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In contrast to the extensive study of domain reversal in ferromagnetic materials, the domain switching process in antiferromagnets is much less studied due to the difficulty of probing antiferromagnetic spins. Using a combination of hysteresis loop, Kerr microscope, and x-ray magnetic linear dichroism measurements, we investigated the antiferromagnetic (AFM) domain switching process in single crystalline Fe/CoO bilayers on MgO(001). We demonstrate that the CoO AFM switching is a Kolmogorov-Avrami process in which the thermal activation energy creates AFM domain nucleation centers which further expand by domain wall propagation. From the temperature- and thickness-dependent measurements, we are able to retrieve quantitatively the important parameter of the CoO AFM activation energy, which is shown to increase linearly with CoO thickness.

Objectives: To establish a reliable ultrasound (US) method of evaluating dynamic extrusion of lateral meniscus in healthy population, and to investigate the pattern of dynamic meniscus extrusion (ME) in lateral meniscus under loading conditions., Methods: The lateral ME was examined via US method in unloaded, double-leg standing, and single-leg standing positions. Two different US measurement methods were compared to the magnetic resonance imaging (MRI) results to determine the optimal measurement methods. The US results obtained by different researchers were tested for interobserver consistency and the results obtained by the same researcher on two separate days were tested for intraobserver consistency. The patterns of dynamic extrusion were compared between medial and lateral sides., Results: A total of healthy 44 volunteers were included in the study, with 86 knees assessed by US, and 25 knees evaluated by MRI. The US evaluation of dynamic lateral ME demonstrated excellent interobserver and intraobserver reliability. The US measurements using method A were consistent with the MRI results with no significant difference (P = .861, intraclass correlation coefficient [ICC] = 0.868), while method B underestimated the lateral ME compared to MRI (P = .001, ICC = 0.649). Lateral ME decreased slightly from unloaded (1.0 ± 0.8 mm) to single-leg standing position (0.8 ± 0.8 mm), whereas medial ME increased significantly in both double-leg and single-leg standing positions (2.4 ± 0.7 mm, 2.6 ± 0.7 mm)., Conclusion: A novel US evaluation method of lateral ME was established with reliable and accurate results compared to the MRI. Lateral ME in healthy populations decreased slightly as the loadings increased, which was different from the pattern of dynamic extrusion in medial meniscus., (© 2024 American Institute of Ultrasound in Medicine.)

Understanding the interactions between different RNA modifications is essential for unraveling their biological functions. Here, we report NanoPsiPy, a computational pipeline that employs nanopore direct RNA sequencing to identify pseudouridine (Ψ) sites and quantify their levels at single-nucleotide resolution. We validated NanoPsiPy by transcriptome-wide profiling of PUS7-dependent Ψ sites in poly-A RNA and rRNA. NanoPsiPy leverages Ψ-induced U-to-C basecalling errors in nanopore sequencing data, allowing detection of both low and high stoichiometric Ψ sites. We identified 8,624 PUS7-dependent Ψ sites in 1,246 mRNAs encoding proteins associated with ribosome biogenesis, translation, and energy metabolism. Importantly, integrative analysis revealed that PUS7 knockdown increases global mRNA N 6 -methyladenosine (m 6 A) and 5-methylcytosine (m 5 C) levels, suggesting an antagonistic relationship between Ψ and these modifications. Our study underscores the potential of nanopore direct RNA sequencing in revealing the co-regulation of RNA modifications and the capacity of NanoPsiPy in analyzing pseudouridylation and its impact on other RNA modifications.

Utilizing spin pumping, we present a comparative study of the spin-charge conversion in RuO_{2}(101) and RuO_{2}(110) films. RuO_{2}(101) shows a robust in-plane crystal-axis dependence, whereas RuO_{2}(110) exhibits an isotropic but stronger one. Symmetry-based analysis and first-principles calculations reveal that the spin-charge conversion in RuO_{2}(110) originates from the inverse spin Hall effect (ISHE) due to nodal lines splitting. In RuO_{2}(101), the ISHE also dominates although the inverse spin splitting effect (ISSE) may coexist. These findings, in sharp contrast to previously attributed ISSE, are further corroborated by the reciprocal relation between the spin pumping and the spin-torque ferromagnetic resonance measurements.

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule l-2-hydroxyglutarate (l-2HG) is elevated in the most common histology of renal cancer. Similarly to other oncometabolites, l-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that l-2HG remodels amino acid metabolism in renal cancer cells through combined effects on histone methylation and RNA N6-methyladenosine. The combined effects of l-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high-l-2HG kidney cancers demonstrate reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high-l-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.

Objective: The purpose of this study is to analyze the changes in inflammatory markers and efficacy in the treatment of senior patients with type 2 diabetes mellitus (T2DM) and community-acquired pneumonia with continuous subcutaneous insulin infusion (CSII)., Methods: A total of 105 senior patients with T2DM and community-acquired pneumonia, were randomly divided into two groups, viz., treatment group and control group-52 patients in the treatment group were treated with CSII, and 53 patients in the control group with multiple daily insulin injections (MDI). The changes in fasting blood glucose, postprandial blood glucose, total number of white blood cells, neutrophils, percentage of neutrophils, lymphocytes, percentage of lymphocytes, C-reactive protein, serum amyloid A, procalcitonin, interleukin-6 indexes, and the improvement in clinical outcome between the two groups were compared on the 5th and the 10th day of treatment., Results: In the treatment group, there were 52 patients with an average age of (73.7 ± 8.5) years, which included 28 males and 24 females. In the control group, there were 53 patients, with 27 males and 26 females, with an average age of (74.8 ± 8.8) years. On the 5th and the 10th day of the treatment, the fasting blood glucose, postprandial blood glucose, total number of white blood cells, neutrophils, percentage of neutrophils, lymphocytes, percentage of lymphocytes, C-reactive protein, serum amyloid A, procalcitonin and interleukin-6 of the treatment group were better than that of the control group (P < 0.05). The use of CSII was associated with a higher probability of a prompt recovery (P < 0.05)., Conclusion: The administration of CSII in the treatment of senior patients with T2DM and community-acquired pneumonia can effectively control fasting and postprandial blood glucose, significantly reduce the levels of inflammatory markers, and improve infection treatment efficacy., (© 2024. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Background: Hyaluronic acid (HA) filler-induced vascular embolism that threatens skin integrity is an urgent situation. There is increasing evidence that percutaneous intra-arterial hyaluronidase injection is an effective therapeutic technique for it. However, until now, there is a lack of a unifying protocol about the technique., Objectives: This study aims to provide a conclusion of percutaneous intra-arterial hyaluronidase injection along with adjunctive measures on the treatment of occlusions precipitated by HA-based filler and develop a stepwise treatment protocol., Methods: We searched PubMed for peer-reviewed studies, consensus statements, case series, and case reports using a variety of keywords., Results: High-dose, pulsed hyaluronidase is the mainstay for the treatment of HA filler-induced embolism, but percutaneous intra-arterial hyaluronidase injection is a more effective technique. Until now, hyaluronidase is injected into three arteries percutaneously, including facial artery, supratrochlear artery, and superficial temporal artery. Furthermore, the adjunctive measures that may optimize clearance of an occlusion and/or skin barrier repair such as the use of image guidance and CGF should be considered., Conclusion: Vascular occlusions that threaten skin integrity are an urgent matter which requires accurate diagnosis and effective intervention. Percutaneous intra-arterial hyaluronidase injection along with adjunctive measures performed in a stepwise manner is key to an optimal outcome., No Level Assigned: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Both cholesterol and oxidized cholesterol (OXC) are present in human diets. The incidence of inflammatory bowel diseases (IBDs) is increasing in the world. The present study was to investigate the mechanism by which OXC promotes colitis using C57BL/6 mice as a model. Results shown that more severe colitis was developed in OXC-treated mice with the administration of dextran sulfate sodium (DSS) in water. Direct effects of short-term OXC exposure on gut barrier or inflammation were not observed in healthy mice. However, OXC exposure could cause gut microbiota dysbiosis with a decrease in the relative abundance of short-train fatty acids (SCFAs)-producing bacteria (Lachnospiraceae&#95;NK4A136&#95;group and Blautia) and an increase in the abundance of some potential harmful bacteria (Bacteroides). OXC-induced symptoms of colitis were eliminated when mice were administered with antibiotic cocktails, indicating the promoting effect of OXC on DSS-induced colitis was mediated by its effect on gut microbiota. Moreover, bacteria-depleted mice colonized with gut microbiome from OXC-DSS-exposed mice exhibited a severe colitis, further proving the gut dysbiosis caused by OXC exposure was the culprit in exacerbating the colitis. It was concluded that dietary OXC exposure increased the susceptibility of colitis in mice by causing gut microbiota dysbiosis., 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 B.V. All rights reserved.)

High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins, with implications for treatment of high-risk neuroblastoma., Significance: Caffeine treatment and FOXM1 inhibition can both enhance the antitumor effect of statins by blocking the molecular and metabolic processes that confer statin resistance, indicating potential combination therapeutic strategies for neuroblastoma. See related commentary by Stouth et al., p. 2091., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: The purpose of this study is to establish a prognostic model to predict postrecurrence survival (PRS) probability after initial resection of hepatocellular carcinoma (HCC)., Study Design: Patients with recurrent HCC after curative resection were identified through a multicenter consortium (training cohort, TC); data were from a separate institution were used as validation cohort (VC). The α-fetoprotein (AFP) tumor burden score (ATS) was defined as the distance from the origin on a 3-dimensional Cartesian coordinate system that incorporated 3 variables: largest tumor diameter ( x axis), number of tumors ( y axis), and ln AFP ( z axis). ATS was calculated using the Pythagorean theorem: ATS 2 = (largest tumor diameter) 2 + (number of tumors) 2 + (ln AFP) 2 , where ATS d and ATS r represent ATS at the time of initial diagnosis and at the time of recurrence, respectively. The final model was ATS m = ATS d + 4 × ATS r . Predictive performance and discrimination of the ATS model were evaluated and compared with traditional staging systems., Results: The ATS model demonstrated strong predictive performance of PRS in both the TC (area under the curve [AUC] 0.70) and VC (AUC 0.71). An ATS-based nomogram was able to stratify patients accurately into low- and high-risk categories relative to PRS (TC: ATS m ≤ 27, 74.9 months vs. ATS m ≥ 28, 23.3 months; VC: ATS m ≤ 27, 59.4 months vs. ATS m ≥ 28, 15.1 months; both p < 0.001). The ATS model predicted PRS among patients undergoing curative or noncurative treatment of HCC recurrence (both p < 0.05). Of note, the ATS model outperformed the Barcelona Clinic Liver Cancer (BCLC), China Liver Cancer (CNLC), and American Joint Committee on Cancer (AJCC) staging systems relative to 1-, 2-, 3-, 4- and 5-year PRS (AUC 0.70, vs. BCLC, AUC 0.50, vs. CNLC, AUC 0.54, vs. AJCC, AUC 0.51)., Conclusions: The ATS model had excellent prognostic discriminatory power to stratify patients relative to PRS., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Cisplatin is a widely used chemotherapy drug; however, it induces both acute and chronic kidney diseases (CKD) in patients with cancer. The pathogenesis of cisplatin-induced CKD is unclear, and effective renoprotective approaches are not available. Here, we report that repeated low-dose cisplatin (RLDC) treatment of C57BL/6 mice induced chronic cellular senescence in kidney tubules, accompanied with tubular degeneration and profibrotic phenotype transformation that culminated in maladaptive repair and renal fibrosis. Suppression of tubular senescence by senolytic drugs ABT-263 and Fisetin attenuated renal fibrosis and improved tubular repair, as indicated by restoration of tubular regeneration and renal function. In vitro, RLDC also induced senescence in mouse proximal tubular (BUMPT) cells. ABT-263 eliminated senescent BUMPT cells following RLDC treatment, reversed the profibrotic phenotype of the cells, and increased their clonogenic activity. Moreover, ABT-263 alleviated the paracrine effect of RLDC-treated BUMPT cells on fibroblasts for fibrosis. Consistently, knockdown of p16 suppressed post-RLDC senescence and fibrotic changes in BUMPT cells and alleviated their paracrine effects on renal fibroblast proliferation. These results indicate that persistent induction of tubular senescence plays an important role in promoting cisplatin-induced CKD. Targeting senescent tubular cells may be efficient for improvement of kidney repair and for the prevention and treatment of cisplatin-induced CKD.

Background: Necrosis of frontotemporal skin and/or the ipsilateral scalp with subsequent alopecia after hyaluronic acid (HA) filler injection into the temple is rare complications with superficial temporal artery embolization are suspected as the major pathological mechanism. The main treatment currently is intralesional hyaluronidase (HAase) injection, but the effectiveness of percutaneous superficial temporal arterial HAase injection still lacks consensus., Objectives: To investigate the effectiveness of superficial temporal arterial HAase injection in dissolving HA filler-induced necrosis of frontotemporal skin and/or the ipsilateral scalp with subsequent alopecia., Methods: Five recent clinical cases with necrosis of frontotemporal skin and/or the ipsilateral scalp with subsequent alopecia after HA filler injection into the temple were analyzed retrospectively. The patients underwent HAase injection via superficial temporal artery combined with adjunctive treatments, and the clinical progress was observed., Results: Significant improvement was observed in terms of necrosis of frontotemporal skin and the ipsilateral scalp after treatment, and the patients were relieved of their clinical symptoms. Alopecia occurred approximately 1 to 2 weeks after HA filler injection, and the well-defined alopecia areas were formed 15 to 20 days after HAase injection. Patients were followed for 3 to 6 months. During follow-up, the skin lesions of all patients were restored to near normal appearance. Hair regrowth was observed 2 to 3 months after HAase treatment, and hair density nearly reached the normal level 3 to 4 months later., Conclusions: Percutaneous superficial temporal arterial HAase injection is an effective treatment option for HA filler-induced necrosis of frontotemporal skin and/or the ipsilateral scalp with subsequent alopecia., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Western diet with a higher intake of fat and cholesterol has been claimed as an intestinal inflammation trigger. Human diet contains both cholesterol and oxidized cholesterol. Oxidized cholesterol has been claimed to be associated with various inflammation diseases, but its effects on colitis and gut microbiome remain largely unknown. The present study was the first time to investigate the effect of the oxidized cholesterol on gut microbiota and dextran sodium sulfate-induced colitis using mice as a model. The results showed that oxidized cholesterol promoted colitis by exacerbating bleeding, body weight decrease, colon shortening, gut barrier damage, oxidative stress, and gut inflammation, whereas non-oxidized cholesterol had no effect. Meanwhile, oxidized cholesterol could adversely modulate the gut microbiota by increasing the relative abundance of pro-inflammatory bacteria (including Escherichia - Shigella and Bacteroides ) and decreasing that of beneficial bacteria ( Lachnospiraceae&#95;NK4A136&#95;group and Odoribacter ). In addition, oxidized cholesterol significantly reduced the production of fecal short-chain fatty acids in colitis mice. It was concluded that oxidized cholesterol was a potential dietary factor of gut dysbiosis.

In a joint effort of both experiments and first-principles calculations, we resolve a hotly debated controversy and provide a coherent picture on the pure spin transport between Ag/Bi and ferromagnets. We demonstrate a strong inverse Rashba-Edelstein effect (IREE) at the interface in between Ag/Bi with a ferromagnetic metal (FM) but not with a ferromagnetic insulator. This is in sharp contrast to the previously claimed IREE at Ag/Bi interface or inverse spin Hall effect dominated spin transport. A more than one order of magnitude modulation of IREE signal is realized for different Ag/Bi-FM interfaces, casting strong tunability and a new direction for searching efficient spintronics materials.

Neuroblastoma is a pediatric cancer responsible for approximately 15% of all childhood cancer deaths. Aberrant MYCN activation, as a result of genomic MYCN amplification, is a major driver of high-risk neuroblastoma, which has an overall survival rate of less than 50%, despite the best treatments currently available. Metabolic reprogramming is an integral part of the growth-promoting program driven by MYCN, which fuels cell growth and proliferation by increasing the uptake and catabolism of nutrients, biosynthesis of macromolecules, and production of energy. This reprogramming process also generates metabolic vulnerabilities that can be exploited for therapy. In this review, we present our current understanding of metabolic reprogramming in neuroblastoma, focusing on transcriptional regulation as a key mechanism in driving the reprogramming process. We also highlight some important areas that need to be explored for the successful development of metabolism-based therapy against high-risk neuroblastoma.

Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multiomic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening, and transcriptomic data across more than 700 solid tumor cell lines and identified dihydroorotate dehydrogenase (DHODH), a critical enzyme in pyrimidine synthesis, as a potential treatment target. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of less than 10%. In xenograft and transgenic neuroblastoma mouse models treated with the DHODH inhibitor brequinar, tumor growth was dramatically reduced, and survival was extended. Furthermore, brequinar treatment was shown to reduce the expression of MYC targets in 3 neuroblastoma models in vivo. A combination of brequinar and temozolomide was curative in the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy. Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma, and we propose this combination for clinical testing.

Objectives: To identify the role and mechanism of a male specific gene, SRY, in I/R-induced hepatic injury., Background: Males are more vulnerable to I/R injury than females. However, the mechanism of these sex-based differences remains poorly defined., Methods: Clinicopathologic data of patients who underwent hepatic resection were identified from an international multi-institutional database. Liver specific SRY TG mice were generated, and subjected to I/R insult with their littermate WT controls in vivo. In vitro experiments were performed by treating primary hepatocytes from TG and WT mice with hypoxia/reoxygen-ation stimulation., Results: Clinical data showed that postoperative aminotransferase level, incidence of overall morbidity and liver failure were markedly higher among 1267 male versus 508 female patients who underwent hepatic resection. SRY was dramatically upregulated during hepatic I/R injury. Overexpression of SRY in male TG mice and ectopic expression of SRY in female TG mice exacerbated liver I/R injury compared with WTs as manifested by increased inflammatory reaction, oxidative stress and cell death in vivo and in vitro. Mechanistically, SRY interacts with Glycogen synthase kinase-3β (GSK-3β) and β-catenin, and promotes phosphorylation and degradation of β-catenin, leading to suppression of the downstream FOXOs, and activation of NF-κBand TLR4 signaling. Furthermore, activation of β-catenin almost completely reversed the SRYoverexpression-mediated exacerbation of hepatic I/R damage., Conclusions: SRY is a novel hepatic I/R mediator that promotes hepatic inflammatory reaction, oxidative stress and cell necrosis via inhibiting Wnt/β-catenin signaling, which accounts for the sex-based disparity in hepatic I/R injuries., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although laparoscopic technology has achieved rapid development in the surgical field, it has not been applied to liver transplantation, primarily because of difficulties associated with laparoscopic vascular anastomosis. In this study, we introduced a new magnetic-assisted vascular anastomosis technique and explored its application in laparoscopic liver transplantation in pigs., Methods: Two sets of magnetic vascular anastomosis rings (MVARs) with different diameters were developed. One set was used for anastomosis of the suprahepatic vena cava (SHVC) and the other set was used for anastomosis of the infrahepatic vena cava (IHVC) and portal vein (PV). Six laparoscopic orthotopic liver transplantations were performed in pigs. Donor liver was obtained via open surgery. Hepatectomy was performed in the recipients through laparoscopic surgery. Anastomosis of the SHVC was performed using hand-assisted magnetic anastomosis, and the anastomosis of the IHVC and PV was performed by magnetic anastomosis with or without hand assistance., Results: Liver transplants were successfully performed in five of the six cases. Postoperative ultrasonographic examination showed that the portal inflow was smooth. However, PV bending and blood flow obstruction occurred in one case because the MVARs were attached to each other. The durations of loading of MVAR in the laparoscope group and manual assistance group for IHVC and PV were 13 ± 5 vs. 5 ± 1 min (P < 0.01) and 10 ± 2 vs. 4 ± 1 min (P < 0.05), respectively. The durations of MVAR anastomosis in the laparoscope group and manual assistance group for IHVC and PV were 5 ± 1 vs. 1 ± 1 min (P < 0.01), and 5 ± 1 vs. 1 ± 1 min (P < 0.01), respectively. The anhepatic phase was 43 ± 4 min in the laparoscope group and 23 ± 2 min in the manual assistance group (P < 0.01)., Conclusions: Our study showed that magnetic-assisted laparoscopic liver transplantation can be successfully carried out in pigs., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2022 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Raf-1 kinase inhibitor protein was first identified as a negative regulator of the Raf signaling pathway. Subsequently, it was shown to have a causal role in containing cancer progression and metastasis. Early studies suggested that RKIP blocks cancer progression by inhibiting the Raf-1 pathway. However, it is not clear if the RKIP tumor and metastasis suppression function involve other targets. In addition to the Raf signaling pathway, RKIP has been found to modulate several other signaling pathways, affecting diverse biological functions including immune response. Recent advances in medicine have identified both positive and negative roles of immune response in cancer initiation, progression and metastasis. It is possible that one way that RKIP exerts its effect on cancer is by targeting an immune response mechanism. Here, we provide evidence supporting the causal role of tumor and metastasis suppressor RKIP in downregulating signaling pathways involved with immune response in breast cancer cells and discuss its potential ramification on cancer therapy.

In this article, the consensus of networked underactuated robotic systems subject to fixed and switched communication networks is discussed by developing some novel event-triggered control algorithms, which can synchronously guarantee the convergence of the active states, the boundedness of the velocities of passive actuators, and the exclusion of Zeno behaviors. In the cases of fixed networks, the sufficient criteria are established for the presented distributed event-triggered mechanisms with and without using neighbors' velocities, in order to achieve a better tradeoff between the communication load and system performance. Besides, in the situation of switched networks, the sufficient criterion is established by assuming that the union of the network has a spanning tree. A distributed sampled-data rule is constructed to decide when to update its own and neighbors' estimated positions, and thus further reduces the unnecessary control cost. Finally, by further extending the main results to three other sampled-data control algorithms, several examples with performance comparisons are provided to validate the efficiency and advantages of the theoretical results.

The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated with increased tumor cell apoptosis. Inhibition of aerobic glycolysis enzyme LDHA and G6PD had no significant effects on tumor cell survival. Ablation of G6PD had no significant effect on human mesothelioma and colon carcinoma xenograft growth in athymic mice. However, activation of G6PD with the G6PD-selective activator AG1 induced tumor cell death. AG1 increased tumor cell ROS production and the resultant extrinsic and intrinsic death pathways, mitochondrial processes, and unfolded protein response in tumor cells. Consistent with increased tumor cell death in vitro, AG1 suppressed human mesothelioma xenograft growth in a dose-dependent manner in vivo. Furthermore, AG1 treatment significantly increased tumor-bearing mouse survival in an intra-peritoneum xenograft athymic mouse model. Therefore, in human mesothelioma and colon carcinoma, G6PD is not essential for tumor growth. G6PD acts as a metabolic checkpoint to control metabolic flux towards the PPP to promote tumor cell apoptosis, and its expression is repressed by its promotor H3K9me3 deposition., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Cisplatin induces both acute and chronic nephrotoxicity during chemotherapy in patients with cancer. Presented here is the first study of single-nucleus RNA sequencing (snRNA-seq) of cisplatin-induced nephrotoxicity. Repeated low-dose cisplatin treatment (RLDC) led to decreases in renal function and kidney weight in mice at 9 weeks. The kidneys of these mice showed tubular degeneration and dilation. snRNA-seq identified 16 cell types and 17 cell clusters in these kidneys. Cluster-by-cluster comparison demonstrated cell type-specific changes in gene expression and identified a unique proximal tubule (PT) injury/repair cluster that co-expressed the injury marker kidney injury molecule-1 (Kim1) and the proliferation marker Ki-67. Compared with control, post-RLDC kidneys had 424 differentially expressed genes in PT cells, including tubular transporters and cytochrome P450 enzymes involved in lipid metabolism. snRNA-seq also revealed transcriptional changes in potential PT injury markers (Krt222, Eda2r, Ltbp2, and Masp1) and repair marker (Bex4). RLDC induced inflammation and proinflammatory cytokines (RelB, TNF-α, Il7, Ccl2, and Cxcl2) and the expression of fibrosis markers (fibronectin, collagen I, connective tissue growth factor, vimentin, and α-smooth muscle actin). Together, these results provide new insights into RLDC-induced transcriptional changes at the single-cell level that may contribute to the development of chronic kidney problems in patients with cancer after cisplatin chemotherapy., (Copyright © 2022 American Society for Investigative Pathology. All rights reserved.)

Background: Granzyme B is a key effector of cytotoxic T lymphocytes (CTLs), and its expression level positively correlates with the response of patients with mesothelioma to immune checkpoint inhibitor immunotherapy. Whether metabolic pathways regulate Gzmb expression in CTLs is incompletely understood., Methods: A tumor-specific CTL and tumor coculture model and a tumor-bearing mouse model were used to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in CTL function and tumor immune evasion. A link between granzyme B expression and patient survival was analyzed in human patients with epithelioid mesothelioma., Results: Mesothelioma cells alone are sufficient to activate tumor-specific CTLs and to enhance aerobic glycolysis to induce a PD-1 hi Gzmb lo CTL phenotype. However, inhibition of lactate dehydrogenase A, the key enzyme of the aerobic glycolysis pathway, has no significant effect on tumor-induced CTL activation. Tumor cells induce H3K9me3 deposition at the promoter of G6pd , the gene that encodes the rate-limiting enzyme G6PD in the pentose phosphate pathway, to downregulate G6pd expression in tumor-specific CTLs. G6PD activation increases acetyl-coenzyme A (CoA) production to increase H3K9ac deposition at the Gzmb promoter and to increase Gzmb expression in tumor-specific CTLs converting them from a Gzmb lo to a Gzmb hi phenotype, thus increasing CTL tumor lytic activity. Activation of G6PD increases Gzmb + tumor-specific CTLs and suppresses tumor growth in tumor-bearing mice. Consistent with these findings, GZMB expression level was found to correlate with increased survival in patients with epithelioid mesothelioma., Conclusion: G6PD is a metabolic checkpoint in tumor-activated CTLs. The H3K9me3/G6PD/acetyl-CoA/H3K9ac/Gzmb pathway is particularly important in CTL activation and immune evasion in epithelioid mesothelioma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The serine synthesis pathway (SSP) involving metabolic enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) drives intracellular serine biosynthesis and is indispensable for cancer cells to grow in serine-limiting environments. However, how SSP is regulated is not well understood. Here, we report that activating transcription factor 3 (ATF3) is crucial for transcriptional activation of SSP upon serine deprivation. ATF3 is rapidly induced by serine deprivation via a mechanism dependent on ATF4, which in turn binds to ATF4 and increases the stability of this master regulator of SSP. ATF3 also binds to the enhancers/promoters of PHGDH, PSAT1, and PSPH and recruits p300 to promote expression of these SSP genes. As a result, loss of ATF3 expression impairs serine biosynthesis and the growth of cancer cells in the serine-deprived medium or in mice fed with a serine/glycine-free diet. Interestingly, ATF3 expression positively correlates with PHGDH expression in a subset of TCGA cancer samples., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Metabolic reprogramming is an integral part of the growth-promoting program driven by the MYC family of oncogenes. However, this reprogramming also imposes metabolic dependencies that could be exploited therapeutically. Here we report that the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is an attractive therapeutic target for MYCN-amplified neuroblastoma, a childhood cancer with poor prognosis. Gene expression profiling and metabolomic analysis reveal that MYCN promotes pyrimidine nucleotide production by transcriptional upregulation of DHODH and other enzymes of the pyrimidine-synthesis pathway. Genetic and pharmacological inhibition of DHODH suppresses the proliferation and tumorigenicity of MYCN-amplified neuroblastoma cell lines. Furthermore, we obtain evidence suggesting that serum uridine is a key factor in determining the efficacy of therapeutic agents that target DHODH. In the presence of physiological concentrations of uridine, neuroblastoma cell lines are highly resistant to DHODH inhibition. This uridine-dependent resistance to DHODH inhibitors can be abrogated by dipyridamole, an FDA-approved drug that blocks nucleoside transport. Importantly, dipyridamole synergizes with DHODH inhibition to suppress neuroblastoma growth in animal models. These findings suggest that a combination of targeting DHODH and nucleoside transport is a promising strategy to overcome intrinsic resistance to DHODH-based cancer therapeutics., (© 2021. The Author(s).)

Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis. Dimethylarginine dimethylaminohydrolase (DDAH) is a hydrolytic enzyme that is primarily responsible for eliminating asymmetric dimethylarginine, and it plays a role in the pathogenesis of cardiovascular and cerebrovascular diseases. The DDAH2 subtype is expressed in organs rich in induced nitric oxide synthase, including the heart, the placenta, and the cerebral endothelium during cerebral ischemia, in the stress state, or under neurotoxicity. Overexpression of the DDAH2 gene can inhibit asymmetric dimethylarginine-induced peripheral circulating endothelial cell dysfunction. However, it is unknown whether this polymorphism regulates plasma asymmetric dimethylarginine levels in patients with leukoaraiosis. In this double-blind study, we recruited 46 patients with leukoaraiosis and 46 healthy, matched controls. Plasma asymmetric dimethylarginine levels were determined using enzyme-linked immunoassays. Genomic DNA was isolated from whole blood samples, and polymerase chain reaction, SmaI restriction enzyme digestion, restriction fragment length polymorphisms, and agarose electrophoresis were used to detect DDAH2 (-449 G/C) gene polymorphisms. The results revealed that 95.65% of leukoaraiosis patients had recessive genetic models (GG and CG), while 89.13% of healthy control subjects had dominant genetic models (CC and CG). There was a significant difference in the genotype composition ratio between leukoaraiosis patients and healthy controls (P = 0.0002). The frequency of G alleles in the leukoaraiosis patients (71.74%) was significantly higher than in healthy controls, whereas the frequency of C alleles was lower (χ 2 = 13.9580, P = 0.0002). Furthermore, asymmetric dimethylarginine concentrations in subjects with the GG genotype were significantly higher than in subjects with the CG and CC genotypes (Kruskal-Wallis H = 24.5955, P < 0.0001). In addition, the GG genotype of DDAH2 (-449 G/C) was more common in patients with leukoaraiosis. These findings suggest that the G allele of DDAH2 (-449 G/C) is a risk factor for leukoaraiosis morbidity and is correlated with high levels of asymmetric dimethylarginine. This study was approved by the Institutional Ethics Committee of The 2nd Affiliated Hospital of Harbin Medical University of China (approval No. KY2016-177) on July 28, 2016., Competing Interests: None

Background: Coronavirus disease 2019 (COVID-19) is a serious and even lethal respiratory illness. The mortality of critically ill patients with COVID-19, especially short term mortality, is considerable. It is crucial and urgent to develop risk models that can predict the mortality risks of patients with COVID-19 at an early stage, which is helpful to guide clinicians in making appropriate decisions and optimizing the allocation of hospital resoureces., Methods: In this retrospective observational study, we enrolled 949 adult patients with laboratory-confirmed COVID-19 admitted to Tongji Hospital in Wuhan between January 28 and February 12, 2020. Demographic, clinical and laboratory data were collected and analyzed. A multivariable Cox proportional hazard regression analysis was performed to calculate hazard ratios and 95% confidence interval for assessing the risk factors for 30-day mortality., Results: The 30-day mortality was 11.8% (112 of 949 patients). Forty-nine point nine percent (474) patients had one or more comorbidities, with hypertension being the most common (359 [37.8%] patients), followed by diabetes (169 [17.8%] patients) and coronary heart disease (89 [9.4%] patients). Age above 50 years, respiratory rate above 30 beats per minute, white blood cell count of more than10 × 10 9 /L, neutrophil count of more than 7 × 10 9 /L, lymphocyte count of less than 0.8 × 10 9 /L, platelet count of less than 100 × 10 9 /L, lactate dehydrogenase of more than 400 U/L and high-sensitivity C-reactive protein of more than 50 mg/L were independent risk factors associated with 30-day mortality in patients with COVID-19. A predictive CAPRL score was proposed integrating independent risk factors. The 30-day mortality were 0% (0 of 156), 1.8% (8 of 434), 12.9% (26 of 201), 43.0% (55 of 128), and 76.7% (23 of 30) for patients with 0, 1, 2, 3, ≥4 points, respectively., Conclusions: We designed an easy-to-use clinically predictive tool for assessing 30-day mortality risk of COVID-19. It can accurately stratify hospitalized patients with COVID-19 into relevant risk categories and could provide guidance to make further clinical decisions., Competing Interests: None., (Copyright © 2021 The Chinese Medical Association, published by Wolters Kluwer Health, Inc.)

Background: Preoperative α-fetoprotein (AFP) level levels may help select patients with hepatocellular carcinoma (HCC) for surgery. The objective of the current study was to assess an AFP model to predict tumor recurrence and patient survival after curative resection for HCC., Methods: Patients undergoing curative-intent resection for HCC between 2000 and 2017 were identified from a multi-institutional database. AFP score was calculated based on the last evaluation before surgery. Probabilities of tumor recurrence and overall survival (OS) were compared according to an AFP model., Results: A total of 825 patients were included. An optimal cut-off AFP score of 2 was identified with an AFP score ≥3 versus ≤2 independently predicting tumor recurrence and OS. Net reclassification improvements indicated the AFP model was superior to the Barcelona Clinic Liver Cancer (BCLC) system to predict recurrence (p < 0.001). Among patients with BCLC B-C, AFP score ≤2 identified a subgroup of patients with AFP levels of ≤100 ng/mL with a low 5-year recurrence risk (≤2 45.2% vs. ≥3 61.8%, p = 0.046) and favorable 5-year OS (≤2 54.5% vs. ≥3 39.4%, p = 0.035). In contrast, among patients within BCLC 0-A, AFP score ≥3 identified a subgroup of patients with AFP values > 1000 ng/mL with a high 5-year recurrence (≥3 47.9% vs. ≤2% 38.4%, p = 0.046) and worse 5-year OS (≥3 47.8% vs. ≤2 65.9%, p < 0.001). In addition, the AFP score independently correlated with vascular invasion, tumor differentiation and capsule invasion., Conclusions: The AFP model was more accurate than the BCLC system to identify which HCC patients may benefit the most from surgical resection., Competing Interests: Conflict of interest We have no financial or commercial interests to disclose., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Laparoscopic splenectomy (LS) has been proven to be a safe and advantageous procedure. To ensure that resections of appropriate difficulty are selected, an objective preoperative grading of difficulty is required. We aimed to develop a predictive difficulty grading of LS based on intraoperative complications., Methods: A total of 272 non-traumatic patients who underwent LS were identified from a regional medical center. Patients were randomized into a training cohort (n = 222) and a validation cohort (n = 50). Data on demographics, medical and surgical history, operative and pathological characteristics, and postoperative outcome details were collected. Univariate and multivariate analyses of risk factors for intraoperative complications were performed to develop a difficulty scoring system. The Spearman correlation coefficient was used to evaluate the relationship between the difficulty grading score and intraoperative outcomes. Receiver operating characteristic (ROC) curve was used to evaluate the discriminatory power of this scoring system., Results: Three preoperative factors (spleen weight, esophagogastric varices, and INR) had a significant effect on operative time, bleeding, and conversion to open surgery. We created a difficulty grading score with three levels of difficulty: low (≤ 4 points), medium (5-6 points), and high (≥ 7 points), based on the three preoperative parameters. The correlation was highly significant (P < 0.01) according to Spearman's correlation. The area under the ROC curve was 0.695 (95% CI 0.630-0.755). The external validation showed significant correlations with the present model, with an AUC of 0.725 (95% CI 0.580-0.842). The comparison between our difficulty score and the previous grading system in the 272-patient cohort presented a significant difference in the AUC (0.701, 95% CI 0.643-0.755 vs. 0.644, 95% CI 0.584-0.701, P = 0.0452)., Conclusion: The present difficulty scoring system, based on preoperative factors, has good performance in predicting the risk of intraoperative complications of LS and could be helpful for enabling appropriate case selection with respect to the current experience of a surgeon.

BACKGROUND The aim of the present study was to evaluate the prognosis among patients with a single large hepatocellular carcinoma (HCC) >5 cm compared with other patients in Barcelona Clinic Liver Cancer (BCLC) stage A or stage B. MATERIAL AND METHODS Data on patients with BCLC stage A/B HCC were collected between 2008 and 2012. BCLC stage A was subclassified as A1 (single tumor, 2-5 cm, or 2-3 nodules £3 cm), or A2 (single tumor >5 cm). Overall survival (OS) was evaluated and compared. RESULTS Among 1005 patients with HCC, 455 were stage A1, 188 were stage A2, and 362 were stage B. The OS of stage A2 patients was significantly worse than that of stage A1 patients (median survival, 30.6 vs. 43.2 months, p5 cm had a comparable survival with BCLC stage B. HCC >5 cm should therefore be classified as an intermediate stage.

Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of unc-51-like autophagy-activating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.

Blocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin "trap" and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.

Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.

Magnetic compression anastomosis (MCA) has been appreciated as an innovative alternative to manual suturing in vascular reconstruction. However, magnetic devices have limitations in their applications. The present study aimed to introduce a newly developed magnetic device for end-to-end vascular anastomosis. Twenty male New Zealand rabbits were randomly assigned to receive end-to-end postcaval vein anastomosis using either a newly designed MCA device (Group MCA) or continuous-interrupted suturing (Group CIS). The anastomotic patency was evaluated by Doppler or venography immediately, 1 week, and 12 weeks after surgery. Anastomotic quality was evaluated gross and microscopic histological study 12 weeks after surgery. The procedure was successfully performed and all animals survived until sacrifice. The duration of surgery and anastomosis time in Group MCA were significantly shorter compared to Group CIS (all p < 0.001), and the incidence of anastomotic patency and postoperative morbidity were comparable between the two groups (all p > 0.05). Hematoxylin-eosin staining showed that anastomotic intima from Group MCA was much smoother with more regularly arranged endothelial cells than from compared to the Group CIS. A novel MCA device was successfully applied in rabbit vascular anastomosis. We demonstrated the reliability and effectiveness of this newly developed MCA in this study.

The amino acid antiporter system Xc - is important for the synthesis of glutathione (GSH) that functions to prevent lipid peroxidation and protect cells from nonapoptotic, iron-dependent death (i.e., ferroptosis). While the activity of system Xc - often positively correlates with the expression level of its light chain encoded by SLC7A11, inhibition of system Xc - activity by small molecules (e.g., erastin) causes a decrease in the intracellular GSH level, leading to ferroptotic cell death. How system Xc - is regulated during ferroptosis remains largely unknown. Here we report that activating transcription factor 3 (ATF3), a common stress sensor, can promote ferroptosis induced by erastin. ATF3 suppressed system Xc - , depleted intracellular GSH, and thereby promoted lipid peroxidation induced by erastin. ATF3 achieved this activity through binding to the SLC7A11 promoter and repressing SLC7A11 expression in a p53-independent manner. These findings thus add ATF3 to a short list of proteins that can regulate system Xc - and promote ferroptosis repressed by this antiporter.

A novel PEG-A6-conjugated irinotecan derivative 8 was designed and synthesized as antitumor agent by the PEGylation and A6-peptide modification of irinotecan. In vivo antitumor activity screening assay revealed that 8 exhibited better in vivo antiproliferation activity than irinotecan and its previous PEG-cRGD-conjugated derivative BGC0222 in MIA PaCa-2, NCI-H446, MDA-MB-231, HT-29 and NCI-N87 xenograft models, while the tumor of one in six mice in NCI-H446 assay and the tumors of two in six mice in MIA PaCa-2 assay completely subsided and disappeared within the 21-day period of 8-treatment, indicating that 8 should be a potential antitumor agent., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Genomic amplification of the oncogene MYCN is a major driver in the development of high-risk neuroblastoma, a pediatric cancer with poor prognosis. Given the challenge in targeting MYCN directly for therapy, we sought to identify MYCN-dependent metabolic vulnerabilities that can be targeted therapeutically. Here, we report that the gene encoding glycine decarboxylase (GLDC), which catalyzes the first and rate-limiting step in glycine breakdown with the production of the one-carbon unit 5,10-methylene-tetrahydrofolate, is a direct transcriptional target of MYCN. As a result, GLDC expression is markedly elevated in MYCN-amplified neuroblastoma tumors and cell lines. This transcriptional upregulation of GLDC expression is of functional significance, as GLDC depletion by RNA interference inhibits the proliferation and tumorigenicity of MYCN-amplified neuroblastoma cell lines by inducing G1 arrest. Metabolomic profiling reveals that GLDC knockdown disrupts purine and central carbon metabolism and reduces citrate production, leading to a decrease in the steady-state levels of cholesterol and fatty acids. Moreover, blocking purine or cholesterol synthesis recapitulates the growth-inhibitory effect of GLDC knockdown. These findings reveal a critical role of GLDC in sustaining the proliferation of neuroblastoma cells with high-level GLDC expression and suggest that MYCN amplification is a biomarker for GLDC-based therapeutic strategies against high-risk neuroblastoma.

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN -amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN -amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy. See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818 ., (©2019 American Association for Cancer Research.)

Background: Mitochondria are dynamic organelles that undergo fission and fusion. During cell stress, mitochondrial dynamics shift to fission, leading to mitochondrial fragmentation, membrane leakage, and apoptosis. Mitochondrial fragmentation requires the cleavage of both outer and inner membranes, but the mechanism of inner membrane cleavage is unclear. Bif-1 and prohibitin-2 may regulate mitochondrial dynamics., Methods: We used azide-induced ATP depletion to incite cell stress in mouse embryonic fibroblasts and renal proximal tubular cells, and renal ischemia-reperfusion to induce stress in mice. We also used knockout cells and mice to determine the role of Bif-1, and used multiple techniques to analyze the molecular interaction between Bif-1 and prohibitin-2., Results: Upon cell stress, Bif-1 translocated to mitochondria to bind prohibitin-2, resulting in the disruption of prohibitin complex and proteolytic inactivation of the inner membrane fusion protein OPA1. Bif-1-deficiency inhibited prohibitin complex disruption, OPA1 proteolysis, mitochondrial fragmentation, and apoptosis. Domain deletion analysis indicated that Bif-1 interacted with prohibitin-2 via its C-terminus. Notably, mutation of Bif-1 at its C-terminal tryptophan-344 not only prevented Bif-1/prohibitin-2 interaction but also reduced prohibitin complex disruption, OPA1 proteolysis, mitochondrial fragmentation, and apoptosis, supporting a pathogenic role of Bif-1/prohibitin-2 interaction. In mice, Bif-1 bound prohibitin-2 during renal ischemia/reperfusion injury, and Bif-1-deficiency protected against OPA1 proteolysis, mitochondrial fragmentation, apoptosis and kidney injury., Conclusions: These findings suggest that during cell stress, Bif-1 regulates mitochondrial inner membrane by interacting with prohibitin-2 to disrupt prohibitin complexes and induce OPA1 proteolysis and inactivation., (Copyright © 2019 by the American Society of Nephrology.)

Metabolic disorder is one of the most obvious pathophysiological characteristics of patients with severe burn or trauma, which leads to high mortality of patients with severe burn or trauma. Metabonomics is a newly developed subject which provides new research concepts and ideas for studying the changes of metabolism in a disease condition. Based on the analysis of group indicators, metabonomic technique not only can systematically study the change rules of metabolites, which helps to further clarify the pathophysiological mechanism of burn or trauma, but also is helpful to find some significant biomarkers with important clinical value so as to provide new insight for the therapy of burn or trauma. This paper reviews the research progress of application of metabonomics in the treatment of severe burn or trauma in recent years.

Background and Aim: Post-pancreaticoduodenectomy hemorrhage (PPH) is a potentially lethal complication. The objective of this study was to explore the risk factors of PPH and to evaluate the treatment options., Methods: Clinical data of 739 consecutive patients undergoing pancreaticoduodenectomy between 2009 and 2017 were collected from a prospectively maintained database. Univariate and multivariate analysis was performed by logistic regression model to evaluate potential risk factors associated with early and late PPH., Results: The morbidity of PPH was 8.7% (64/739), while the mortality was 12.5% (8/64). Twenty-two (34.4%) patients developed PPH within postoperative day 1 (early PPH) whereas 42 (65.6%) patients after postoperative day 1 (late PPH). No significant risk factor was identified associated with early PPH, whereas pancreatic duct diameter < 0.4 cm, and intra-abdominal complications, such as pancreatic fistula, intra-abdominal abscess, and delayed gastric emptying, were independently correlated with late PPH. There were 10 (15.6%) grade A, 28 (43.8%) grade B, and 26 (40.6%) grade C bleedings. The bleeding sites were verified by endoscopy, angiography, and/or exploratory laparotomy in 23 of 54 (42.6%) patients with grade B or C hemorrhage. Seven out of nine (78%) patients with arterial bleeding were cured by angiography and embolization, while 10 of 11 (90.9%) patients with anastomotic, venous, or retroperitoneum bleeding were rescued by laparotomy. Ten patients with grade A and 22 patients with grade B or C hemorrhage were treated successfully by blood transfusion and hemostatic medications., Conclusions: Hemorrhage following pancreaticoduodenectomy is a common and lethal complication. Treatment strategies should be tailored according to different etiologies., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The neural crest is a transient embryonic tissue that initially generates neural crest stem cells, which then migrate throughout the body to give rise to a variety of mature tissues. It was proposed that the fate of neural crest cells is gradually determined via environmental cues from the surrounding tissues. In the present study, neural crest cells were isolated and identified from mouse embryos. Bone morphogenetic protein 4 (BMP4) and Neuregulin (NRG) were employed to induce the differentiation of neural crest cells. Treatment with BMP4 revealed neuron-associated differentiation; cells treated with NRG exhibited differentiation into the Schwann cell lineage, a type of glia. Soft agar clonogenic and neurosphere formation assays were conducted to investigate the effects of N-Myc (MYCN) overexpression in neural crest cells; the number of colonies and neurospheres notably increased after 14 days. These findings demonstrated that the direction of cell differentiation may be affected by altering the factors present in the surrounding environment. In addition, MYCN may serve a key role in regulating neural crest cell differentiation.

Objective: To explore the clinical value of nasal endoscope combined with supporting laryngoscope surgery in the treatment of polyps of vocal cord. Method: Ninety-four patients with vocal cord polyps were randomly divided into the control group (47 cases) and the observation group (47 cases). The patients in the control group were treated with simply supporting laryngoscope surgery while the patients in the observation group were treated with nasal endoscope combined with supporting laryngoscope. The therapeutic effects, voice function changes before and after operation, complications and recurrence of the two groups were observed. Result: The total effective rate was 93.62% in the observation group, compared to 78.72% in the control group, the difference was statistically significant ( P <0.05). The incidence of postoperative complications in the observation group was 8.51%, compared with 25.53% in the control group, the difference was statistically significant ( P <0.05). Six months after operation, there was no recurrence in the observation group, but the recurrence rate in the control group was 4.26%. There was no significant difference between the two groups ( P >0.05). 12 months after operation, the recurrence rate of the observation group was 2.13%, compared with 14.89% of the control group, the difference was statistically significant ( P <0.05). Conclusion: Nasal endoscope combined with supporting laryngoscope for vocal cord polyps has a definite effect and can significantly improve the voice function of patients with high safety and low recurrence rate, which is worthy of promotion.., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Induction of differentiation is a therapeutic strategy in high-risk neuroblastoma, a childhood cancer of the sympathetic nervous system. Neuroblastoma differentiation requires transcriptional upregulation of neuronal genes. How this process is regulated at epigenetic levels is not well understood. Here we report that the histone H3 lysine 27 demethylase KDM6B is an epigenetic activator of neuroblastoma cell differentiation. KDM6B mRNA expression is downregulated in poorly differentiated high-risk neuroblastomas and upregulated in differentiated tumors, and high KDM6B expression is prognostic for better survival in neuroblastoma patients. In neuroblastoma cell lines, KDM6B depletion promotes cell proliferation, whereas KDM6B overexpression induces neuronal differentiation and inhibits cell proliferation and tumorgenicity. Mechanistically, KDM6B epigenetically activates the transcription of neuronal genes by removing the repressive chromatin marker histone H3 lysine 27 trimethylation. In addition, we show that KDM6B functions downstream of the retinoic acid-HOXC9 axis in inducing neuroblastoma cell differentiation: KDM6B expression is upregulated by retinoic acid via HOXC9, and KDM6B is required for HOXC9-induced neuroblastoma cell differentiation. Finally, we present evidence that KDM6B interacts with HOXC9 to target neuronal genes for epigenetic activation. These findings identify a KDM6B-dependent epigenetic mechanism in the control of neuroblastoma cell differentiation, providing a rationale for reducing histone H3 lysine 27 trimethylation as a strategy for enhancing differentiation-based therapy in high-risk neuroblastoma.

Objective: To explore the relationship between endometrial thickness and clinical pregnancy outcomes in frozen-thawed embryo transfer cycles. Methods: A prospective study was performed for 1 475 frozen-thawed embryo transfer cycles at Peking University People's Hospital from January 2014 to December 2015. The patients were divided into different groups according to endometrial thickness of ovulation day in natural menstrual cycles or endometrial transformation day in hormone replacement cycles;patients with thin endometrium were enndometrial thickness ≤6 mm. Then the clinical pregnancy outcomes including clinical pregnancy rate, embryo implantation rate, abortion rate, multiple birth rate and live birth rate were analyzed. Results: In all, 1 475 frozen-thawed embryo transfer cycles were analyzed. The mean age of patients was (32.5±3.9) years old and mean endometrial thickness was (9.2±1.9) mm, and mean number of embryos was 2.03±0.37. The study included 518 (35.1%) natural menstrual cycles and 957 (64.9%) hormone replacement cycles. The number of embryo-transfer cycles and blastocyst-transfer cycles were respectively 700 (47.5%) and 775 (52.5%) . The overall clinical pregnancy rate, embryo implantation rate, abortion rate, multiple birth rate and live birth rate were 54.4%, 35.7%, 23.3%, 24.1%, 43.9%, respectively. The ectopic pregnancy rate in the study was 0.6%. In patients with thin endometrium,there were significant differences in 2 pronucleus count ( P= 0.016) and available embryo count ( P= 0.024) between cycles that resulted in pregnancy and those that did not;besides, the use of sildenafil and growth hormone did not improve pregnancy outcomes in patients with thin endometrium ( P= 0.183, P= 0.400) . The clinical pregnancy rate, embryo implantation rate and live birth rate of embryo-transfer and blastocyst-transfer were similar in patients with thin endometrium (all P> 0.05) . Conclusions: Patients with thin endometrium have poor pregnancy outcomes. The clinical pregnancy rate, embryo implantation rate and live birth rate of embryo-transfer and blastocyst-transfer are similar in patients with thin endometrium. Compared thin endometrium and non-thin endometrium patients, the clinical pregnancy rate and live birth rate of blastocysts have more substantial decline than those of embryos. Improving the quality of embryo could improve the pregnancy outcome of patients with thin endometrium. Sildenafil and growth hormone could not improve pregnancy outcome in patients with thin endometrium.