironment of malignant gliomas promote tumor growth and progression. Although immune evasion has been implicated in these processes, the mechanisms underlying the regulation of CD47‐SIRPα‐mediated immune evasion under hypoxic conditions remain unclear. Therefore, this study aimed to explore the mechanisms through which CD47‐SIRPα modulates immune evasion in a cobalt chloride (CoCl2)‐induced hypoxic microenvironment of malignant gliomas. Human and mouse glioma cell lines were used to investigate immune evasion in vitro. After membrane protein extraction and nucleoplasmic isolation, we downregulated the expression levels of transport receptors to elucidate the regulation of CD47‐SIRPα transport. The CoCl2‐induced hypoxic microenvironment attenuated microglial phagocytosis in glioma cells. Enhanced CD47‐SIRPα interaction promoted immune evasion, which negatively affected tumor clearance. In addition, the intracellular transport of CD47 was promoted in the CoCl2‐induced hypoxic state. This process was regulated by regulator of chromosome condensation 1 (RCC1) and sortilin in the nuclear cytoplasm and cytoplasmic membrane, respectively. These results demonstrate the CD47‐SIRPα‐mediated immune escape mechanism of the CoCl2‐induced glioma hypoxic environment, which is associated with enhanced intracellular transport of CD47. Our findings provide a theoretical basis for the potential development of novel therapies targeting CD47‐SIRPα.

Abstract Glioblastoma, IDH-Wild type (GBM, CNS WHO Grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor with high morbidity, high mortality, and poor patient prognosis. The global burden of GBM is increasing notably due to limited treatment options, drug delivery problems, and the lack of characteristic molecular targets. OTU deubiquitinase 4 (OTUD4) is a potential predictive factor for several cancers such as breast cancer, liver cancer, and lung cancer. However, its function in GBM remains unknown. In this study, we found that high expression of OTUD4 is positively associated with poor prognosis in GBM patients. Moreover, we provided in vitro and in vivo evidence that OTUD4 promotes the proliferation and invasion of GBM cells. Mechanism studies showed that, on the one hand, OTUD4 directly interacts with cyclin-dependent kinase 1 (CDK1) and stabilizes CDK1 by removing its K11, K29, and K33-linked polyubiquitination. On the other hand, OTUD4 binds to fibroblast growth factor receptor 1 (FGFR1) and reduces FGFR1’s K6 and K27-linked polyubiquitination, thereby indirectly stabilizing CDK1, ultimately influencing the activation of the downstream MAPK signaling pathway. Collectively, our results revealed that OTUD4 promotes GBM progression via OTUD4-CDK1-MAPK axis, and may be a prospective therapeutic target for GBM treatment.

City gas stations (CGSs) play a crucial role in ensuring a stable and safe supply of natural gas to urban users. However, as the service time of stations increases and the performance of components deteriorates, concerns about the safety and reliability of these station have grown among operators and local government authorities. This paper proposes a fuzzy reliability assessment methodology for CGSs that considers the polymorphism of component faults and the uncertainties associated with fault relationships, failure probabilities, and fault magnitudes. The methodology utilizes T-S fuzzy gates to describe the correlation among events and constructs a T-S fuzzy fault tree for CGSs. Component fault states are represented using fuzzy numbers, and a fuzzy group decision-making approach is introduced to evaluate the current fault magnitude of components. To handle the uncertainty caused by sparse failure sample data, a Bayesian updating estimation method is presented to estimate the failure probabilities of components. Furthermore, T-S fuzzy importance analysis is applied to identify the weak points in the CGS system. The effectiveness of the developed methodology is demonstrated through a case study of reliability analysis of a city gas distribution station. The research findings provide valuable support for optimizing the design and implementing preventive maintenance of CGSs.

IntroductionMolecular subgroups influence the vascular architecture within medulloblastomas, particularly the wingless (WNT) subgroup, which contributes to its propensity for primary tumor hemorrhage. Whether this mechanism affects intraoperative blood loss remains unknown. This study aimed to assess the association between WNT medulloblastoma and the predisposition for blood loss.MethodsThis was a retrospective observational study using data from a neuro-oncology center comprising molecular data on patients treated between December 31, 2014, and April 30, 2023. Differences between WNT and other subgroups in the risk of primary outcome-intraoperative blood loss were assessed using multivariable-adjusted linear regression.ResultsOf the 148 patients included in the analysis, 18 patients (12.2%) had WNT, 42 (28.4%) had sonic hedgehog (SHH) TP53-wildtype, 7 (4.7%) had SHH TP53-mutant, and 81 (54.7%) were non-WNT/ non-SHH. The WNT subgroup more frequently underwent primary intratumoral hemorrhage (22% vs. 3.8%; p = 0.011). The median intraoperative blood loss was 400.00 (interquartile range [IQR] 250, 500) mL for WNT and 300.00 [200, 400] mL for the other subgroups (p = 0.136), with an adjusted β of 135.264 (95% confidence intervals [CI], 11.701–258.827; p = 0.032). Similar results were observed in both midline and noninfiltrative margin medulloblastoma.DiscussionWNT medulloblastoma is typically associated with primary intratumoral hemorrhage and intraoperative blood loss. The validity of determining the surgical approach based on predicted molecular subtypes from imaging data is questionable. However, attempting to engage in risk communication with patients in a molecular-specific way is worthwhile to validate.

IntroductionTravel satisfaction as experienced by rural residents is closely related to personal physical and mental health, as well as rural economic conditions. An improved rural road environment can be expected to enhance villagers’ satisfaction with regards to visits to markets, but to date this has not been established empirically.MethodsIn this study, a questionnaire was designed to obtain local residents’ evaluations of road environment characteristics for periodic market travel. And we use an Oprobit regression model and Importance-Performance Map Analysis (IPMA) to explore the heterogeneity of the 14 key elements of the “home-to-market” road environment impact on villagers’ satisfaction under different modes of travel.ResultsThe results of the study reveal that villagers expressed dissatisfaction with the current lack of sidewalks and non-motorized paths, and except for road traffic disturbances and road deterioration, which did not significantly affect mode of travel, other factors proved significant. Significantly, bus services are associated with a significant positive effect on walking, non-motorized and bus travel satisfaction, while distance travel also affects walking, non-motorized and motorized travel satisfaction. It is worth noting that greening and service facilities negatively affect motorized travel satisfaction. In summary, road width, sidewalks, bus service, and road deterioration, are among the elements most in need of urgent improvement for all modes of travel.DiscussionThe characteristics of the road environment that influence satisfaction with travel to the periodic market vary by travel mode, and this study is hoped to provide data support and optimization recommendations for the improvement of the rural road environment in China and other countries.

Background Mobile elements (MEs) constitute a major portion of the genome in primates and other higher eukaryotes, and they play important role in genome evolution and gene function. MEs can be divided into two fundamentally different classes: DNA transposons which transpose in the genome in a “cut-and-paste” style, and retrotransposons which propagate in a “copy-and-paste” fashion via a process involving transcription and reverse-transcription. In primate genomes, DNA transposons are mostly dead, while many retrotransposons are still highly active. We report here the identification of a unique group of MEs, which we call “retro-DNAs”, for their combined characteristics of these two fundamentally different ME classes. Methods A comparative computational genomic approach was used to analyze the reference genome sequences of 10 primate species consisting of five apes, four monkeys, and marmoset. Results From our analysis, we identified a total of 1,750 retro-DNAs, representing 748 unique insertion events in the genomes of ten primate species including human. These retro-DNAs contain sequences of DNA transposons but lack the terminal inverted repeats (TIRs), the hallmark of DNA transposons. Instead, they show characteristics of retrotransposons, such as polyA tails, longer target-site duplications (TSDs), and the “TT/AAAA” insertion site motif, suggesting the use of the L1-based target-primed reverse transcription (TPRT) mechanism. At least 40% of these retro-DNAs locate into genic regions, presenting potentials for impacting gene function. More interestingly, some retro-DNAs, as well as their parent sites, show certain levels of expression, suggesting that they have the potential to create more retro-DNA copies in the present primate genomes. Conclusions Although small in number, the identification of these retro-DNAs reveals a new mean for propagating DNA transposons in primate genomes without active canonical DNA transposon activity. Our data also suggest that the TPRT machinery may transpose a wider variety of DNA sequences in the genomes.

Ginsenoside Rg1 (Rg1), a monomer saponin component, is one of the components with the highest content in total saponins of Panaxnotoginseng. It had various pharmacological effects. The bioavailability of oral tablets is only 1–20 %, and it is eliminated quickly in the blood. The development of new dosage forms and new routes of administration of ginsenoside Rg1 with sustained release and high bioavailability has become a significant problem to be solved. The Rg1 liposomes study used a thin film dispersion ultrasound method for its preparation. This study focused the pharmacokinetic parameters of ginsenoside Rg1 liposomes in rats through the lung perfusion method. Ginsenoside Rg1 liposomes were round and uniform in shape, the particle size was 2–3 μm, and the encapsulation efficiency of ginsenoside Rg1 liposome was 51.2 %. Results showed that, after pulmonary administration of ginsenoside Rg1, the time of ginsenoside Rg1 detected by Rg1 liposomes was longer than that of Rg1 solution, the relative bioavailability of ginsenoside Rg1 liposome lung administration AUC liposome/AUC solution = 122.67 %. These results provided the scientific theoretical and experimental basis for further development of new dosage forms and new routes of administration of ginsenoside Rg1.

BackgroundPreeclampsia (PE) is one of the most common hypertensive diseases, affecting 2%-8% of all pregnancies. The high maternal and fetal mortality rates of PE are due to a lack of early identification of affected pregnant women that would have led to closer monitoring and care. Recent data suggest that misfolded proteins might be a promising biomarker for PE prediction, which can be detected in urine samples of pregnant women according to their congophilia (aggregated) characteristic. ObjectiveThe main purpose of this trial is to evaluate the value of the urine congophilia-based detection of misfolded proteins for the imminent prediction of PE in women presenting with suspected PE. The secondary objectives are to demonstrate that the presence of urine misfolded proteins correlates with PE-related maternal or neonatal adverse outcomes, and to establish an accurate PE prediction model by combining misfolded proteins with multiple indicators. MethodsAt least 300 pregnant women with clinical suspicion of PE will be enrolled in this prospective cohort study. Participants should meet the following inclusion criteria in addition to a suspicion of PE: ≥18 years old, gestational week between 20+0 and 33+6, and single pregnancy. Consecutive urine samples will be collected, blinded, and tested for misfolded proteins and other PE-related biomarkers at enrollment and at 4 follow-up visits. Clinical assessments of PE status and related complications for all participants will be performed at regular intervals using strict diagnostic criteria. Investigators and participants will remain blinded to the results. Follow-up will be performed until 42 days postpartum. Data from medical records, including maternal and fetal outcomes, will be collected. The performance of urine misfolded proteins alone and combined with other biomarkers or clinical variables for the prediction of PE will be statistically analyzed. ResultsEnrollment started in July 2023 and was still open upon manuscript submission. As of March 2024, a total of 251 eligible women have been enrolled in the study and enrollment is expected to continue until August 2024. Results analysis is scheduled to start after all participants reach the follow-up endpoint and complete clinical data are collected. ConclusionsUpon completion of the study, we expect to derive an accurate PE prediction model, which will allow for proactive management of pregnant women with clinical suspicion of PE and possibly reduce the associated adverse pregnancy outcomes. The additional prognostic value of misfolded proteins is also expected to be confirmed. Trial RegistrationChinese Clinical Trials Registry ChiCTR2300074878; https://www.chictr.org.cn/showproj.html?proj=202096 International Registered Report Identifier (IRRID)PRR1-10.2196/54026

ObjectiveTo observe the efficacy and safety of pelvic floor magnetic stimulation (PFMS) combined with mirabegron in female patients with refractory overactive bladder (OAB) symptoms.Patients and methodsA total of 160 female patients with refractory OAB symptoms were prospectively randomized into two groups. Eighty cases in the combination group accepted PFMS and mirabegron therapy and 80 cases as control only accepted mirabegron therapy (The clinical trial registry number: ChiCTR2200070171). The lower urinary tract symptoms, OAB questionnaire (OAB-q) health-related quality of life (HRQol), symptom bother score and OABSS between two groups were compared at the 1st, 2nd and 4th week ends.ResultsAll of 160 patients were randomly assigned to two groups, of which 80 patients were included in the combination group and 80 in the mirabegron group. The incidences of LUTS, including urgency, frequent urination, and incontinence episodes, in the 2nd week and the 4th week after combination treatment were significantly lower than those in the mirabegron group (p 0.05). With respect to secondary variables, the OAB-q HRQol score in the combination group was statistically superior in comparison with that in the mirabegron group between the 2nd week and the 4th week (p

The anthocyanin compound cyanidin 3-O-glucoside (C3G) is a natural pigment widely used in food and nutraceutical industries. Its microbial synthesis by E. coli is a promising alternative to the traditional extraction methods. However, part of the synthesized C3G accumulates in the cytoplasm, thus potentially causing growth inhibition and product degradation. Therefore, it is necessary to enhance C3G secretion via exploration of native transporters facilitating C3G export. In this study, we report the screening and verification of native multidrug resistance transporters from 40 candidates in E. coli that can improve the extracellular C3G production when using catechin as the substrate. Overexpression of single transporter genes including fsr, yebQ, ynfM, mdlAB, and emrKY were found to increase C3G production by 0.5- to 4.8-fold. Genetic studies indicated that mdlAB and emrKY are vital transporters in the secretion of C3G. Our study reveals a set of new multidrug resistance transporters for the improvement of microbial biosynthesis of C3G and other anthocyanins.

Abstract A chemiluminescent immunoassay for human serum Cystatin C (Cys C) was established using a direct-antibody sandwich model. The immunoassay kit uses magnetic separation technology, using magnetic particles as the reaction solid phase, alkaline phosphatase as the marker enzyme, and a new chemiluminescent substrate APLS as the substrate. It has the characteristics of high sensitivity and short reaction time. This product uses high-affinity antibodies, resulting in a high specificity. The established method showed good accuracy, uniformity, and stability. The limit of detection was 2.39 ng/mL. The intra-assay coefficient of variation (CV) was 3.36%–6.00%, the interassay CV was 4.12%–5.35%, and the recovery rate was 99.07%. The correlation coefficient (r) of Cys-C kit was 0.999388 ≥ 0.9900. The accuracy of the developed method was tested by automatic chemiluminescence instrument (P > 0.05). The lowest titer was 0.92500, and the highest was 1.10000. The developed method showed a good correlation with the product from Roche by comparing these two kits in 240 clinical samples from China. In total, 1392 clinical patient from China samples were measured using the reagent kit developed in this study.

Abstract With the deepening of human research on deep space exploration, our research on the soft landing methods of landers has gradually deepened. Adding a buffer and energy-absorbing structure to the leg structure of the lander has become an effective design solution. Based on the energy-absorbing structure of the leg of the interstellar lander, this paper studies the appearance characteristics of the predatory feet of the Odontodactylus scyllarus. The predatory feet of the Odontodactylus scyllarus can not only hit the prey highly when preying, but also can easily withstand the huge counter-impact force. The predatory feet structure of the Odontodactylus scyllarus, like a symmetrical cone, shows excellent rigidity and energy absorption capacity. Inspired by this discovery, we used SLM technology to design and manufacture two nickel-titanium samples, which respectively show high elasticity, shape memory, and get better energy absorption capacity. This research provides an effective way to design and manufacture high-mechanical energy-absorbing buffer structures using bionic 3D printing technology and nickel-titanium alloys.

Abstract Background Mutations in the cardiac sodium channel gene SCN5A cause Brugada syndrome (BrS), an arrhythmic disorder that is a leading cause of sudden death and lacks effective treatment. An association between SCN5A and Wnt/β-catenin signaling has been recently established. However, the role of Wnt/β-catenin signaling in BrS and underlying mechanisms remains unknown. Methods Three healthy control subjects and one BrS patient carrying a novel frameshift mutation (T1788fs) in the SCN5A gene were recruited in this study. Control and BrS patient-specific induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using nonintegrated Sendai virus. All iPSCs were differentiated into cardiomyocytes using monolayer-based differentiation protocol. Action potentials and sodium currents were recorded from control and BrS iPSC-derived cardiomyocytes (iPSC-CMs) by single-cell patch clamp. Results BrS iPSC-CMs exhibited increased burden of arrhythmias and abnormal action potential profile featured by slower depolarization, decreased action potential amplitude, and increased beating interval variation. Moreover, BrS iPSC-CMs showed cardiac sodium channel (Nav1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Nav1.5 loss-of-function observed in BrS iPSC-CMs were accompanied by aberrant activation of Wnt/β-catenin signaling. Notably, inhibition of Wnt/β-catenin significantly rescued Nav1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, SCN5A-encoded Nav1.5 interacts with β-catenin, and reduced expression of Nav1.5 leads to re-localization of β-catenin in BrS iPSC-CMs, which aberrantly activates Wnt/β-catenin signaling to suppress SCN5A transcription. Conclusions Our findings suggest that aberrant activation of Wnt/β-catenin signaling contributes to the pathogenesis of SCN5A-related BrS and point to Wnt/β-catenin as a potential therapeutic target.

Gene therapy holds great promise for curing cancer by editing the deleterious genes of tumor cells, but the lack of vector systems for efficient delivery of genetic material into specific tumor sites in vivo has limited its full therapeutic potential in cancer gene therapy. Over the past two decades, increasing studies have shown that lentiviral vectors (LVs) modified with different glycoproteins from a donating virus, a process referred to as pseudotyping, have altered tropism and display cell-type specificity in transduction, leading to selective tumor cell killing. This feature of LVs together with their ability to enable high efficient gene delivery in dividing and non-dividing mammalian cells in vivo make them to be attractive tools in future cancer gene therapy. This review is intended to summarize the status quo of some typical pseudotypings of LVs and their applications in basic anti-cancer studies across many malignancies. The opportunities of translating pseudotyped LVs into clinic use in cancer therapy have also been discussed.

Purpose: To explore the Oxford classification and prognostic risk stratification of the non-invasive evaluation of immunoglobulin A nephropathy (IgAN) or immunoglobulin A vasculitis with nephritis (IgAVN) in children using multiparametric magnetic resonance imaging (MRI). Materials and Methods: Forty-four children diagnosed with IgAN or IgAVN were included. Patients with 80-month risk scores >10% were categorized as the high-risk group, while others constituted the low-risk group. The T2* and apparent diffusion coefficient (ADC) values of the renal cortex and medulla were measured. Clinical and pathological parameters were also assessed. Univariate and multivariate logistic regression analyses were performed to identify the indicators associated with the high-risk group. Receiver operating characteristic (ROC) curves were drawn and the areas under the curve (AUCs) were calculated to evaluate the diagnostic performance variables for differentiating the high-risk group from the low-risk group. Results: Only the T2*Cortex and mean arterial pressure (MAP) were independently reliable in both the univariate and multivariate analyses. The AUCs for differentiating the high-risk group from the low-risk group of T2*Cortex, MAP, and their combination model were 0.907, 0.881, and 0.947, respectively. Conclusions: Multiparametric MRI parameters, especially T2* values, could be used as new biomarkers to provide a new dimension in chronic kidney disease-related research and could play an important role in the non-invasive prognosis of children with IgAN or IgAVN.

Urgent detection of calculous pyonephrosis is crucial for surgical planning and preventing severe outcomes. This study aims to evaluate the performance of computed tomography (CT)-based radiomics and a three-dimensional convolutional neural network (3D-CNN) model, integrated with independent clinical factors, to identify patients with calculous pyonephrosis. We recruited 182 patients receiving either percutaneous nephrostomy tube placement or percutaneous nephrolithotomy for calculous hydronephrosis or pyonephrosis. The regions of interest were manually delineated on plain CT images and the CT attenuation value (HU) was measured. Radiomics analysis was performed using least absolute shrinkage and selection operator (LASSO). A 3D-CNN model was also developed. The better-performing machine-learning model was combined with independent clinical factors to build a comprehensive clinical machine-learning model. The performance of these models was assessed using receiver operating characteristic analysis and decision curve analysis. Fever, blood neutrophils, and urine leukocytes were independent risk factors for pyonephrosis. The radiomics model showed higher area under the curve (AUC) than the 3D-CNN model and HU (0.876 vs. 0.599, 0.578; p = 0.003, 0.002) in the testing cohort. The clinical machine-learning model surpassed the clinical model in both the training (0.975 vs. 0.904, p = 0.019) and testing (0.967 vs. 0.889, p = 0.045) cohorts.

Abstract Background CEUS LI-RADS (Contrast Enhanced Ultrasound Liver Imaging Reporting and Data System) has good diagnostic efficacy for differentiating hepatic carcinoma (HCC) from solid malignant tumors. However, it can be problematic in patients with both chronic hepatitis B and extrahepatic primary malignancy. We explored the diagnostic performance of LI-RADS criteria and CEUS-based machine learning (ML) models in such patients. Methods Consecutive patients with hepatitis and HCC or liver metastasis (LM) who were included in a multicenter liver cancer database between July 2017 and January 2022 were enrolled in this study. LI-RADS and enhancement features were assessed in a training cohort, and ML models were constructed using gradient boosting, random forest, and generalized linear models. The diagnostic performance of the ML models was compared with LI-RADS in a validation cohort of patients with both chronic hepatitis and extrahepatic malignancy. Results The mild washout time was adjusted to 54 s from 60 s, increasing accuracy from 76.8 to 79.4%. Through feature screening, washout type II, rim enhancement and unclear border were identified as the top three predictor variables. Using LI-RADS to differentiate HCC from LM, the sensitivity, specificity, and AUC were 68.2%, 88.6%, and 0.784, respectively. In comparison, the random forest and generalized linear model both showed significantly higher sensitivity and accuracy than LI-RADS (0.83 vs. 0.784; all P

Abstract Background Multiparametric magnetic resonance imaging (MP-MRI) has high sensitivity for diagnosing breast cancers but cannot always be used as a routine diagnostic tool. The present study aimed to evaluate whether the diagnostic performance of perfluorobutane (PFB) contrast-enhanced ultrasound (CEUS) is similar to that of MP-MRI in breast cancer and whether combining the two methods would enhance diagnostic efficiency. Patients and methods This was a head-to-head, prospective, multicenter study. Patients with breast lesions diagnosed by US as Breast Imaging Reporting and Data System (BI-RADS) categories 3, 4, and 5 underwent both PFB-CEUS and MP-MRI scans. On-site operators and three reviewers categorized the BI-RADS of all lesions on two images. Logistic-bootstrap 1000-sample analysis and cross-validation were used to construct PFB-CEUS, MP-MRI, and hybrid (PFB-CEUS + MP-MRI) models to distinguish breast lesions. Results In total, 179 women with 186 breast lesions were evaluated from 17 centers in China. The area under the receiver operating characteristic curve (AUC) for the PFB-CEUS model to diagnose breast cancer (0.89; 95% confidence interval [CI] 0.74, 0.97) was similar to that of the MP-MRI model (0.89; 95% CI 0.73, 0.97) (P = 0.85). The AUC of the hybrid model (0.92, 95% CI 0.77, 0.98) did not show a statistical advantage over the PFB-CEUS and MP-MRI models (P = 0.29 and 0.40, respectively). However, 90.3% false-positive and 66.7% false-negative results of PFB-CEUS radiologists and 90.5% false-positive and 42.8% false-negative results of MP-MRI radiologists could be corrected by the hybrid model. Three dynamic nomograms of PFB-CEUS, MP-MRI and hybrid models to diagnose breast cancer are freely available online. Conclusions PFB-CEUS can be used in the differential diagnosis of breast cancer with comparable performance to MP-MRI and with less time consumption. Using PFB-CEUS and MP-MRI as joint diagnostics could further strengthen the diagnostic ability. Trial registration Clinicaltrials.gov; NCT04657328. Registered 26 September 2020. IRB number 2020-300 was approved in Chinese PLA General Hospital. Every patient signed a written informed consent form in each center.

Objective The study aimed to explore the association between the site of interictal epileptic discharges (IEDs) on postoperative electroencephalogram (EEG) and seizure recurrence after antiepileptic drug (AED) withdrawal. The study hypothesizes that the concordance of IED sites with surgical sites indicates incomplete resection of epileptic focus, while non-concordance of IED sites with surgical sites indicates postoperative changes or cortical stimulation. The former has a higher risk of seizure recurrence.Methods We retrospectively analyzed the postoperative EEG pattern of 182 consecutive children who underwent resection surgery. To identify the risk factors for seizure recurrence, we compared the attributes of seizure recurred and seizure-free groups by univariate and multivariate analyses. AED tapering was standardized, involving a 25% reduction in the dose of a single type of AED every 2 weeks, independent of the presurgical AED load.Results We attempted AED withdrawal in 116 (63.7%) children. Twenty-eight (24.1%) children experienced seizure recurrence during or after AED withdrawal. A greater number of AEDs used at the time of surgery (p=0.005), incomplete resection (p=0.001), and presence of IED on postoperative EEG (p=0.011) are predictors of seizure recurrence. The completeness of resection and seizure recurrence after AED withdrawal were related to the presence of IED on the EEG, but not to the concordance of IED with surgical sites.Conclusion For children with abnormal EEG, the decision to discontinue AED should be made more cautiously, regardless of the relative location of the discharge site and the surgical site.

Summary: Background: Ablation has been recommended by worldwide guidelines as first-line treatment for hepatocellular carcinoma (HCC), while evidence regarding its efficacy for primary intrahepatic cholangiocarcinoma (iCCA) is lacking. We aimed to study the efficacy of ablation in treating iCCA by comparing its prognosis with surgery. Methods: In this real-world multicenter cohort study from January 2009 to June 2022, 10,441 iCCA patients from ten tertiary hospitals were identified. Patients who underwent curative-intent microwave ablation (MWA) or liver resection (LR) for tumors within Milan criteria were included. One-to-many propensity score matching (PSM) at variable ratios (1:n ≤4) was used to balance baseline characteristics. Mediation analysis was applied to identify potential mediators of the survival difference. Findings: 944 patients were finally enrolled in this study, with 221 undergoing MWA and 723 undergoing LR. After PSM, 203 patients in the MWA group were matched with 588 patients in the LR group. The median follow-up time was 4.7 years. Compared with LR, MWA demonstrated similar overall survival (5-year 44.8% versus 40.4%; HR 0.96, 95% CI 0.71–1.29, P = .761). There was an improvement in the 5-year disease-free survival rate for MWA from 17.1% during the period of 2009–2016 to 37.3% during 2017–2022, becoming comparable to the 40.8% of LR (P = .129). The proportion of ablative margins ≥5 mm increased from 25% to 61% over the two periods, while this proportion of surgical margins was 62% and 77%, respectively. 34.5% of DFS disparity can be explained by the mediation effect of margins (P

AbstractObjective To compare the long-term efficacy and safety of microwave ablation (MWA) as first-line therapy for hepatocellular carcinoma (HCC) adjacent versus nonadjacent to the gallbladder.Materials and Methods From 2006 to 2018, 657 patients with ≤5 cm HCC who underwent percutaneous ultrasound-guided MWA as first-line therapy from 5 hospitals were enrolled in this retrospective study. Patients were grouped into the adjacent group (n = 49) and the nonadjacent group (n = 608) according to whether the tumor was adjacent to the gallbladder. Propensity score matching (PSM) was used to balance baseline variables between the two groups.Results Forty-eight patient pairs were matched after PSM. For the PSM cohort, during a median follow-up time of 60 months, there were no differences in PFS (hazard ratio [HR], 1.011; 95% confidence interval [CI], 0.647-1.578; p = 0.963) or OS (HR 0.925; 95% CI 0.522-1.639; p = 0.789) between the adjacent and nonadjacent groups. Univariate and multivariate analyses revealed that the tumor adjacent to the gallbladder was not an independent risk factor for PFS or OS (all p > 0.05). Subgroup analysis showed comparable PFS and OS between the two groups in the 0.05). In addition to more use of assistive technology (p 0.05) to the nonadjacent group.Conclusion There were comparable long-term efficacy and complications between patients with HCC adjacent and nonadjacent to the gallbladder treated with MWA.

AbstractPurpose To compare the efficacy of ultrasound-guided percutaneous microwave ablation (MWA) without subsequent lumpectomy and breast-conserving surgery (BCS) in patients with early breast cancer (BC).Materials and methods This retrospective cohort study enrolled 106 patients with early BC (T0/1/2 N0/1 M0) treated by MWA (n = 21) or BCS (n = 85) from October 2014 to December 2020. Propensity score matching (PSM) was performed to balance the baseline characteristics between MWA and BCS groups. The tumor progression, overall survival (OS), disease-specific survival (DSS), complications, and cosmetic results were compared.Results After PSM, there were 21 patients with balanced baseline characteristics in each group. After a median follow-up of 43 months (range, 15–89 months), there was no significant difference in tumor progression (10% vs 2%, p = 0.18), OS (96% vs 99%, p = 0.36), DSS (100% vs 99%, p > 0.99), and complications (0% vs 19%, p = 0.58). The operation time of MWA was shorter (60 min vs 101 min, p

AbstractBackground The range of an ablation zone (AZ) plays a crucial role in the treatment effect of microwave ablation (MWA). The aim of this study was to analyze the factors influencing the AZ range.Methods Fourteen factors in four areas were included: patient-related factors (sex, age), disease-related factors (tumor location, liver cirrhosis), serological factors (ALT, AST, total protein, albumin, total bilirubin, direct bilirubin, and platelets), and MWA parameters (ablation time, power, and needle type). Multiple sequence MRI was used to delineate AZ by three radiologists using 3D Slicer. MATLAB was used to calculate the AZ length, width, and area of the largest section. Linear regression analysis was used to analyze influencing factors. Moreover, a subgroup analysis was conducted for patients with viral hepatitis.Result 220 patients with 290 tumors were included between 2010–2021. In addition to MWA parameters, cirrhosis and tumor location were significant factors that influenced AZ (p

AbstractObjectives Current predictors are largely unsatisfied for early recurrence (ER) of hepatocellular carcinoma (HCC) after thermal ablation. We aimed to explore the prognostic value of peripheral immune factors (PIFs) for better ER prediction of HCC after thermal ablation.Methods Patients who received peripheral blood mononuclear cells (PBMCs) tests before thermal ablation were included. Clinical parameters and 18 PIFs were selected to construct ModelClin, ModelPIFs and the hybrid ModelPIFs-Clin. Model performances were evaluated using area under the curve (AUC), and recurrence-free survival (RFS) were analyzed by Kaplan-Meier analysis and log-rank tests.Results 244 patients were included and were randomly divided in 3:1 ratio to discovery and validation cohorts. Clinical parameters including tumor size and AFP, and PIFs including neutrophils, platelets, CD3+CD16+CD56+ NKT and CD8+CD28- T lymphocytes were selected. The ModelPIFs-Clin showed increase in predictive performance compared with ModelClin, with the AUC improved from 0.664 (95%CI:0.588–0.740) to 0.801 (95%CI:0.734–0.867) in discovery cohort (p

Background Previous studies have failed to investigate the specific effects of advanced age on survival outcomes by considering the Charlson Comorbidity Index (CCI) and age permutation in patients with T1a renal cell carcinoma (T1a RCC) treated by microwave ablation (MWA). Notably, RCC guidelines recommended radiofrequency ablation (RFA) and active surveillance (AS) are both treatment options for elderly T1a RCC, but whether MWA is superior to AS in light of higher heating efficiency and larger ablation zone compared with RFA is not clear. This study aimed to investigate the specific effects of advanced age on survival outcomes of T1a RCC patients stratified by CCI score and indicate better intervention for elderly T1a RCC between MWA and AS. Methods This was a retrospective study. We retrospectively reviewed 237 patients with T1a RCC who had undergone MWA over the last 16 years. Data were analyzed by Cox regression and Landmark analysis. Interaction tests and propensity score matching were used to account for potential biases. We compared the overall survival (OS) and cancer-specific survival (CSS) rates of patients ≥75 years in our study with corresponding figures from 4251 counterparts undergoing AS in published articles. Results Using patients ＜75 years with a CCI ≤2 as a reference, the hazard ratio (HR) and 95% confidence interval (CI) of OS for patients＜75 years with a CCI ≥3, patients ≥75 years with a CCI ≤2, and patients ≥75 years with CCI ≥3, were 2.954 (1.139-7.663), 3.48 (1.487-8.146), and 3.357 (1.162-9.698), respectively. The adverse effect of an age ≥75 years on OS was attenuated in patients with a CCI ≥3. The attenuation lasted for 62.5 months of follow-up ( P = .017). Notably, advanced age exerted a protective effect on progression-free survival (PFS) in patients with a CCI ≥3, increasing the 8-year PFS from 67.8% to 100% ( P = .049). Relative to 1-, 3-, 5-, and 8-year survival data for patients aged ≥75 undergoing AS, the OS rates for 5-year follow-up were always better in MWA. However, beyond 5 years, the OS rates dropped to levels that were similar to AS. Conclusions Advanced age exerts adverse effects and significantly protective effects on OS and PFS, respectively, in T1a RCC patients with a CCI ≥ 3. According to our study, elderly patients with T1a RCC underwent radical MWA may yield a better medium-term OS relative to AS.

BackgroundFocal cortical dysplasia (FCD) IIb and tuberous sclerosis complex (TSC) are common causes of drug-resistant epilepsy in children. However, the etiologies related to the development of FCD IIb and TSC are not fully understood. α-synuclein (α-syn) is a member of synucleins family that plays crucial roles in modulating synaptic transmission in central nervous system. Here, we explored the expression profiles and potential pathogenic functions of α-syn in cortical lesions of epileptic patients with FCD IIb and TSC.MethodsSurgical specimens from epileptic patients with FCD IIb and TSC, as well as FCD rats generated by in utero X-ray-radiation were adopted in this study and studied with immunohistochemistry, immunofluorescence, western blotting, and co-immunoprecipitation etc. molecular biological techniques.ResultOur results showed that α-syn expression was reduced in FCD IIb and TSC lesions. Specifically, α-syn protein was intensely expressed in dysplastic neurons (DNs) and balloon cells (BCs) in FCD IIb lesions, whereas was barely detected in DNs and giant cells (GCs) of TSC lesions. Additionally, p-α-syn, the aggregated form of α-syn, was detected in DNs, BCs, GCs, and glia-like cells of FCD IIb and TSC lesions. We previous showed that the function of N-methyl-D-aspartate receptor (NMDAR) was enhanced in FCD rats generated by X-ray-radiation. Here, we found the interaction between α-syn and NMDAR subunits NMDAR2A, NMDAR2B were augmented in cortical lesions of FCD patients and FCD rats.ConclusionThese results suggested a potential role of α-syn in the pathogenesis of FCD IIb and TSC by interfering with NMDAR.

Summary: Thyroid nodules are a common disease, and fine needle aspiration cytology (FNAC) is the primary method to assess their malignancy. For the diagnosis of follicular thyroid nodules, however, FNAC has limitations. FNAC can classify them only as Bethesda IV nodules, leaving their exact malignant status and pathological type undetermined. This imprecise diagnosis creates difficulties in selecting the follow-up treatment. In this retrospective study, we collected ultrasound (US) image data of Bethesda IV thyroid nodules from 2006 to 2022 from five hospitals. Then, US image-based artificial intelligence (AI) models were trained to identify the specific category of Bethesda IV thyroid nodules. We tested the models using two independent datasets, and the best AI model achieved an area under the curve (AUC) between 0.90 and 0.95, demonstrating its potential value for clinical application. Our research findings indicate that AI could change the diagnosis and management process of Bethesda IV thyroid nodules.

Abstract Background Although human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are a promising cell resource for cardiovascular research, these cells exhibit an immature phenotype that hampers their potential applications. The inwardly rectifying potassium channel Kir2.1, encoded by the KCNJ2 gene, has been thought as an important target for promoting electrical maturation of iPSC-CMs. However, a comprehensive characterization of morphological and functional changes in iPSC-CMs overexpressing KCNJ2 (KCNJ2 OE) is still lacking. Methods iPSC-CMs were generated using a 2D in vitro monolayer differentiation protocol. Human KCNJ2 construct with green fluorescent protein (GFP) tag was created and overexpressed in iPSC-CMs via lentiviral transduction. The mixture of iPSC-CMs and mesenchymal cells was cocultured with decellularized natural heart matrix for generation of 3D human engineered heart tissues (EHTs). Results We showed that mRNA expression level of KCNJ2 in iPSC-CMs was dramatically lower than that in human left ventricular tissues. KCNJ2 OE iPSC-CMs yielded significantly increased protein expression of Kir2.1 and current density of Kir2.1-encoded IK1. The larger IK1 linked to a quiescent phenotype that required pacing to elicit action potentials in KCNJ2 OE iPSC-CMs, which can be reversed by IK1 blocker BaCl2. KCNJ2 OE also led to significantly hyperpolarized maximal diastolic potential (MDP), shortened action potential duration (APD) and increased maximal upstroke velocity. The enhanced electrophysiological maturation in KCNJ2 OE iPSC-CMs was accompanied by improvements in Ca2+ signaling, mitochondrial energy metabolism and transcriptomic profile. Notably, KCNJ2 OE iPSC-CMs exhibited enlarged cell size and more elongated and stretched shape, indicating a morphological phenotype toward structural maturation. Drug testing using hERG blocker E-4031 revealed that a more stable MDP in KCNJ2 OE iPSC-CMs allowed for obtaining significant drug response of APD prolongation in a concentration-dependent manner. Moreover, KCNJ2 OE iPSC-CMs formed more mature human EHTs with better tissue structure and cell junction. Conclusions Overexpression of KCNJ2 can robustly enhance maturation of iPSC-CMs in electrophysiology, Ca2+ signaling, metabolism, transcriptomic profile, cardiomyocyte structure and tissue engineering, thus providing more accurate cellular model for elucidating cellular and molecular mechanisms of cardiovascular diseases, screening drug-induced cardiotoxicity, and developing personalized and precision cardiovascular medicine.

Glioblastoma multiforme (GBM) is the most aggressive form of glioma and the most common primary tumor of the central nervous system. Despite significant advances in clinical management strategies and diagnostic techniques for GBM in recent years, it remains a fatal disease. The current standard of care includes surgery, radiation, and chemotherapy, but the five-year survival rate for patients is less than 5%. The search for a more precise diagnosis and earlier intervention remains a critical and urgent challenge in clinical practice. The Notch signaling pathway is a critical signaling system that has been extensively studied in the malignant progression of glioblastoma. This highly conserved signaling cascade is central to a variety of biological processes, including growth, proliferation, self-renewal, migration, apoptosis, and metabolism. In GBM, accumulating data suggest that the Notch signaling pathway is hyperactive and contributes to GBM initiation, progression, and treatment resistance. This review summarizes the biological functions and molecular mechanisms of the Notch signaling pathway in GBM, as well as some clinical advances targeting the Notch signaling pathway in cancer and glioblastoma, highlighting its potential as a focus for novel therapeutic strategies.

The unique properties of silicon nanotubes (SiNTs) are expected to provide them with a very wide range of application potential in nanoelectronic devices, lithium-ion batteries, sensors, field-effect transistors, magnetic nanodevices, hydrogen reservoirs, optoelectronic devices, field emission display devices, and quantum computers, and they are a new one-dimensional nanomaterial with a wide range of applications in the future. Although researchers have already prepared SiNTs in the laboratory, there are not many research reports on SiNTs, especially the preparation of B and P doped SiNTs and analysis based on spectroscopic techniques. Our research group used silicon sources (SiO2 and Si) that had not been previously reported or catalyzed by the rare earth element lanthanum (La). The optimal experimental conditions for the preparation of SiNTs, as well as the doping preparation and study of B and P, were explored by thermal evaporation. Finally, SEM, Raman spectroscopy, selected area electron diffraction, HRTEM, XRD, PL spectroscopy, and other characterization methods were performed on the experimental samples. The experimental results show that 1280 °C was the best experimental temperature for the preparation of SiNTs. Under experimental conditions of 1280 °C, doping of B favored the synthesis of silicon nanowires and SiNTs, and the number of products generated was from least to most: no added B2O3 < 0.1 g B2O3 < 0.2 g B2O3 < 0.3 g B2O3 < 0.4 g B2O3. Under the experimental conditions of 1280 °C, when the amount of doped B2O3 is large (2.2 g), a “needle” structure product is generated. Under experimental conditions of 1400 °C, when the ratio of doped P to the original material is 1:9, a new material that has not been previously reported is generated. Through relevant research and the findings of this paper, it is hoped that it can be helpful for the future research and application of SiNTs.

Immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of a variety of malignancies. As its use increases, the unique immune-mediated toxicity profile of ICls are becoming apparent. We report a case of immune-related endocrine adverse events (irAE) in a patient with hepatocellular carcinoma treated with anti-programmed cell death protein 1 (PD-1) (tislelizumab). Although many irAEs have been reported, few cases of severe thyrotoxicosis have been described after immunotherapy in the literature. We present the case of a 49-year-old male who experienced a Grade 3 tislelizumab-related adverse reaction according to Common Terminology Criteria for Adverse Events (CTCAE5.0) and received methylprednisolone, thiamazole, and levothyroxine sodium tablets. Early identification of irAEs, risk factors, regular monitoring, use of steroids and/or immunoglobulins, and adjuvant supportive care are critical to the clinical prognosis of patients. It should be underlined that the tumor benefits of ICI therapy outweigh the risks associated with ICI-induced endocrine disorders, and ICI treatment should not be stopped or delayed except in rare cases (adrenal crisis, severe thyrotoxicosis). The familiarity of healthcare professionals with irAEs of the thyroid when thyrotoxicosis occurs is important to facilitate an effective diagnosis and appropriate treatment of this increasingly common thyroid disorder.

The transient receptor potential vanilloid subfamily 1 (TRPV1) is a polymodal nociceptor that is highly expressed in sensory nerves. Activation of TRPV1 receptors excites primary afferent nociceptors by opening cation channels, allowing the influx of Na+ and Ca2+ ions into the cytoplasm. Here, a TRPV1 knockout human embryonic stem cell line was generated using the CRISPR/Cas9 genome-editing technology to further study the function of TRPV1. The cell line confirmed with normal pluripotency and karyotype.

Summary: Background: Brugada syndrome (BrS) is a cardiac channelopathy that can result in sudden cardiac death (SCD). SCN5A is the most frequent gene linked to BrS, but the genotype–phenotype correlations are not completely matched. Clinical phenotypes of a particular SCN5A variant may range from asymptomatic to SCD. Here, we used comparison of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from a SCN5A mutation-positive (D356Y) BrS family with severely affected proband, asymptomatic mutation carriers (AMCs) and healthy controls to investigate this variation. Methods: 26 iPSC lines were generated from skin fibroblasts using nonintegrated Sendai virus. The generated iPSCs were differentiated into cardiomyocytes using a monolayer-based differentiation protocol. Findings: D356Y iPSC-CMs exhibited increased beat interval variability, slower depolarization, cardiac arrhythmias, defects of Na+ channel function and irregular Ca2+ signaling, when compared to controls. Importantly, the phenotype severity observed in AMC iPSC-CMs was milder than that of proband iPSC-CMs, an observation exacerbated by flecainide. Interestingly, the iPSC-CMs of the proband exhibited markedly decreased Ca2+ currents in comparison with control and AMC iPSC-CMs. CRISPR/Cas9-mediated genome editing to correct D356Y in proband iPSC-CMs effectively rescued the arrhythmic phenotype and restored Na+ and Ca2+ currents. Moreover, drug screening using established BrS iPSC-CM models demonstrated that quinidine and sotalol possessed antiarrhythmic effects in an individual-dependent manner. Clinically, venous and oral administration of calcium partially reduced the malignant arrhythmic events of the proband in mid-term follow-up. Interpretation: Patient-specific and genome-edited iPSC-CMs can recapitulate the varying phenotypic severity of BrS. Our findings suggest that preservation of the Ca2+ currents might be a compensatory mechanism to resist arrhythmogenesis in BrS AMCs. Funding: National Key R&D Program of China (2017YFA0103700), National Natural Science Foundation of China (81922006, 81870175), Natural Science Foundation of Zhejiang Province (LD21H020001, LR15H020001), National Natural Science Foundation of China (81970269), Key Research and Development Program of Zhejiang Province (2019C03022) and Natural Science Foundation of Zhejiang Province (LY16H020002).

Summary: Background: Ultrasonography is the most widely used technique to diagnose echinococcosis; however, challenges in using this technique and the demand on medical resources, especially in low-income or remote areas, can delay diagnosis. We aimed to develop a deep convolutional neural network (DCNN) model based on ultrasonography to identify echinococcosis and its types, especially alveolar echinococcosis. Methods: This retrospective, large-scale, multicentre study used ultrasound images from patients assessed at 84 hospitals in China, obtained between Jan 1, 2002, and Dec 31, 2021. Patients with a diagnosis of cystic echinococcosis, alveolar echinococcosis, or seven other types of focal liver lesions were included. We tested ResNet-50, ResNext-50, and VGG-16 as the backbone network architecture for a classification DCNN model and input the perinodular information from the ultrasound images. We trained and validated the DCNN model to diagnose and classify echinococcosis using still greyscale ultrasound images of focal liver lesions in four stages: differentiating between echinococcosis and other focal liver lesions (stage one); differentiating cystic echinococcosis, alveolar echinococcosis, and other focal liver lesions (stage two); differentiating cystic echinococcosis, alveolar echinococcosis, benign other focal liver lesions, and malignant focal liver lesions (stage three); and differentiating between active and transitional cystic echinococcosis and inactive cystic echinococcosis (stage four). We then tested the algorithm on internal, external, and prospective test datasets. The performance of DCNN was also compared with that of 12 radiologists recruited between Jan 15, 2022, and Jan 28, 2022, from Qinghai, Xinjiang, Anhui, Henan, Xizang, and Beijing, China, with different levels of diagnostic experience for echinococcosis and other focal liver lesions in a subset of ultrasound data that were randomly chosen from the prospective test dataset. The study is registered at ClinicalTrials.gov (NCT03871140). Findings: The study took place between Jan 1, 2002, and Dec 31, 2021. In total, to train and test the DCNN model, we used 9631 liver ultrasound images from 6784 patients (2819 [41·7%] female patients and 3943 [58·3%] male patients) from 87 Chinese hospitals. The DCNN model was trained with 6328 images, internally validated with 984 images, and tested with 2319 images. The ResNet-50 network architecture outperformed VGG-16 and ResNext-50 and was generalisable, with areas under the receiver operating characteristic curve (AUCs) of 0·982 (95% CI 0·960–0·994), 0·984 (0·972–0·992), and 0·913 (0·886–0·935) in distinguishing echinococcosis from other focal liver lesions; 0·986 (0·966–0·996), 0·962 (0·946–0·975), and 0·900 (0·872–0·924) in distinguishing alveolar echinococcosis from cystic echinococcosis and other focal liver lesions; and 0·974 (0·818–1·000), 0·956 (0·875–0·991), and 0·944 (0·844–0·988) in distinguishing active and transitional cystic echinococcosis from inactive echinococcosis in the three test datasets. Specifically, in patients with the hepatitis B or hepatitis C virus, the model could distinguish alveolar echinococcosis from hepatocellular carcinoma with an AUC of 0·892 (0·812–0·946). In identifying echinococcosis, the model showed significantly better performance compared with senior radiologists from a high-endemicity area (AUC 0·942 [0·904–0·967] vs 0·844 [0·820–0·866]; p=0·027) and improved the diagnostic ability of junior, attending, and senior radiologists before and after assistance with AI with comparison of AUCs of 0·743 (0·714–0·770) versus 0·850 (0·826–0·871); p

Objective To compare the long-term efficacy of microwave ablation (MWA) for subcapsular and non-subcapsular hepatocellular carcinomas (HCCs) using propensity score matching (PSM). Materials and methods Using a multicenter database, we enrolled 430 patients (347 men, 83 women; age range, 15–71 years) with HCCs who received percutaneous ultrasound-guided MWA, between January 2012 and December 2018. The patients were grouped as follows, based on whether the tumor was adjacent to the capsule: subcapsular group (n = 142) and non-subcapsular group (n = 142). To evaluate the correlation between subcapsular position and efficacy of MWA, a Cox proportional hazards model was used to calculate disease-free survival (DFS) and overall survival (OS) based on PSM data. Results In total, 142 pairs of patients were matched. In the PSM cohort, the 1-year, 3-year, and 5-year DFS rates of the subcapsular and non-subcapsular groups were 84%, 61%, and 47%, respectively, and 85%, 67%, and 58%, respectively, while the 1-year, 3-year, and 5-year OS rates were 98%, 90%, and 84%, respectively, and 98%, 90%, and 88%, respectively. In the PSM cohort, subcapsular position was not an independent risk factor for DFS (hazard ratio [HR] = 1.291, p = 0.196) or OS (HR = 0.926, p = 0.866). Additionally, there were no significant differences in the incidence of local tumor progression, major complications, technical success rate, number of puncture needles, and postoperative hospital stay between the two groups (p > 0.05). Conclusion There were no significant differences in DFS, OS, incidence of local tumor progression, and major complications between patients with subcapsular and non-subcapsular HCCs treated with MWA.

Objective To evaluate the potential risk factors influencing cure rate of ultrasound-guided microwave ablation (MWA) for primary hyperparathyroidism (PHPT). Materials and methods Seventy five patients (25 males and 50 females; mean age, 56.80 ± 12.34; age range, 26–85) with PHPT undergoing MWA under ultrasound guidance were enrolled between May 2017 and December 2020. The cure rate and complications were evaluated after treatment. The potential factors influencing cure rate of ultrasound-guided MWA for PHPT were analyzed by univariate and multivariate binary logistic regression. Results Fifty six of 75 patients had normal PTH and serum calcium levels after at least 6 months after one session MWA, and the cure rate was 74.7% (56/75). 6 uncured patients received the second session MWA during follow-up, and the cure rate achieved 81.3% (61/75) after the second session MWA. Voice changes occurred in 4 patients (5.33%) and recovered within 3 months after ablation without special treatment. Nodule volume was the independent risk factor associated with cure in PHPT patients undergoing MWA, whether after one session (p = 0.0224; odds ratio, 0.67) or the second session MWA (p = 0.0408; odds ratio, 0.74). The cutoff value for nodule volume in predicting the cure was 0.96 cm3 (one session: sensitivity, 76.8%; specificity, 73.7%; the second session: sensitivity, 72.1%; specificity, 71.4%). Conclusion In conclusion, parathyroid nodule volume was the independent risk factor associated with cure in PHPT patients undergoing MWA.

Objective To develop and validate an ultrasonic radiomics model for predicting the recurrence and differentiation of hepatocellular carcinoma (HCC). Convolutional neural network (CNN) ResNet 18 and Pyradiomics were used to analyze gray-scale-ultrasonic images to predict the prognosis and degree of differentiation of HCC.Methods This retrospective study enrolled 513 patients with HCC who underwent preoperative grayscale-ultrasonic imaging, and their clinical characteristics were observed. Patients were randomly divided into training (n = 413) and validation (n = 100) cohorts. CNN ResNet 18 and Pyradiomics were used to analyze ultrasonic images of HCC and peritumoral images to develop a prognostic and differentiation model. Clinical characteristics were integrated into the radiomics model and patients were stratified into high- and low-risk groups. The predictive effect was evaluated using the C-index and receiver operating characteristic (ROC) curve.Results The model combined with ResNet 18 and clinical characteristics achieved a good predictive ability. The C-indices of early recurrence (ER), late recurrence (LR), and recurrence-free survival (RFS) were 0.695 (0.561–0.789), 0.715 (0.623–0.800) and 0.721 (0.647–0.795), respectively, in the validation cohort, which was superior to the clinical model and ultrasonic semantic model. The model could stratify patients into high- and low-risk groups, which showed significant differences (p

Abstract Objectives To evaluate the association between adipose tissue distribution and early allograft dysfunction (EAD) in liver transplantation (LT) recipients. Methods A total of 175 patients who received LT from April 2015 to September 2020 were enrolled in this retrospective study. The areas of abdominal adipose tissue and skeletal muscle of all patients were measured based on the preoperative CT images. The appropriate statistical methods including the propensity score-matched (PSM) analysis were performed to identify the association between adipose tissue distribution and EAD. Results Of 175 LT recipients, 55 patients (31.4%) finally developed EAD. The multivariate logistic analysis revealed that preoperative serum albumin (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.17–0.70), platelet–lymphocyte ratio (OR 2.35, 95% CI 1.18–4.79), and visceral adipose tissue (VAT) area (OR 3.17, 95% CI 1.56–6.43) were independent associated with EAD. After PSM analysis, VAT area was still significantly associated with EAD (OR 3.95, 95% CI 1.16–13.51). In survival analysis, no significant difference was identified in one-year graft failure (log-rank: p = 0.487), and conversely result was identified in overall survival (OS) (log-rank: p = 0.012; hazard ratio (HR) 4.10, 95% CI 1.27–13.16). Conclusions LT recipients with high VAT area have higher risk for the occurrence of EAD, and high VAT area might have certain clinical value for predicting the poor OS of patients. For LT candidates with large amount of VAT, the clinicians can take clinical interventions by suggesting physical and nutritional treatments to improve outcomes after LT.

Despite being a common therapy for hepatocellular carcinoma (HCC), insufficient thermal ablation can leave behind tumor residues that can cause recurrence. This is believed to augment M2 inflammatory macrophages that usually play a pro-tumorigenic role. To address this problem, we designed d-mannose-chelated iron oxide nanoparticles (man-IONPs) to polarize M2-like macrophages into the antitumor M1 phenotype. In vitro and in vivo experiments demonstrated that man-IONPs specifically targeted M2-like macrophages and accumulated in peri-ablation zones after macrophage infiltration was augmented under insufficient microwave ablation (MWA). The nanoparticles simultaneously induced polarization of pro-tumorigenic M2 macrophages into antitumor M1 phenotypes, enabling the transformation of the immunosuppressive microenvironment into an immunoactivating one. Post-MWA macrophage polarization exerted robust inhibitory effects on HCC progression in a well-established orthotopic liver cancer mouse model. Thus, combining thermal ablation with man-IONPs can salvage residual tumors after insufficient MWA. These results have strong potential for clinical translation.

Xujiahui (XJH) station in downtown Shanghai holds the longest continuous daily temperature series in China, which is unique for assessing modern climate change and impacts but must be homogenised. The present work established a set of homogenised monthly and daily surface air temperature (SAT) series during 1873–2019 at XJH. Two major inhomogeneous break points (around 1954 and 1993) were identified in the original SAT series, which had been overlooked in previous works. The inhomogeneous biases were adjusted via the inter-station deviation analysis. The adjusted SAT series shows a warming trend of 1.9 °C per century compared with 1.7 °C per century in the original series. The multi-decadal variations of quasi-32-year and quasi-64-year periods are weaker in the adjusted series than in the original series, suggesting overestimated multi-decadal variability in the original data due to inhomogeneous biases. Relative to the early period 1873–1900, the recent decade (the 2010s) is warmer by 2.2 °C. Urbanisation has been responsible for approximately 19.3% of the rapid warming since the 1980s. The high and low SAT extremes exhibit significant warming, especially after the 1970s. The trend in the low SAT extremes in the adjusted series is substantially larger than that in the original series, implying that previous studies might underestimate the warming in cold extremes.

Abstract Background High early recurrence (ER) of hepatocellular carcinoma (HCC) after microwave ablation (MWA) represents a sign of aggressive behavior and severely worsens prognosis. The aim of this study was to estimate the outcome of HCC following MWA and develop a response algorithmic strategy based on multiparametric MRI and clinical variables. Methods In this retrospective study, we reviewed the records of 339 patients (mean age, 62 ± 12 years; 106 men) treated with percutaneous MWA for HCC between January 2014 and December 2017 that were evaluated by multiparametric MRI. These patients were randomly split into a development and an internal validation group (3:1). Logistic regression analysis was used to screen imaging features. Multivariate Cox regression analysis was then performed to determine predictors of ER (within 2 years) of MWA. The response algorithmic strategy to predict ER was developed and validated using these data sets. ER rates were also evaluated by Kaplan–Meier analysis. Results Based on logistic regression analyses, we established an image response algorithm integrating ill-defined margins, lack of capsule enhancement, pre-ablative ADC, ΔADC, and EADC to calculate recurrence scores and define the risk of ER. In a multivariate Cox regression model, the independent risk factors of ER (p

Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition. We previously reported the MT-RNR2 variant associated with HCM that results in mitochondrial dysfunction. Here, we screened a mitochondria-associated compound library by quantifying the mitochondrial membrane potential of HCM cybrids and the survival rate of HCM-induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) in galactose media. 1-Deoxynojirimycin (DNJ) was identified to rescue mitochondrial function by targeting optic atrophy protein 1 (OPA1) to promote its oligomerization, leading to reconstruction of the mitochondrial cristae. DNJ treatment further recovered the physiological properties of HCM iPSC-CMs by improving Ca2+ homeostasis and electrophysiological properties. An angiotensin II-induced cardiac hypertrophy mouse model further verified the efficacy of DNJ in promoting cardiac mitochondrial function and alleviating cardiac hypertrophy in vivo. These results demonstrated that DNJ could be a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy. Our findings will help elucidate the mechanism of HCM and provide a potential therapeutic strategy.