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Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or G q signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34 Nter . Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ-S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1-G q -Ca 2+ -eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Vascular injury is central to the pathogenesis and progression of cardiovascular diseases, however, fostering alternative strategies to alleviate vascular injury remains a persisting challenge. Given the central role of cell-derived nitric oxide (NO) in modulating the endogenous repair of vascular injury, NO-generating proteolipid nanovesicles (PLV-NO) are designed that recapitulate the cell-mimicking functions for vascular repair and replacement. Specifically, the proteolipid nanovesicles (PLV) are versatilely fabricated using membrane proteins derived from different types of cells, followed by the incorporation of NO-generating nanozymes capable of catalyzing endogenous donors to produce NO. Taking two vascular injury models, two types of PLV-NO are tailored to meet the individual requirements of targeted diseases using platelet membrane proteins and endothelial membrane proteins, respectively. The platelet-based PLV-NO (pPLV-NO) demonstrates its efficacy in targeted repair of a vascular endothelium injury model through systemic delivery. On the other hand, the endothelial cell (EC)-based PLV-NO (ePLV-NO) exhibits suppression of thrombosis when modified onto a locally transplanted small-diameter vascular graft (SDVG). The versatile design of PLV-NO may enable a promising therapeutic option for various vascular injury-evoked cardiovascular diseases., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objective: To investigate the influence of the dead space in disposable blood sampling needle on activated partial thromboplastin time (APTT), FVIII level and pharmacokinetic (PK) profiles in children with hemophilia., Methods: Children (<18 years) with severe hemophilia A were enrolled. After three days' washout-period, blood samples were collected at pre-dose, 1 h, 3 h, 9 h, 24 h and 48 h post-infusion. At each timepoint, two 2 mL vacuum tubes with 3.2% trisodium citrate were used. The first tube was signed as 'non-standard' (NS) and the second tube was signed as 'standard' (S). FVIII activities were evaluated by one-stage assay. WAPPS-Hemo was used to generate PK profiles like half-life time (t 1/2 ), clearance (CL), trough level and time to 1, 2 and 5IU/dL after a dose of 50 ± 10IU/dL. The FVIII activities at 9 h and 24 h post-infusion were put into WAPPS and thus brought four combinations by true or biased FVIII level that used., Result: Compared with standard-collected blood samples, prolonged APTT results ( P -values < 0.01) and decreased FVIII activity ( P -values < 0.05) were revealed in those non-standard blood samples. The corresponding bias was in positive relation to both APTT-S (r = 0.44, P  < 0.0001) and FVIII-S level(r = 0.68, P  < 0.001). The FVIII bias percentage got larger as FVIII-S level reduced (r = -0.24, P  < 0.01). During the four combinations of FVIII activity at 9 h and 24 h, statistically longer t 1/2 , lower CL and longer time to 1, 2 or 5IU/dL were observed in 9H-S&24H-S group and 9H-NS&24H-S group., Conclusion: While using vacuum tubes for clotting indicators and PK profiles, the dead space of blood sampling needle should be eliminated in advance.

Reactive oxygen species (ROS) play crucial roles in element cycling and pollutant dynamics, but their variations and mechanisms in the rhizosphere of submerged macrophytes are poorly investigated. This study investigated the light-dark cycle fluctuations and periodic variations in ROS, redox-active substances, and microbial communities in the rhizosphere of Vallisneria natans. The results showed sustained production and significant diurnal fluctuations in the O 2 •- and •OH from 27.6 ± 3.7 to 61.7 ± 3.0 μmol/kg FW and 131.0 ± 6.8 to 195.4 ± 8.7 μmol/kg FW, respectively, which simultaneously fluctuated with the redox-active substances. The ROS contents in the rhizosphere were higher than those observed in non-rhizosphere sediments over the V. natans growth period, exhibiting increasing-decreasing trends. According to the redundancy analysis results, water-soluble phenols, fungi, and bacteria were the main factors influencing ROS production in the rhizosphere, showing contribution rates of 74.0, 17.3, and 4.4 %, respectively. The results of partial least squares path modeling highlighted the coupled effects of redox-active substances and microbial metabolism. Our findings also demonstrated the degradation effect of ROS in rhizosphere sediments of submerged macrophytes. This study provides experimental evidence of ROS-related rhizosphere effects and further insights into submerged macrophytes-based ecological restoration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Detecting coronary stenosis accurately in X-ray angiography (XRA) is important for diagnosing and treating coronary artery disease (CAD). However, challenges arise from factors like breathing and heart motion, poor imaging quality, and the complex vascular structures, making it difficult to identify stenosis fast and precisely. In this study, we proposed a Quantum Diffusion Model with Spatio-Temporal Feature Sharing to Real-time detect Stenosis (STQD-Det). Our framework consists of two modules: Sequential Quantum Noise Boxes module and spatio-temporal feature module. To evaluate the effectiveness of the method, we conducted a 4-fold cross-validation using a dataset consisting of 233 XRA sequences. Our approach achieved the F1 score of 92.39% with a real-time processing speed of 25.08 frames per second. These results outperform 17 state-of-the-art methods. The experimental results show that the proposed method can accomplish the stenosis detection quickly and accurately.

Background: Region-specific immune environments in the epididymis influence the immune responses to uropathogenic Escherichia coli (UPEC) infection, a relevant cause of epididymitis in men. Toll-like receptors (TLRs) are essential to orchestrate immune responses against bacterial infections. The epididymis displays region-specific inflammatory responses to bacterial-derived TLR agonists, such as lipopolysaccharide (LPS; TLR4 agonist) and lipoteichoic acid (LTA; TLR2/TLR6 agonist), suggesting that TLR-associated signaling pathways could influence the magnitude of inflammatory responses in epididymitis., Objectives: To investigate the expression and regulation of key genes associated with TLR4 and TLR2/TLR6 signaling pathways during epididymitis induced by UPEC, LPS, and LTA in mice., Material and Methods: Epididymitis was induced in mice using UPEC, ultrapure LPS, or LTA, injected into the interstitial space of the initial segment or the lumen of the vas deferens close to the cauda epididymidis. Samples were harvested after 1, 5, and 10 days for UPEC-treated animals and 6 and 24 h for LPS-/LTA-treated animals. Ex vivo epididymitis was induced by incubating epididymal regions from naive mice with LPS or LTA. RT-qPCR and Western blot assays were conducted., Results: UPEC infection up-regulated Tlr2, Tlr4, and Tlr6 transcripts and their associated signaling molecules Cd14, Ticam1, and Traf6 in the cauda epididymidis but not in the initial segment. In these epididymal regions, LPS and LTA differentially modulated Tlr2, Tlr4, Tlr6, Cd14, Myd88, Ticam1, Traf3, and Traf6 expression levels. NFKB and AP1 activation was required for LPS- and LTA-induced up-regulation of TLR-associated signaling transcripts in the cauda epididymidis and initial segment, respectively., Conclusion: The dynamic modulation of TLR4 and TLR2/TLR6 signaling pathways gene expression during epididymitis indicates bacterial-derived antigens elicit an increased tissue sensitivity to combat microbial infection in a spatial manner in the epididymis. Differential activation of TLR-associated signaling pathways may contribute to fine-tuning inflammatory responses along the epididymis., (© 2024 American Society of Andrology and European Academy of Andrology.)

The E3 ubiquitin ligase MdSINA11 targets the jasmonate ZIM domain protein MdJAZ2 for ubiquitination and degradation through the 26S proteasome pathway, thereby initiating jasmonate signaling and jasmonic acid-triggered anthocyanin biosynthesis in apple., (© 2024 Institute of Botany, Chinese Academy of Sciences.)

Objectives: Type 2 diabetes (T2DM), a recognized risk factor for periodontitis, is characterized by insulin resistance. However, the molecular mechanisms concerning the role of insulin resistance in linking T2DM and periodontitis remain poorly elucidated due to the absence of an appropriate T2DM cell model. We aimed to explore an appropriate model of T2DM in human periodontal ligament stem cells (hPDLSCs) and uncover the involved mechanisms., Materials and Methods: hPDLSCs were incubated with common reagents for recapitulating insulin resistance state including high glucose (HG) (15, 25, 35, 45 mM), glucosamine (0.8, 8, 18, 28, 38 mM), or palmitic acid (PA; 100, 200, 400, 800 μM), combined with LPS for 48 h. The insulin signaling pathway, inflammation, and pyroptosis were detected by western blots and quantitative real-time polymerase chain reaction (RT-qPCR). The effects on osteogenesis were evaluated by alkaline phosphatase staining, alizarin red S staining, RT-qPCR, and western blots., Results: HG failed to recapitulate insulin resistance. Glucosamine was sufficient to induce insulin resistance but failed to trigger inflammation. In total, 100 and 200 μM PA exhibited the most proinflammatory, insulin resistance, and pyroptosis induced role, and inhibited the osteogenic differentiation of hPDLSCs., Conclusion: Palmitic acid is a promising candidate for developing T2DM model in hPDLSCs., (© 2023 Wiley Periodicals LLC.)

Development of low temperature catalytic pyrolysis technology for heated tobacco sheets is expected to increase the aroma of heated tobacco products and improve their overall smoking quality. In this study, the low temperature pyrolysis performances of heated tobacco sheets catalyzed by various anionic sodium salts were investigated using TG-DTG, Py-GC-MS technology and smoke routine chemical composition analysis. The results showed that the total weight loss between 100°C and 300°C increased by 7.8%-13.15% after adding various anionic sodium salts, among which, sodium acetate and sodium tartrate showed a relatively higher weight loss. The relative content of free hydroxyacetone, furfuryl alcohol, butyrolactone and megastigmatrienone in the pyrolysis gas increased, while the relative content of free nicotine decreased. With the change of anionic species, the catalytic decomposition ability of cellulose, lignin, and other substances may change, resulting in the distribution alteration of compounds in the pyrolysis gas. After adding sodium acetate and sodium citrate, the release of total particulate matter (TPM), glycerol, and nicotine in flue gas increased. Overall, the addition of sodium acetate and sodium citrate showed a higher low temperature pyrolysis performance of heated tobacco sheets. The research results in this paper provide data support for changing the low temperature catalytic pyrolysis performance of heated tobacco sheets by adjusting the type of anions in sodium salts., Competing Interests: Authors XZ, QW, DA, HT, ZZ, KC, YW, WQ, BoL, YN, and BiL were employed by China Tobacco Henan Industrial Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Wang, Ai, Tian, Zhang, Cao, Wang, Qi, Li, Niu, Meng, Gao and Li.)

Importance: It remained unclear that the efficacy comparison between low-dose immune tolerance induction (LD-ITI) incorporating immunosuppressants (IS) when severe hemophilia A (SHA) patients had inhibitor-titer ≥200 Bethesda Units (BU)/mL (LD-ITI-IS 200 regimen) and LD-ITI combining with IS when SHA patients had inhibitor-titer ≥40 BU/mL (LD-ITI-IS 40 regimen)., Objective: To compare the efficacy of the LD-ITI-IS 200 regimen with that of the LD-ITI-IS 40 regimen for SHA patients with high-titer inhibitors., Methods: A prospective cohort study on patients receiving LD-ITI-IS 200 compared to those receiving LD-ITI-IS 40 from January 2021 to December 2023. Both received LD-ITI [FVIII 50 IU/kg every other day]. IS (rituximab + prednisone) was added when peak inhibitor tier ≥200 BU/mL in the LD-ITI-IS 200 regimen and ≥40 BU/mL in the LD-ITI-IS 40 regimen. Success is defined as a negative inhibitor plus FVIII recovery ≥66% of the expected., Results: We enrolled 30 patients on LD-ITI-IS 200 and 64 patients on LD-ITI-IS 40 , with similar baseline clinical characteristics. A lower IS-use rate was discovered in the LD-ITI-IS 200 regimen compared to the LD-ITI-IS 40 regimen (30.0% vs. 62.5%). The two regimens (LD-ITI-IS 200 vs. LD-ITI-IS 40 ) had similar success rate (70.0% vs. 79.7%), median time to success (9.4 vs. 10.6 months), and annualized bleeding rate during ITI (3.7 vs. 2.8). The cost to success was lower for LD-ITI-IS 200 than for LD-ITI-IS 40 (2107 vs. 3256 US Dollar/kg). Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS 200 regimen) and 28 IS-using (on LD-ITI-IS 40 regimen) had similar success rates (70.0% vs. 78.6%) and time to success (9.0 vs. 8.8 months)., Interpretation: In LD-ITI, IS are not necessary for inhibitor titer <200 BU/mL., Competing Interests: Man‐Chiu Poon declares no conflict of interest for this work. However, he has otherwise received an honorarium for events sponsored by Takeda and for attending advisory Board meetings for KVR Pharm, Novo Nordisk, Octapharma, and Sobi. The other authors declare no conflict of interest., (© 2024 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.)

Lipotoxicity refers to the accumulation of lipids in tissues other than adipose tissue (body fat). It is one of the major pathophysiological mechanisms responsible for the progression of diabetes complications such as non-alcoholic fatty liver disease and diabetic nephropathy. Accumulating evidence indicates that lipotoxicity also contributes significantly to the toxic effects of diabetes on periodontitis. Therefore, we reviewed the current in vivo, in vitro, and clinical evidence of the detrimental effects of lipotoxicity on periodontitis, focusing on its molecular mechanisms, especially oxidative and endoplasmic reticulum stress, inflammation, ceramides, adipokines, and programmed cell death pathways. By elucidating potential therapeutic strategies targeting lipotoxicity and describing their associated mechanisms and clinical outcomes, including metformin, statins, liraglutide, adiponectin, and omega-3 PUFA, this review seeks to provide a more comprehensive and effective treatment framework against diabetes-associated periodontitis. Furthermore, the challenges and future research directions are proposed, aiming to contribute to a more profound understanding of the impact of lipotoxicity on periodontitis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. Here, to explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3 and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely, thymosin beta 4, thymosin beta 10 and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Accurately reconstructing 4D critical organs contributes to the visual guidance in X-ray image-guided interventional operation. Current methods estimate intraoperative dynamic meshes by refining a static initial organ mesh from the semantic information in the single-frame X-ray images. However, these methods fall short of reconstructing an accurate and smooth organ sequence due to the distinct respiratory patterns between the initial mesh and X-ray image. To overcome this limitation, we propose a novel dual-stage complementary 4D organ reconstruction (DSC-Recon) model for recovering dynamic organ meshes by utilizing the preoperative and intraoperative data with different respiratory patterns. DSC-Recon is structured as a dual-stage framework: 1) The first stage focuses on addressing a flexible interpolation network applicable to multiple respiratory patterns, which could generate dynamic shape sequences between any pair of preoperative 3D meshes segmented from CT scans. 2) In the second stage, we present a deformation network to take the generated dynamic shape sequence as the initial prior and explore the discriminate feature (i.e., target organ areas and meaningful motion information) in the intraoperative X-ray images, predicting the deformed mesh by introducing a designed feature mapping pipeline integrated into the initialized shape refinement process. Experiments on simulated and clinical datasets demonstrate the superiority of our method over state-of-the-art methods in both quantitative and qualitative aspects.

Reaction of [CuH(PPh 3 )] 6 with 1 equiv. of Tl(OTf) results in formation of [Cu 6 TlH 6 (PPh 3 ) 6 ][OTf] ([1]OTf]), which can be isolated in good yields. Variable-temperature 1 H NMR spectroscopy, in combination with density functional theory (DFT) calculations, confirms the presence of a rare Tl-H orbital interaction. According to DFT, the 1 H chemical shift of the Tl-adjacent hydride ligands of [1] + includes 7.7 ppm of deshielding due to spin-orbit effects from the heavy Tl atom. This study provides valuable new insights into a rare class of metal hydrides, given that [1][OTf] is only the third isolable species reported to contain a Tl-H interaction., (© 2024 Wiley-VCH GmbH.)

Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.

Background: The existing face matching method requires a point cloud to be drawn on the real face for registration, which results in low registration accuracy due to the irregular deformation of the patient's skin that makes the point cloud have many outlier points., Methods: This work proposes a non-contact pose estimation method based on similarity aspect graph hierarchical optimization. The proposed method constructs a distance-weighted and triangular-constrained similarity measure to describe the similarity between views by automatically identifying the 2D and 3D feature points of the face. A mutual similarity clustering method is proposed to construct a hierarchical aspect graph with 3D pose as nodes. A Monte Carlo tree search strategy is used to search the hierarchical aspect graph for determining the optimal pose of the facial 3D model, so as to realize the accurate registration of the facial 3D model and the real face., Results: The proposed method was used to conduct accuracy verification experiments on the phantoms and volunteers, which were compared with four advanced pose calibration methods. The proposed method obtained average fusion errors of 1.13 ± 0.20 mm and 0.92 ± 0.08 mm in head phantom and volunteer experiments, respectively, which exhibits the best fusion performance among all comparison methods., Conclusions: Our experiments proved the effectiveness of the proposed pose estimation method in facial augmented reality., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest related to this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The heavy-metal ion critical role in γ-dicalcium silicate (γ-C 2 S) both in terms of solidification mechanism and hydration is still unclear. In this work, the solidification mechanism and the effect on initiating hydration of these three heavy-metal ions (Ba, Cd, and Cr) in γ-C 2 S is systemically studied by well-defined ab initio calculations. The calculated results show that the solid solution tendency of ions originates from the charge contribution, and the charge localization caused by the doping of Cr ions weakens the surface water adsorption. These insights will provide theoretical guidance for the low-carbon cement development by γ-C 2 S., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.

Appropriate DNA end synapsis, regulated by core components of the synaptic complex including KU70-KU80, LIG4, XRCC4, and XLF, is central to non-homologous end joining (NHEJ) repair of chromatinized DNA double-strand breaks (DSBs). However, it remains enigmatic whether chromatin modifications can influence the formation of NHEJ synaptic complex at DNA ends, and if so, how this is achieved. Here, we report that the mitotic deacetylase complex (MiDAC) serves as a key regulator of DNA end synapsis during NHEJ repair in mammalian cells. Mechanistically, MiDAC removes combinatorial acetyl marks on histone H2A (H2AK5acK9ac) around DSB-proximal chromatin, suppressing hyperaccumulation of bromodomain-containing protein BRD4 that would otherwise undergo liquid-liquid phase separation with KU80 and prevent the proper installation of LIG4-XRCC4-XLF onto DSB ends. This study provides mechanistic insight into the control of NHEJ synaptic complex assembly by a specific chromatin signature and highlights the critical role of H2A hypoacetylation in restraining unscheduled compartmentalization of DNA repair machinery., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Ki-67 expression levels in breast cancer have prognostic and predictive significance. Therefore, accurate Ki-67 evaluation is important for optimal patient care. Although an algorithm developed by the International Ki-67 in Breast Cancer Working Group (IKWG) improves interobserver variability, it is tedious and time-consuming. In this study, we simplify IKWG algorithm and evaluate its interobserver agreement among breast pathologists in Ki-67 evaluation., Methods: Six subspecialized breast pathologists (4 juniors, 2 seniors) assessed the percentage of positive cells in 5% increments in 57 immunostained Ki-67 slides. The time spent on each slide was recorded. Two rounds of ring study (R1, R2) were performed before and after training with the modified IKWG algorithm (eyeballing method at 400× instead of counting 100 tumor nuclei per area). Concordance was assessed using Kendall's and Kappa coefficients., Results: Analysis of ordinal scale ratings for all categories with 5% increments showed almost perfect agreement in R1 (0.821) and substantial in R2 (0.793); Seniors and juniors had substantial agreement in R1 (0.718 vs. 0.649) and R2 (0.756 vs. 0.658). In dichotomous scale analysis using 20% as the cutoff, the overall agreement was moderate in R1 (0.437) and R2 (0.479), among seniors (R1: 0.436; R2: 0.437) and juniors (R1: 0.445; R2: 0.505). Average scoring time per case was higher in R2 (71 vs. 37 s)., Conclusion: The modified IKWG algorithm does not significantly improve interobserver agreement. A better algorithm or assistance from digital image analysis is needed to improve interobserver variability in Ki-67 evaluation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipid metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis, which is an important risk factor for AAA; however, the potential contribution of GM3 to AAA development has not been investigated., Methods: We performed a metabolomics study to evaluated GM3 level in plasma of human patients with AAA. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through Western blotting and immunofluorescence staining. RNA sequencing, affinity purification and mass spectrometry, proteomic analysis, surface plasmon resonance analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA., Results: We found significantly reduced plasma levels of GM3 in human patients with AAA. GM3 content and ST3GAL5 expression were decreased in abdominal aortic vascular SMCs in patients with AAA and an AAA mouse model. RNA sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs induced ferroptosis. We showed that GM3 interacted directly with the extracellular domain of TFR1 (transferrin receptor 1), a cell membrane protein critical for cellular iron uptake, and disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development in mice, whereas GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic vascular SMCs, and markedly decreased AAA incidence., Conclusions: Together, these results suggest that GM3 dysregulation promotes ferroptosis of vascular SMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for AAA., Competing Interests: Disclosures None.

The segmentation of the orbit in computed tomography (CT) images plays a crucial role in facilitating the quantitative analysis of orbital decompression surgery for patients with Thyroid-associated Ophthalmopathy (TAO). However, the task of orbit segmentation, particularly in postoperative images, remains challenging due to the significant shape variation and limited amount of labeled data. In this paper, we present a two-stage semi-supervised framework for the automatic segmentation of the orbit in both preoperative and postoperative images, which consists of a pseudo-label generation stage and a semi-supervised segmentation stage. A Paired Copy-Paste strategy is concurrently introduced to proficiently amalgamate features extracted from both preoperative and postoperative images, thereby augmenting the network discriminative capability in discerning changes within orbital boundaries. More specifically, we employ a random cropping technique to transfer regions from labeled preoperative images (foreground) onto unlabeled postoperative images (background), as well as unlabeled preoperative images (foreground) onto labeled postoperative images (background). It is imperative to acknowledge that every set of preoperative and postoperative images belongs to the identical patient. The semi-supervised segmentation network (stage 2) utilizes a combination of mixed supervisory signals from pseudo labels (stage 1) and ground truth to process the two mixed images. The training and testing of the proposed method have been conducted on the CT dataset obtained from the Eye Hospital of Wenzhou Medical University. The experimental results demonstrate that the proposed method achieves a mean Dice similarity coefficient (DSC) of 91.92% with only 5% labeled data, surpassing the performance of the current state-of-the-art method by 2.4%., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Concurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence is still the main failure pattern, accounting for more than half of all treatment failures, indicating that the sensitivity of radiotherapy still needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by chemoradiotherapy could promote esophageal tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity and improve local control., Methods: We did a multicenter, single-arm, phase 2 trial in China. Patients with locally advanced esophageal cancer were enrolled in this study. In induction phase, patients received two cycles of sintilimab, paclitaxel and carboplatin once per 21 days. In concurrent phase, patients were treated with five cycles of carboplatin and paclitaxel once per week concurrent with radiotherapy of 50.4Gy delivered in 28 fractions. The primary endpoint was 2-year local control rate. Hypoxia and vessel normalization was assessed before and after induction phase using immunofluorescence and perfusion CT. This trial is registered with ClinicalTrials.gov (NCT03985046)., Findings: Seventy-five patients with esophageal cancer were enrolled in this study between October 2019 and April 2021. The median follow-up of surviving patients was 33.6 months (IQR 29.3-35.7). The 2-year local control rate was 81.7% (95% confidence interval, 72.7%-90.7%), which was much higher than that in concurrent chemoradiation only (71.3%) in previous studies. Vascular normalization and hypoxia alleviation were observed in both biopsy specimens and perfusion CT., Interpretation: The addition of induction immunotherapy to standard concurrent chemoradiotherapy could improve radiosensitivity for locally advanced esophageal cancer as non-surgical treatment. New treatment combination led to higher local control rate through promoting vascular normalization and alleviating hypoxia. Our findings suggest that induction immunotherapy followed by concurrent chemoradiotherapy could be a potential option in future treatment., Funding: National Natural Science Foundation of China and Shanghai Rising-Star Program., Competing Interests: We declare no competing interests., (© 2024 The Author(s).)

Feature matching of monocular laparoscopic videos is crucial for visualization enhancement in computer-assisted surgery, and the keys to conducting high-quality matches are accurate homography estimation, relative pose estimation, as well as sufficient matches and fast calculation. However, limited by various monocular laparoscopic imaging characteristics such as highlight noises, motion blur, texture interference and illumination variation, most exiting feature matching methods face the challenges of producing high-quality matches efficiently and sufficiently. To overcome these limitations, this paper presents a novel sequential coupling feature descriptor to extract and express multilevel feature maps efficiently, and a dual-correlate optimized coarse-fine strategy to establish dense matches in coarse level and adjust pixel-wise matches in fine level. Firstly, a novel sequential coupling swin transformer layer is designed in feature descriptor to learn and extract multilevel feature representations richly without increasing complexity. Then, a dual-correlate optimized coarse-fine strategy is proposed to match coarse feature sequences under low resolution, and the correlated fine feature sequences is optimized to refine pixel-wise matches based on coarse matching priors. Finally, the sequential coupling feature descriptor and dual-correlate optimization are merged into the Sequential Coupling Dual-Correlate Network (SeCo DC-Net) to produce high-quality matches. The evaluation is conducted on two public laparoscopic datasets: Scared and EndoSLAM, and the experimental results show the proposed network outperforms state-of-the-art methods in homography estimation, relative pose estimation, reprojection error, matching pairs number and inference runtime. The source code is publicly available at https://github.com/Iheckzza/FeatureMatching., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Automatic vessel segmentation is a critical area of research in medical image analysis, as it can greatly assist doctors in accurately and efficiently diagnosing vascular diseases. However, accurately extracting the complete vessel structure from images remains a challenge due to issues such as uneven contrast and background noise. Existing methods primarily focus on segmenting individual pixels and often fail to consider vessel features and morphology. As a result, these methods often produce fragmented results and misidentify vessel-like background noise, leading to missing and outlier points in the overall segmentation. To address these issues, this paper proposes a novel approach called the progressive edge information aggregation network for vessel segmentation (PEA-Net). The proposed method consists of several key components. First, a dual-stream receptive field encoder (DRE) is introduced to preserve fine structural features and mitigate false positive predictions caused by background noise. This is achieved by combining vessel morphological features obtained from different receptive field sizes. Second, a progressive complementary fusion (PCF) module is designed to enhance fine vessel detection and improve connectivity. This module complements the decoding path by combining features from previous iterations and the DRE, incorporating nonsalient information. Additionally, segmentation-edge decoupling enhancement (SDE) modules are employed as decoders to integrate upsampling features with nonsalient information provided by the PCF. This integration enhances both edge and segmentation information. The features in the skip connection and decoding path are iteratively updated to progressively aggregate fine structure information, thereby optimizing segmentation results and reducing topological disconnections. Experimental results on multiple datasets demonstrate that the proposed PEA-Net model and strategy achieve optimal performance in both pixel-level and topology-level metrics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Biliary interventional procedures require physicians to track the interventional instrument tip (Tip) precisely with X-ray image. However, Tip positioning relies heavily on the physicians' experience due to the limitations of X-ray imaging and the respiratory interference, which leads to biliary damage, prolonged operation time, and increased X-ray radiation., Methods: We construct an augmented reality (AR) navigation system for biliary interventional procedures. It includes system calibration, respiratory motion correction and fusion navigation. Firstly, the magnetic and 3D computed tomography (CT) coordinates are aligned through system calibration. Secondly, a respiratory motion correction method based on manifold regularization is proposed to correct the misalignment of the two coordinates caused by respiratory motion. Thirdly, the virtual biliary, liver and Tip from CT are overlapped to the corresponding position of the patient for dynamic virtual-real fusion., Results: Our system is respectively evaluated and achieved an average alignment error of 0.75 ± 0.17 mm and 2.79 ± 0.46 mm on phantoms and patients. The navigation experiments conducted on phantoms achieve an average Tip positioning error of 0.98 ± 0.15 mm and an average fusion error of 1.67 ± 0.34 mm after correction., Conclusion: Our system can automatically register the Tip to the corresponding location in CT, and dynamically overlap the 3D virtual model onto patients to provide accurate and intuitive AR navigation., Significance: This study demonstrates the clinical potential of our system by assisting physicians during biliary interventional procedures. Our system enables dynamic visualization of virtual model on patients, reducing the reliance on contrast agents and X-ray usage.

Background: Monocular depth estimation plays a fundamental role in clinical endoscopy surgery. However, the coherent illumination, smooth surfaces, and texture-less nature of endoscopy images present significant challenges to traditional depth estimation methods. Existing approaches struggle to accurately perceive depth in such settings., Method: To overcome these challenges, this paper proposes a novel multi-scale residual fusion method for estimating the depth of monocular endoscopy images. Specifically, we address the issue of coherent illumination by leveraging image frequency domain component space transformation, thereby enhancing the stability of the scene's light source. Moreover, we employ an image radiation intensity attenuation model to estimate the initial depth map. Finally, to refine the accuracy of depth estimation, we utilize a multi-scale residual fusion optimization technique., Results: To evaluate the performance of our proposed method, extensive experiments were conducted on public datasets. The structural similarity measures for continuous frames in three distinct clinical data scenes reached impressive values of 0.94, 0.82, and 0.84, respectively. These results demonstrate the effectiveness of our approach in capturing the intricate details of endoscopy images. Furthermore, the depth estimation accuracy achieved remarkable levels of 89.3 % and 91.2 % for the two models' data, respectively, underscoring the robustness of our method., Conclusions: Overall, the promising results obtained on public datasets highlight the significant potential of our method for clinical applications, facilitating reliable depth estimation and enhancing the quality of endoscopy surgical procedures., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest related to this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Endothelial cells (EC) play essential roles in retinal vascular homeostasis. This study aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing. Systematic analysis of cellular compositions and cell-cell interaction networks identified a unique EC cluster with high inflammatory gene expression in diabetic retina; sphingolipid metabolism is a prominent aspect correlated with changes in retinal function. Among sphingolipid-related genes, alkaline ceramidase 2 (ACER2) showed the most significant increase. Plasma samples of patients with nonproliferative diabetic retinopathy (NPDR) with diabetic macular edema (DME) or without DME (NDME) and active proliferative DR (PDR) were collected for mass spectrometry analysis. Metabolomic profiling revealed that the ceramide levels were significantly elevated in NPDR-NDME/DME and further increased in active PDR compared with control patients. In vitro analyses showed that ACER2 overexpression retarded endothelial barrier breakdown induced by ceramide, while silencing of ACER2 further disrupted the injury. Moreover, intravitreal injection of the recombinant ACER2 adeno-associated virus rescued diabetes-induced vessel leakiness, inflammatory response, and neurovascular disease in diabetic mouse models. Together, this study revealed a new diabetes-specific retinal EC population and a negative feedback regulation pathway that reduces ceramide content and endothelial dysfunction by upregulating ACER2 expression. These findings provide insights into cell-type targeted interventions for diabetic retinopathy., (© 2024 by the American Diabetes Association.)

Glabridin is a natural isoflavone with estrogen receptor agonism and significant anti-tumor activity. Additionally, glabridin has a regulation effect on PI3K/AKT/mTOR pathway, but its exact target remains unclear. In this study, we evaluated the antitumor activity of glabridin against breast cancer and prostate cancer cells, and further clarified its targeting to PI3K. We found that glabridin could significantly inhibit the cell viability of human breast cancer and prostate cancer cell lines. It induced caspase activation cascade and cell apoptosis through decreasing the mitochondrial transmembrane potential and increasing the intracellular reactive oxygen species (ROS). Moreover, glabridin could attenuate epithelial-mesenchymal transition (EMT) progression by inhibiting cell migration. PharmMapper calculation showed that PI3Kγ might be the most potential target protein because of the highest Normal Fit score (0.9735) and z'-score (0.9797). Molecular docking and bio-layer interferometry (BLI) analysis further demonstrated the PI3Kγ targeting of glabridin. In vivo experiments showed that glabridin can effectively inhibit the tumor growth of breast cancer xenograft model, and does not show obvious hepatorenal toxicity. Moreover, glabridin could effectively promote the anti-proliferation and pro-apoptotic effects of tamoxifen on MDA-MB-231 cell and taxol on DU145 cell. Elucidating the targeting of glabridin to PI3K may lay a theoretical foundation for the structural derivatization of glabridin, which is expected to greatly promote the application and development of glabridin in the field of cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Culinary medicine (CM) addresses diseases through nutrition and culinary education. To promote access to educational material for people with diabetes and engagement in virtual classes, we created a virtual culinary medicine toolkit (VCMT) sensitive to literacy levels and language preferences. The VCMT was developed to accompany existing virtual CM programs and help improve participant interaction and retention, offering educational materials for providers and participants. The provider VCMT offers level-setting education to reduce mixed nutrition messaging, including educational resources discussing inclusive nutrition and mindful eating topics. Each handout has a QR code and link to engaging, animated videos that provide further explanation. The participant VCMT offers a range of fundamental cooking skill videos and infographics, including knife skills and preparing whole grains and healthy beverages. Participant handouts and animated videos, which are played during the virtual CM class, allow participants to learn more about diabetes management and food literacy topics, including interpreting nutrition labels, and are employed during a CM to facilitate discussion and reflection. The animated videos replace a traditional slide-based lecture, allowing space for patient-centered facilitated discussions during virtual cooking sessions. The VCMT could guide the development of virtual CM interventions to shift learning from lecture-based to patient-centered discussions via a visual and inclusive medium.

Land use/cover change is an important driving factor for carbon stock changes in terrestrial ecosystems and affects the carbon cycle of the whole ecosystem. Taking Kunming City as a case study, based on the modified carbon density coefficient, this study analyzed the spatio-temporal characteristics of carbon storage changes in the terrestrial ecosystem under different land use scenarios from 2000 to 2020 and "three-line" constraints by coupling the carbon storage module of the InVEST model and CA-Markov model. The results showed that:① cultivated land, forest land, and grassland were the main types of land use in Kunming City, and land use transfer also occurred among the three types. ② From 2000 to 2020, the overall carbon storage in Kunming City was low in the south and high in the north, and the carbon storage decreased yearly with a cumulative loss of 5.27×10 6 t. The degradation of forest land and grassland was the main reason for the decrease in carbon storage. ③ From 2020 to 2030, the carbon storage of the four scenarios should decrease, and the decline in carbon storage in the inertia development scenario was the most obvious, which was mainly caused by the rapid expansion of construction land. The cultivated land protection scenario effectively slowed down the reduction in carbon storage compared with the inertia development scenario. The ecological protection scenario could enhance the carbon sequestration capacity of the study area, with carbon storage reaching 262.49×10 6 t, but could not effectively control the reduction in cultivated land area. The scenario of preventing urban expansion effectively inhibited the disorderly expansion of construction land and indirectly prevented further reduction in carbon storage. Therefore, the cultivated land protection scenario, ecological protection scenario, and urban expansion prevention scenario can be considered comprehensively in the study area, which could not only increase the carbon sink space of the study area but also ensure food and ecological security.

Fractional flow reserve (FFR) is considered as the gold standard for diagnosing coronary myocardial ischemia. Existing 3D computational fluid dynamics (CFD) methods attempt to predict FFR noninvasively using coronary computed tomography angiography (CTA). However, the accuracy and efficiency of the 3D CFD methods in coronary arteries are considerably limited. In this work, we introduce a multi-dimensional CFD framework that improves the accuracy of FFR prediction by estimating 0D patient-specific boundary conditions, and increases the efficiency by generating 3D initial conditions. The multi-dimensional CFD models contain the 3D vascular model for coronary simulation, the 1D vascular model for iterative optimization, and the 0D vascular model for boundary conditions expression. To improve the accuracy, we utilize clinical parameters to derive 0D patient-specific boundary conditions with an optimization algorithm. To improve the efficiency, we evaluate the convergence state using the 1D vascular model and obtain the convergence parameters to generate appropriate 3D initial conditions. The 0D patient-specific boundary conditions and the 3D initial conditions are used to predict FFR (FFR C ). We conducted a retrospective study involving 40 patients (61 diseased vessels) with invasive FFR and their corresponding CTA images. The results demonstrate that the FFR C and the invasive FFR have a strong linear correlation (r = 0.80, p < 0.001) and high consistency (mean difference: 0.014 ±0.071). After applying the cut-off value of FFR (0.8), the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of FFR C were 88.5%, 93.3%, 83.9%, 84.8%, and 92.9%, respectively. Compared with the conventional zero initial conditions method, our method improves prediction efficiency by 71.3% per case. Therefore, our multi-dimensional CFD framework is capable of improving the accuracy and efficiency of FFR prediction significantly., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Medical image segmentation and registration are two fundamental and highly related tasks. However, current works focus on the mutual promotion between the two at the loss function level, ignoring the feature information generated by the encoder-decoder network during the task-specific feature mapping process and the potential inter-task feature relationship. This paper proposes a unified multi-task joint learning framework based on bi-fusion of structure and deformation at multi-scale, called BFM-Net, which simultaneously achieves the segmentation results and deformation field in a single-step estimation. BFM-Net consists of a segmentation subnetwork (SegNet), a registration subnetwork (RegNet), and the multi-task connection module (MTC). The MTC module is used to transfer the latent feature representation between segmentation and registration at multi-scale and link different tasks at the network architecture level, including the spatial attention fusion module (SAF), the multi-scale spatial attention fusion module (MSAF) and the velocity field fusion module (VFF). Extensive experiments on MR, CT and ultrasound images demonstrate the effectiveness of our approach. The MTC module can increase the Dice scores of segmentation and registration by 3.2%, 1.6%, 2.2%, and 6.2%, 4.5%, 3.0%, respectively. Compared with six state-of-the-art algorithms for segmentation and registration, BFM-Net can achieve superior performance in various modal images, fully demonstrating its effectiveness and generalization.

Background: The efficacy of local therapy for patients with oligometastatic oesophageal squamous cell carcinoma is unclear. We aimed to assess the efficacy of local plus systemic therapy compared with systemic therapy alone in patients with oligometastatic oesophageal squamous cell carcinoma., Methods: The ESO-Shanghai 13 trial was a randomised, open-label, multicentre, phase 2 trial. Patients (aged ≥18 years) were recruited from six hospitals in China with histological confirmation of oligometastatic oesophageal squamous cell carcinoma with a controlled primary tumour and one to four metastatic lesions. Eligible patients were randomly assigned via a computer-generated schedule in a 1:1 ratio to receive either systemic therapy alone (ie, systemic therapy only group) or combined systemic and local therapy (ie, systemic and local therapy group). The systemic therapy regimens in both groups were at the discretion of the investigator and included chemotherapy alone, anti-PD-1 antibodies alone, or chemotherapy plus anti-PD-1 antibodies. Local therapy-radiotherapy, surgery, or thermal ablation-was delivered to all metastatic lesions for patients in the systemic and local therapy group. Randomisation was balanced dynamically on three factors: the number of disease sites, the lines of systemic therapy, and the location of the metastases. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, defined as the time from randomisation to progression or death from any cause in the intention-to-treat population. The safety population included all patients who had undergone random assignment and at least one of the intended therapies. This trial is registered with ClinicalTrials.gov, NCT03904927. The trial is ongoing but closed to new participants., Findings: 116 patients were screened for enrolment between March 5, 2019, and Sept 16, 2021, and 104 patients who met the eligibility criteria were randomly assigned to the systemic and local therapy group (n=53) or the systemic therapy only group (n=51). 20 (38%) patients in the systemic plus local therapy group and 23 (45%) patients in the systemic therapy only group received anti-PD-1 antibody-based systemic therapy; three patients in the systemic and local therapy group did not receive systemic therapy. At a median follow-up of 30·5 months (IQR 24·7-37·8), median progression-free survival was 15·3 months (95% CI 10·1-20·5) in the systemic and local therapy group versus 6·4 months (5·2-7·6) in the systemic therapy only group (stratified hazard ratio 0·26 [95% CI 0·16-0·42]; stratified log rank p<0·0001). Grade 1-2 acute oesophagitis was more common in the systemic and local therapy group than in the systemic therapy only group (10 [19%] vs one [2%] patients; p=0·036). The number of patients who had grade 3 or worse treatment-related adverse events was similar between groups (25 [47%] vs 21 [41%]; p=0·538), with the most common adverse events being leukocytopenia (17 [32%] vs 18 [35%]) and neutropenia (19 [36%] vs 20 [39%]). Treatment-related deaths occurred in two patients in the systemic and local therapy group and one patient in the systemic therapy only group., Interpretation: The addition of local treatment for metastases could significantly improve progression-free survival among patients with oligometastatic oesophageal squamous cell carcinoma being treated with systemic therapy. Our findings suggest that combining local and systemic therapy could be a treatment option for patients with oligometastatic oesophageal squamous cell carcinoma, but further support from phase 3 trials is required., Funding: Science and Technology Commission of Shanghai Municipality, National Nature Science Foundation of China, and Shanghai Municipal Health Commission., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The physiological state of an insect can affect its olfactory system. However, the molecular mechanism underlying the effect of nutrition-dependent states on odour-guided behaviours in hoverflies remains unclear. In this study, comparative transcriptome analysis of the antenna and proboscis from Eupeodes corollae under different feeding states was conducted. Compared with the previously published antennal transcriptome, a total of 32 novel chemosensory genes were identified, including 4 ionotropic receptors, 17 gustatory receptors, 9 odorant binding proteins and 2 chemosensory proteins. Analysis of differences in gene expression between different feeding states in male and female antennae and proboscises revealed that the expression levels of chemosensory genes were impacted by feeding state. For instance, the expression levels of EcorOBP19 in female antennae, EcorOBP6 in female proboscis, and EcorOR6 , EcorOR14 , EcorIR5 and EcorIR84a in male antennae were significantly upregulated after feeding. On the other hand, the expression levels of EcorCSP7 in male proboscis and EcorOR40 in male antennae were significantly downregulated. These findings suggest that nutritional state plays a role in the adaptation of hoverflies' olfactory system to food availability. Overall, our study provides important insights into the plasticity and adaptation of chemosensory systems in hoverflies.

The successful mating of the hoverfly and the search for prey aphids are of great significance for biological control and are usually mediated by chemical cues. The odorant receptor co-receptor ( Orco ) genes play a crucial role in the process of insect odor perception. However, the function of Orco in the mating and prey-seeking behaviors of the hoverfly remains relatively unexplored. In this study, we characterized the Orco gene from the hoverfly, Eupeodes corollae , a natural enemy insect. We used the CRISPR/Cas9 technique to knock out the Orco gene of E. corollae , and the EcorOrco -/- homozygous mutant was verified by the genotype analysis. Fluorescence in situ hybridization showed that the antennal ORN of EcorOrco -/- mutant lack Orco staining. Electroantennogram (EAG) results showed that the adult mutant almost lost the electrophysiological response to 15 odorants from three types. The two-way choice assay and the glass Y-tube olfactometer indicated that both the larvae and adults of hoverflies lost their behavioral preference to the aphid alarm pheromone ( E )-β-farnesene (EBF). In addition, the mating assay results showed a significant decrease in the mating rate of males following the knock out of the EcorOrco gene. Although the mating of females was not affected, the amount of eggs being laid and the hatching rate of the eggs were significantly reduced. These results indicated that the EcorOrco gene was not only involved in the detection of semiochemicals in hoverflies but also plays a pivotal role in the development of eggs. In conclusion, our results expand the comprehension of the chemoreceptive mechanisms in the hoverflies and offers valuable insights for the advancement of more sophisticated pest management strategies.

The sustainable and stable population support capacity of a country or region is of great concern. This study proposes a new method for evaluating the land carrying capacity (LCC) based on food nutrition demand and establishes a clear link between nutritional health and land. We delved into the evolving dynamics of food consumption and production structures in China between 1990 and 2020, with a focus on the spatial variations among its 31 provinces. The objectives of this study were to assess the status of LCC, identify the critical nutritional factors constraining LCC enhancement, and propose differentiated pathways for improving LCC. The results showed that: (1) There has been a steady increase in the annual consumption of animal-based products, while plant-based product consumption has declined. (2) Overall, food supply capacity has expanded, displaying an "east high, west low" trend, resulting in an imbalanced food supply level. (3) The LCC for energy and carbohydrates exhibited continuous fluctuating growth but displayed a declining trend after 2018. (4) The pressure on land carrying capacity has shifted from a state of "surplus" to "abundant surplus," signifying a safe food system level. However, significant spatial variations persist, leading to shortages and surpluses. Therefore, this work suggests that addressing these disparities requires the optimization of food consumption structures and increasing the supply of animal-based foods. This approach leverages regional advantages and reduces disparities in regional LCCs. This study provides a valuable reference for ensuring food security in response to unprecedented global changes in sustainable development.

Purpose: Although axillary dissection is no longer indicated for many breast cancer patients with 1-2 positive axillary sentinel lymph nodes (ASLN), intraoperative ASLN assessment is still performed in many institutions for patients undergoing mastectomy or neoadjuvant therapy. With recent advancements in digital pathology, pathologists increasingly evaluate ASLN via remote telepathology. We aimed to compare the performance characteristics of remote telepathology and conventional on-site intraoperative ASLN assessment., Methods: Data from ASLN evaluation for breast cancer patients performed at two sites between April 2021 and October 2022 was collated. Remote telepathology consultation was conducted via the Aperio eSlideManager system., Results: A total of 385 patients were identified during the study period (83 telepathology, 302 on-site evaluations). Although not statistically significant (P = 0.20), the overall discrepancy rate between intraoperative and final diagnoses was slightly higher at 9.6% (8/83) for telepathology compared with 5.3% (16/302) for on-site assessment. Further comparison of performance characteristics of ASLN assessment between telepathology and conventional on-site evaluation revealed no statistically significant differences between deferral rates, discrepancy rates, interpretive or sampling errors, major or minor disagreements, false negative or false positive results as well as clinical impact and turn-around time (P ≥ 0.12)., Conclusion: ASLN assessment via telepathology is not significantly different from conventional on-site evaluation, although it shows a slightly higher overall discrepancy rate between intraoperative and final diagnoses (9.6% vs. 5.3%). Further studies are warranted to ensure accuracy of ASLN assessment via telepathology., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Physical activity is a crucial part of an active lifestyle for haemophiliac children. However, the fear of bleeds has been identified as barriers to participating physical activity for haemophiliac children even with prophylaxis. Lack of evidence and metrics driven by data is key problem., Objectives: We aim to develop machine learning models based on clinical data with multiple potential factors considered to predict risk of physical activity bleeding for haemophilia children with prophylaxis., Methods: From this cohort study, we collected information on 98 haemophiliac children with adequate prophylaxis (trough FVIII:C level > 1 %). The involved potential predictor variables include demographic information, treatment information, physical activity, joint evaluation, and pharmacokinetic parameters, etc. We applied CoxPH, Random Survival Forests (RSF) and DeepSurv to construct prediction models for the risk of bleeding during physical activities. All three survival analysis models were internally and externally validated., Results: A total of 98 patients were enrolled in this study. Their median age was 7.9 (5.5, 10.2) years. The CoxPH, RSF and DeepSurv models' discriminative and calibration abilities were all high, and the RSF model had the best performance (Internal validation: C-index, 0.7648 ± 0.0139; Brier Score, 0.1098 ± 0.0015; External validation: C-index, 0.7260 ± 0.0154; Brier Score, 0.0930 ± 0.0018). The prediction curves demonstrated that the developed RSF model can distinguish the risks well between bleeding and non-bleeding patients, as well as patients with different levels of physical activity. Meanwhile, the feature importance analysis confirmed that physical activity bleeding was deduced by comprehensive effects of various factors, and the importance of different factors on bleeding outcome is discrepant., Conclusions: This study revealed from the mechanism that it is necessary to incorporate multiple factors to accurately predict physical activity related bleeding risk. In clinical practice, the designed machine learning models can provide guidance for children with haemophilia A to positively participate in physical activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Diabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N 6 -methyladenosine (m 6 A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m 6 A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m 6 A modification mechanism in diabetes-associated periodontitis., Methods: Periodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M 6 A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining., Results: Diabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m 6 A level in total RNA. FTO knockdown increased the m 6 A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m 6 A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling., Conclusions: AGEs impaired BMSCs osteogenesis by regulating SOST in an m 6 A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes., (© 2023. The Author(s).)

Background: Clinical practice guidelines (CPGs) are designed to assist doctors in clinical decision making. High-quality research articles are important for the development of good CPGs. Commonly used manual screening processes are time-consuming and labor-intensive. Artificial intelligence (AI)-based techniques have been widely used to analyze unstructured data, including texts and images. Currently, there are no effective/efficient AI-based systems for screening literature. Therefore, developing an effective method for automatic literature screening can provide significant advantages., Methods: Using advanced AI techniques, we propose the Paper title, Abstract, and Journal (PAJO) model, which treats article screening as a classification problem. For training, articles appearing in the current CPGs are treated as positive samples. The others are treated as negative samples. Then, the features of the texts (e.g., titles and abstracts) and journal characteristics are fully utilized by the PAJO model using the pretrained bidirectional-encoder-representations-from-transformers (BERT) model. The resulting text and journal encoders, along with the attention mechanism, are integrated in the PAJO model to complete the task., Results: We collected 89,940 articles from PubMed to construct a dataset related to neck pain. Extensive experiments show that the PAJO model surpasses the state-of-the-art baseline by 1.91% (F1 score) and 2.25% (area under the receiver operating characteristic curve). Its prediction performance was also evaluated with respect to subject-matter experts, proving that PAJO can successfully screen high-quality articles., Conclusions: The PAJO model provides an effective solution for automatic literature screening. It can screen high-quality articles on neck pain and significantly improve the efficiency of CPG development. The methodology of PAJO can also be easily extended to other diseases for literature screening., (© 2023. The Author(s).)

Objectives: To assess current treatment-related outcomes for children with severe and moderate haemophilia A (cHA) in China., Methods: This cross-section Patient Report Outcome (PRO) report collected PRO data of severe and moderate cHAs registered in the 'Hemophilia Home Care Center' database (http://web.bjxueyou.cn) between January 2021 and November 2022. Data included records of bleeding, activities, and concentrates consumption. All patients had a confirmed diagnosis of moderate or severe haemophilia A (FVIII: C ≤ 5%) and were < 18 years old., Results: Among 1038 analysable cases, 9.6% of children with inhibitors had a higher rate of intracranial haemorrhage, dropout school rate, and higher FVIII consumption than children without inhibitors. Among 100 children with inhibitors, 36 patients were treated without immune tolerance induction (ITI), 14 patients with irregular treatment and 50 patients received ITI. Children with ITI had a lower ABR (2.4 (0,6.6) vs. 13.4 (9.5, 26.6), p<.001) and AJBR (0 (0, 3.1) vs. 8.9 (1.6, 19.3), p < .001) compared to those without ITI. Among 938 children without inhibitors, 28.5% received on-demand treatment and 71.5% received prophylaxis. Of 528 children with 1343.8 (1050.4, 2922.9)IU/kg/year median FVIII consumption, 43.0% received low-dose, 43.2% received intermediate-dose, and 13.8% received high-dose regimen; these children with prophylaxis had a lower ABR (3.1 (0, 10.7) vs. 12.8 (2.4, 45.5), p < .001), AJBR (0.5 (0, 3.9) vs. 3.0 (0, 12.0), p < .001) and disability rate (9.0% vs.18.5%, p = .032) compared to children who received on-demand treatment., Conclusion: The high rate of drop-out of school and disability still present a huge gap to meet the needs in China. It is necessary to improve the level of medical accessibility and medicine affordability and strengthen the patient/parent's education in China., (© 2023 John Wiley & Sons Ltd.)

Automatic liver tumor segmentation plays a key role in radiation therapy of hepatocellular carcinoma. In this paper, we propose a novel densely connected U-Net model with criss-cross attention (CC-DenseUNet) to segment liver tumors in computed tomography (CT) images. The dense interconnections in CC-DenseUNet ensure the maximum information flow between encoder layers when extracting intra-slice features of liver tumors. Moreover, the criss-cross attention is used in CC-DenseUNet to efficiently capture only the necessary and meaningful non-local contextual information of CT images containing liver tumors. We evaluated the proposed CC-DenseUNet on the LiTS dataset and the 3DIRCADb dataset. Experimental results show that the proposed method reaches the state-of-the-art performance for liver tumor segmentation. We further experimentally demonstrate the robustness of the proposed method on a clinical dataset comprising 20 CT volumes.

Opinion Statement: Esophageal cancer is a global health problem, which is 7th most common and 6th most deadly cancer. It has been the era of immuno-oncology for esophageal cancer management. Radiation therapy has been one of the key local therapeutic approaches for esophageal cancer treatment, while its role in advanced disease is challenging and debatable. There have been emerging clinical and translational studies of radiation therapy in recurrent or metastatic esophageal cancer. Immunotherapy has been established the standard care of 1st and 2nd line systemic therapies of advanced esophageal cancer, and the development of tumor immunity has opened a new chapter for the esophageal cancer radiation therapy. The current review will summarize the classic radiation therapy research in advanced esophageal cancer, as well as the most recent key findings. The subtitles will cover palliative radiotherapy for dysphagia, re-radiation for recurrent disease, oligo-focal disease management and stereotactic radiation therapy, and radiotherapy with immunotherapy. Radiotherapy plays vital role in multidisciplinary management of advanced EC. External or intratumoral irradiation has been used for palliation of dysphagia and improving QOL in esophageal cancer patients traditionally, while recent clinical and technical advance enables radiotherapy to be considered in recurrent or metastatic disease for curation attention. Novel clinical and translational investigation is opening a new chapter of radiotherapy with immunotherapy for benefiting advanced EC patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Limited studies explored the relationship between lymphocyte recovery after definitive concurrent chemoradiotherapy (dCCRT) and prognosis in esophageal squamous cell carcinoma (ESCC)., Methods: ESCC patients with obtainable absolute lymphocyte counts (ALCs) at 6 months after dCCRT were screened from prospective trials. Patients were divided into groups according to the grade of ALC nadir during radiotherapy (G4 or G1-3) and lymphocyte recovery status, which was assessed by lymphocyte recovery index (LRI), calculated as the ratio of post- to pre-treatment lymphocyte counts. Cox analysis was conducted to evaluate the prognostic significance of lymphocyte recovery status. Irradiated relative volumes of the bone marrow (BM) and spleen and effective dose to immune cells (EDIC) were collected to identify their impacts on lymphocyte recovery status by logistic analysis., Results: 232 patients were enrolled. In 69 patients with G4 ALC nadir (group A and B) and 163 patients with G1-3 ALC nadir (group C and D) during dCCRT, 27 (group A) and 67 (group C) patients showed an insufficient level of lymphocyte recovery (LRI < 60%), and 42 (group B) and 96 (group D) patients showed a satisfactory level of lymphocyte recovery (LRI ≥ 60%). Cox multivariable analysis revealed that inadequate lymphocyte recovery was significantly associated with worse overall survival (HR, 2.80 and 1.70) and local recurrence-free survival (HR, 2.82 and 1.60) both in group A vs group B and group C vs group D. Logistic analysis identified BM V5 (OR 4.24 and 2.29) as an independent predictor of inadequate lymphocyte recovery from G4 or G1-3 ALC nadir, respectively., Conclusions: Insufficient lymphocyte recovery might serve as a valuable prognostic factor, regardless of whether patients experienced G4 or G1-3 ALC nadir during radiotherapy. Additionally, it was observed that a larger relative volume of BM receiving ≥ 5 Gy was correlated with a higher risk of insufficient lymphocyte recovery., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The integration of diversity, equity, inclusion, and belonging (DEIB) principles into healthcare education is essential to ensure culturally sensitive and equitable healthcare delivery. In the domain of nutrition, food, and health, these principles are particularly vital, as diet and food choices are strongly linked to cultural identities and socioeconomic conditions. Despite a growth of DEIB initiatives in undergraduate and graduate medical education, there is a significant gap regarding guidelines for implementing DEIB principles in education around nutrition and food, including that for dietitians, allied health and medical professionals. A literature review was conducted, analyzing peer-reviewed articles and current practices in academic medical education to understand DEIB in nutrition, food, and health. The outcome was the creation of a three-tiered checklist titled "Checklist for Culturally Competent Education in Nutrition". It serves as a roadmap to cultivate culturally competent, equitable, and inclusive healthcare professionals that emphasizes avoiding bias, enhancing awareness, and building practical skills for DEIB implementation around nutrition.

Microwave ablation (MWA) is a minimally invasive procedure for the treatment of liver tumor. Accumulating clinical evidence has considered the minimal ablative margin (MAM) as a significant predictor of local tumor progression (LTP). In clinical practice, MAM assessment is typically carried out through image registration of pre- and post-MWA images. However, this process faces two main challenges: non-homologous match between tumor and coagulation with inconsistent image appearance, and tissue shrinkage caused by thermal dehydration. These challenges result in low precision when using traditional registration methods for MAM assessment. In this paper, we present a local contractive nonrigid registration method using a biomechanical model (LC-BM) to address these challenges and precisely assess the MAM. The LC-BM contains two consecutive parts: (1) local contractive decomposition (LC-part), which reduces the incorrect match between the tumor and coagulation and quantifies the shrinkage in the external coagulation region, and (2) biomechanical model constraint (BM-part), which compensates for the shrinkage in the internal coagulation region. After quantifying and compensating for tissue shrinkage, the warped tumor is overlaid on the coagulation, and then the MAM is assessed. We evaluated the method using prospectively collected data from 36 patients with 47 liver tumors, comparing LC-BM with 11 state-of-the-art methods. LTP was diagnosed through contrast-enhanced MR follow-up images, serving as the ground truth for tumor recurrence. LC-BM achieved the highest accuracy (97.9%) in predicting LTP, outperforming other methods. Therefore, our proposed method holds significant potential to improve MAM assessment in MWA surgeries.

Local associations refer to spatial-temporal correlations that emerge from the biological realm, such as time-dependent gene co-expression or seasonal interactions between microbes. One can reveal the intricate dynamics and inherent interactions of biological systems by examining the biological time series data for these associations. To accomplish this goal, local similarity analysis algorithms and statistical methods that facilitate the local alignment of time series and assess the significance of the resulting alignments have been developed. Although these algorithms were initially devised for gene expression analysis from microarrays, they have been adapted and accelerated for multi-omics next generation sequencing datasets, achieving high scientific impact. In this review, we present an overview of the historical developments and recent advances for local similarity analysis algorithms, their statistical properties, and real applications in analyzing biological time series data. The benchmark data and analysis scripts used in this review are freely available at http://github.com/labxscut/lsareview., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Lung adenocarcinoma (LUAD) has high morbidity and is prone to recurrence. TIMELESS (TIM), which regulates circadian rhythms in Drosophila, is highly expressed in various tumors. Its role in LUAD has gained attention, but the detailed function and mechanism have not been clarified completely at present., Methods: Tumor samples from patients with LUAD patient data from public databases were used to confirm the relationship of TIM expression with lung cancer. LUAD cell lines were used and siRNA of TIM was adopted to knock down TIM expression in LUAD cells, and further cell proliferation, migration and colony formation were analyzed. By using Western blot and qPCR, we detected the influence of TIM on epidermal growth factor receptor (EGFR), sphingosine kinase 1 (SPHK1) and AMP-activated protein kinase (AMPK). With proteomics analysis, we comprehensively inspected the different changed proteins influenced by TIM and did global bioinformatic analysis., Results: We found that TIM expression was elevated in LUAD and that this high expression was positively correlated with more advanced tumor pathological stages and shorter overall and disease-free survival. TIM knockdown inhibited EGFR activation and also AKT/mTOR phosphorylation. We also clarified that TIM regulated the activation of SPHK1 in LUAD cells. And with SPHK1 siRNA to knock down the expression level of SPHK1, we found that EGFR activation were inhibited greatly too. Quantitative proteomics techniques combined with bioinformatics analysis clarified the global molecular mechanisms regulated by TIM in LUAD. The results of proteomics suggested that mitochondrial translation elongation and termination were altered, which were closely related to the process of mitochondrial oxidative phosphorylation. We further confirmed that TIM knockdown reduced ATP content and promoted AMPK activation in LUAD cells., Conclusions: Our study revealed that siTIM could inhibit EGFR activation through activating AMPK and inhibiting SPHK1 expression, as well as influencing mitochondrial function and altering the ATP level; TIM's high expression in LUAD is an important factor and a potential key target in LUAD., Competing Interests: Declaration of competing interest We declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)