Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism.

Isocitrate dehydrogenase (IDH) mutation is a common genetic abnormality in human malignancies characterized by remarkable metabolic reprogramming. Our present study demonstrated that IDH1-mutated cells showed elevated levels of reactive oxygen species and higher demands on Nrf2-guided glutathione de novo synthesis. Our findings showed that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor, which exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with reactive oxygen species derived from IDH1 mutant neomorphic activity. Our findings highlight triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.

Phenolic compounds in water, suspended particulate matter and sediment from Weihe River in Northwest China.

The distribution and ecological risks of 11 phenolic compounds were studied in Weihe River, Northwest China. The concentrations of phenolic compounds were determined by ultra-high performance liquid chromatography (UPLC). The total concentration of 11 phenolic compounds (∑PC11) ranged from 0.06 to 14.12 µg/L with an average of 5.22 µg/L in water, from 0.92 to 34,885 µg/g with an average of 4,446 µg/g in suspended particulate matter (SPM), and from 3.54 to 34.09 µg/g with an average of 11.09 µg/g in sediment. For individual phenolic compound, the mean concentration of pentachlorophenol was the highest in water (2.65 µg/L) and in SPM (3,865 µg/g), while in sediment the mean concentration of 2,4,6-trichlorophenol was the highest (3.05 µg/g). The total concentration of 5 chlorophenols (∑CP5) was significantly higher than that of 6 non-chlorophenols (∑NCP6) in all three studied compartments. The phenolic compounds in Weihe River were at moderate levels in water and at high levels in sediment. The ecological risk assessment results indicated that phenolic compounds exhibited a high ecological risk in Weihe River water. In most sites, the distribution coefficient (Kd) (SPM) was much higher than Kd (sediment), which probably suggested fresh phenolic compounds input in Weihe River.

Multifunctional pDNA-Conjugated Polycationic Au Nanorod-Coated Fe3 O4 Hierarchical Nanocomposites for Trimodal Imaging and Combined Photothermal/Gene Therapy.

It is very desirable to design multifunctional nanocomposites for theranostic applications via flexible strategies. The synthesis of one new multifunctional polycationic Au nanorod (NR)-coated Fe3 O4 nanosphere (NS) hierarchical nanocomposite (Au@pDM/Fe3 O4 ) based on the ternary assemblies of negatively charged Fe3 O4 cores (Fe3 O4 -PDA), polycation-modified Au nanorods (Au NR-pDM), and polycations is proposed. For such nanocomposites, the combined near-infrared absorbance properties of Fe3 O4 -PDA and Au NR-pDM are applied to photoacoustic imaging and photothermal therapy. Besides, Fe3 O4 and Au NR components allow the nanocomposites to serve as MRI and CT contrast agents. The prepared positively charged Au@pDM/Fe3 O4 also can complex plasmid DNA into pDNA/Au@pDM/Fe3 O4 and efficiently mediated gene therapy. The multifunctional applications of pDNA/Au@pDM/Fe3 O4 nanocomposites in trimodal imaging and combined photothermal/gene therapy are demonstrated using a xenografted rat glioma nude mouse model. The present study demonstrates that the proper assembly of different inorganic nanoparticles and polycations is an effective strategy to construct new multifunctional theranostic systems.

Astrocytes modulate a postsynaptic NMDA-GABAA-receptor crosstalk in hypothalamic neurosecretory neurons.

A dynamic balance between the excitatory and inhibitory neurotransmitters glutamate and GABA is critical for maintaining proper neuronal activity in the brain. This balance is partly achieved via presynaptic interactions between glutamatergic and GABA(A)ergic synapses converging into the same targets. Here, we show that in hypothalamic magnocellular neurosecretory neurons (MNCs), a direct crosstalk between postsynaptic NMDA receptors (NMDARs) and GABA(A) receptors (GABA(A)Rs) contributes to the excitatory/inhibitory balance in this system. We found that activation of NMDARs by endogenous glutamate levels controlled by astrocyte glutamate transporters, evokes a transient and reversible potentiation of postsynaptic GABA(A)Rs. This inter-receptor crosstalk is calcium-dependent and involves a kinase-dependent phosphorylation mechanism, but does not require nitric oxide as an intermediary signal. Finally, we found the NMDAR-GABA(A)R crosstalk to be blunted in rats with heart failure, a pathological condition in which the hypothalamic glutamate-GABA balance is tipped toward an excitatory predominance. Together, our findings support a novel form of glutamate-GABA interactions in MNCs, which involves crosstalk between NMDA and GABA(A) postsynaptic receptors, whose strength is controlled by the activity of local astrocytes. We propose this inter-receptor crosstalk to act as a compensatory, counterbalancing mechanism to dampen glutamate-mediated overexcitation. Finally, we propose that an uncoupling between NMDARs and GABA(A)Rs may contribute to exacerbated neuronal activity and, consequently, sympathohumoral activation in such disease conditions as heart failure.

Informal institutions and corporate innovation: A Perspective from Red Culture.

Since the 20th century, Red Culture has served as a significant informal institution guiding revolutionary trajectory and developmental course. However, integrating Red Culture into contemporary corporate management and leveraging its constructive influence within today's market-driven economy necessitates comprehensive exploration and thoughtful consideration. This study aims to explore the potential influence of Red Culture on contemporary innovation. Empirical findings reveal substantial and affirmative effects of Red Culture on corporate innovation. Specifically, a heightened Red Culture ambiance correlates with a marked increase in both innovation input and output within corporate. Further investigation underscores Red Culture's pivotal governance role in mitigating strategic manipulation of innovation and research and development practices, especially within the overarching framework of innovation-driven strategies. Moreover, Red Culture synergizes with formal innovation incentive mechanisms, jointly fostering corporate innovation. This study provides micro-level empirical evidence that elucidates the impact of Red Culture on corporate innovation. Additionally, it furnishes valuable policy insights for the practical implementation and enhancement of pertinent Red Culture initiative.

TC-DTA: predicting drug-target binding affinity with transformer and convolutional neural networks.

Bioinformatics is a rapidly growing field involving the application of computational methods to the analysis and interpretation of biological data. An important task in bioinformatics is the identification of novel drug-target interactions (DTIs), which is also an important part of the drug discovery process. Most computational methods for predicting DTI consider it as a binary classification task to predict whether drug target pairs interact with each other. With the increasing amount of drug-target binding affinity data in recent years, this binary classification task can be transformed into a regression task of drug-target affinity (DTA), which reflects the degree of drug-target binding and can provide more detailed and specific information than DTI, making it an important tool in drug discovery through virtual screening. Effectively predicting how compounds interact with targets can help speed up the drug discovery process. In this study, we propose a deep learning model called TC-DTA for the prediction of the DTA, which makes use of the convolutional neural networks (CNN) and encoder module of the transformer architecture. First, the raw drug SMILES strings and protein amino acid sequences are extracted from the dataset. These are then represented using different encoding methods. We then use CNN and the Transformer's encoder module to extract feature information from drug SMILES strings and protein amino acid sequences, respectively. Finally, the feature information obtained is concatenated and fed into a multi-layer perceptron for prediction of the binding affinity score. We evaluated our model on two benchmark DTA datasets, Davis and KIBA, against methods including KronRLS, SimBoost and DeepDTA. On evaluation metrics such as Mean Squared Error, Concordance Index and r2m index, TC-DTA outperforms these baseline methods. These results demonstrate the effectiveness of the Transformer's encoder and CNN in the extraction of meaningful representations from sequences, thereby improving the accuracy of DTA prediction. The deep learning model for DTA prediction can accelerate drug discovery by identifying drug candidates with high binding affinity to specific targets. Compared to traditional methods, the use of machine learning technology allows for a more effective and efficient drug discovery process.

Surgical results for one-stage VII/VIII schwannoma resection and hemihypoglossal-facial neurorrhaphy.

BACKGROUND: This retrospective study evaluated the outcomes of patients undergoing one-stage resection of VII/VIII schwannomas and hemihypoglossal-facial neurorrhaphy via the translabyrinthine approach (TLA). METHODS: The study encompassed ten consecutive patients with unilateral hearing loss (six women, four men, mean age: 49.5 ± 12.1 years) who underwent surgery. The cohort included two patients with vestibular schwannomas (VSs), four with facial nerve schwannomas (FNSs) (two originating from the geniculate ganglion of the facial nerve and two from the cerebellopontine angle), one with VS regrowth, and three with residual VSs. Preoperative facial nerve function, assessed using the House-Brackmann (HB) scale, was Grade V in one and Grade VI in nine patients. The mean preoperative duration of facial paralysis was 7.5 ± 6.9 months. RESULTS: All patients underwent gross total resection. Postoperatively, one patient experienced cerebrospinal fluid leaks, which were successfully managed with lumbar drains and surgical revisions. At follow-up, facial nerve function improved in all patients: HB Grade V to III in one, HB Grade VI to III in one, HB Grade VI to IV in seven, and Grade VI to V in one. No tumor recurrence was observed during the follow-up period (mean duration: 16.6 ± 9.3 months), and no patient had hemilingual atrophy. CONCLUSION: The TLA for one-stage resection of VII/VIII schwannomas and facial nerve reconstruction is effective in treating both regrowth and residual VSs and FNSs in the cerebellopontine angle or petrosal bone in patients with severe preoperative facial palsy. This technique facilitates simultaneous tumor removal and nerve anastomosis, thereby reducing the need for multiple surgical interventions in patients with hearing loss and compromised facial nerve function.

Plasma extracellular vesicles proteomics in meningioma patients.

Tumor derived Extracellular vesicles (EVs) in circulating system may contain tumor-specific markers, and EV detection in body fluids could become an important tool for early tumor diagnosis, prognosis assessment. Meningiomas are the most common benign intracranial tumors, few studies have revealed specific protein markers for meningiomas from patients' body fluids. In this study, using proximity labeling technology and non-tumor patient plasma as a control, we detected protein levels of EVs in plasma samples from meningioma patients before and after surgery. Through bioinformatics analysis, we discovered that the levels of EV count and protein count in meningioma patients were significantly higher than those in healthy controls, and were significantly decreased postoperatively. Among EV proteins in meningioma patients, the levels of MUC1, SIGLEC11, E-Cadherin, KIT, and TASCTD2 were found not only significantly elevated than those in healthy controls, but also significantly decreased after tumor resection. Moreover, using publicly available GEO databases, we verified that the mRNA level of MUC1, SIGLEC11, and CDH1 in meningiomas were significantly higher in comparison with normal dura mater tissues. Additionally, by analyzing human meningioma specimens collected in this study, we validated the protein levels of MUC1 and SIGLEC11 were significantly increased in WHO grade 2 meningiomas and were positively correlated with tumor proliferation levels. This study indicates that meningiomas secret EV proteins into circulating system, which may serve as specific markers for diagnosis, malignancy predicting and tumor recurrent assessment.

Automated algorithm aided capacity and confidence boost in surgical decision-making training for inferior clivus.

Objective: To assess the impact of automated algorithms on the trainees' decision-making capacity and confidence for individualized surgical planning. Methods: At Chinese PLA General Hospital, trainees were enrolled to undergo decision-making capacity and confidence training through three alternative visual tasks of the inferior clivus model formed from an automated algorithm and given consecutively in three exemplars. The rationale of automated decision-making was used to instruct each trainee. Results: Following automated decision-making calculation in 50 skull base models, we screened out three optimal plans, infra-tubercle approach (ITA), trans-tubercle approach (TTA), and supra-tubercle approach (STA) for 41 (82.00%), 8 (16.00%), and 1 (2.00%) subject, respectively. From September 1, 2023, through November 17, 2023, 62 trainees (median age [range]: 27 [26-28]; 28 [45.16%] female; 25 [40.32%] neurosurgeons) made a decision among the three plans for the three typical models (ITA, TTA, and STA exemplars). The confidence ratings had fine test-retest reliability (Spearman's rho: 0.979; 95% CI: 0.970 to 0.988) and criterion validity with time spent (Spearman's rho: -0.954; 95%CI: -0.963 to -0.945). Following instruction of automated decision-making, time spent (initial test: 24.02 vs. 7.13 in ITA; 30.24 vs. 7.06 in TTA; 34.21 vs. 12.82 in STA) and total hits (initial test: 30 vs. 16 in ITA; 37 vs. 17 in TTA; 42 vs. 28 in STA) reduced significantly; confidence ratings (initial test: 2 vs. 4 in ITA; 2 vs. 4 in TTA; 1 vs. 3 in STA) increased correspondingly. Statistically significant differences (P < 0.05) were observed for the above comparisons. Conclusions: The education tool generated by automated decision-making considers surgical freedom and injury risk for the individualized risk-benefit assessment, which may provide explicit information to increase trainees' decision-making capacity and confidence.

[Analysis of the risk factors for delayed union of extra-articular fractures of the middle and lower third of the tibia treated by locking plate].

OBJECTIVE: To investigate the risk factors for delayed union of extra-articular fractures of the middle and lower third of the tibia treated by locking plate. METHODS: Total of 135 patients of extra-articular fractures of the middle and lower third of the tibia from January 2013 to December 2018 were retrospectively analyzed, including 85 males and 50 females, ranged from 19 to 80 years old. All cases were treated with locking plates. The patients were divided into union group and delayed union group according to the condition of fracture union. The risk factors of delayed healing were determined by univariate analysis of 14 factors that might affect fracture healing first, then the factors with significance were analyzed by binary Logistic regression. RESULTS: There were 13 patients of delayed union, and the rate of delayed union was 9.63%. Univariate analysis showed that delayed union was associated with age, smoking, reduction method, anemia and time of preoperative preparation. Regression analysis showed that age[OR=0.849, 95%CI（0.755, 0.954）, P=0.006], smoking[OR=0.020, 95%CI（0.002, 0.193）, P=0.001], reduction method[OR=23.924, 95%CI（2.210, 258.943）, P=0.009], anemia[OR=0.016, 95%CI（0.001, 0.289）, P=0.005] were the contributory factors for delayed union. CONCLUSION: Young age, smoking, closed reduction and anemia are the risk factors for delayed union of extra-articular fractures of the middle and lower third of the tibia treated by locking plate.

A disease warranting attention from neurosurgeons: primary central nervous system post-transplant lymphoproliferative disorder.

Background: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare condition, posing diagnostic and treatment challenges, with histological biopsy essential for diagnosis. Standardized treatment protocols are lacking. This disease requires urgent attention due to the increasing number of organ transplant surgeries and the use of immunosuppressive agents. Methods: From 2020 to 2023, our center diagnosed five patients with PCNS-PTLD. We reviewed their clinical records and conducted a comprehensive analysis of 22 literatures on PCNS-PTLD cases following renal transplantation or allogeneic hematopoietic stem cell transplantation (HSCT). Results: Four patients had previously received a kidney transplant, one had undergone allogeneic HSCT. The median time from the last transplant surgery to the diagnosis of PCNS-PTLD differs between kidney transplant (21.5 years) and allogeneic HSCT (9 months). Common symptoms included motor weakness (n = 4), headache (n = 2), confusion (n = 2), and nausea (n = 2), with ring-enhancing (n = 5), typically solitary (n = 3) and supratentorial (n = 3) lesions on imaging. Diagnosis involved robot-assisted stereotactic brain biopsy (n = 4) or craniotomy (n = 1), all showing Epstein-Barr virus and CD20 positivity. Most cases (n = 4) were monomorphic diffuse large B-cell lymphoma. Treatment included rituximab (n = 3), surgical resection (n = 2), zanubrutinib (n = 1), whole-brain radiation (n = 1), and methotrexate (n = 1). At the last follow-up, the median duration of follow-up for all patients was 19 months. During this time, 3 patients had died and 2 patients were still alive. Conclusion: In patients with a history of kidney transplantation or allogeneic HSCT who are on long-term immunosuppressive therapy, any neurological symptoms, particularly the presence of supratentorial ring-enhancing masses in the brain on imaging, whether solitary or multiple, should raise high suspicion for this disease, warranting a timely brain biopsy. Additionally, we found that besides reducing immunosuppressants, zanubrutinib may be a potential, safe, and effective treatment for this condition. Moreover, post-surgical administration of rituximab in conjunction with whole-brain radiotherapy also appears to be a potentially safe and effective approach.

Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats.

Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 µM dihydrokainate (DHK)], resulted in a persistent N-methyl-D-aspartate receptor (NMDAR)-mediated inward current (tonic I(NMDA)) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 µM TBOA) evoked an enhanced tonic I(NMDA) activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.

M&A goodwill and corporate technological innovation: The mediating moderating effect of stock pledges.

Identifying whether and how merger and acquisition (M&A) goodwill influences corporate technology innovation is a critical topic in the context of growing M&A activities. Based on the panel data of 2,634 Chinese non-financial listed companies from 2007 to 2019, this paper adopts multiple linear regression and the Bootstrap method to investigate the impact of M&A goodwill on corporate technological innovation and the mechanism through which M&A goodwill affects technological innovation. The results show that: (1) There is a significant negative correlation between M&A goodwill and technological innovation input, with financial constraints acting as the main channels. (2) Non-private corporations enjoy a higher level of financing capacity in terms of debt and equity compared with private corporations, resulting in the absence of the disincentive effect of M&A goodwill on corporate technological innovation inputs, despite the fact that M&A activities also cause massive resource consumption. (3) Stock pledges by controlling shareholders are effective in alleviating the negative impact of M&A goodwill on technological innovation inputs. Furthermore, our results highlight that simple stock pledge measures capture a significant influence of alleviating financing constraints, thereby decreasing the adverse impact of M&A, and hence need to be adequately considered in future M&A and innovation studies. While enriching the literature on the economic consequences of M&A and the research on stock pledge, this paper also provides micro-evidence for an in-depth understanding of the effect of M&A goodwill on technological innovation.

Facial Nerve Schwannoma Resection and Nerve Anastomosis in 1 Stage by Translabyrinthine Approach.

Facial nerve schwannomas (FNS) are rare benign tumors that can develop in any segment of the facial nerve. Patients often experience facial palsy and hearing loss after FNS removal or even before surgery.1-3 Double-stage treatment is usually necessary for tumor resection and reconstruction of facial nerve function.4,5Video 1 describes the translabyrinthine approach for resection of the middle-posterior cranial fossa dumbbell FNS and end-to-side hypoglossal-facial nerve anastomosis in 1 stage. The case presented is of a 28-year-old female patient who suffered from right-side hearing loss for 1.5 years, right facial paralysis for 2 months (House-Brackmann grade V), and a right middle-posterior fossa dumbbell FNS extending from the right cerebellopontine angle area and internal auditory canal. Gross total resection of the tumor and hypoglossal-facial nerve end-to-side anastomosis were performed during the same procedure. Postoperative facial nerve function was House-Brackmann grade III at the 6-month follow-up. The patient experienced no postoperative complications. This case demonstrates the advantages of the translabyrinthine approach for middle-posterior fossa dumbbell FNS. This approach helps in achieving tumor resection and nerve anastomosis in 1 stage by avoiding multiple surgical interventions for patients with hearing loss and impaired facial nerve function. The patient consented to surgery and the publication of her images.

The effective path of green transformation of heavily polluting enterprises promoted by green merger and acquisition-qualitative comparative analysis based on fuzzy sets.

Green merger and acquisition (GMA) is becoming a growing tendency for heavily polluting enterprises in recent years; however, the realization path of green transformation through GMA is still unexplored. Taking 48 Chinese heavily polluting enterprises that had GMA in 2018 as the research object, this paper constructs the "M&A attributes, Organizational characteristics, and External environment" (M-O-E) framework, by using the method of fuzzy-set qualitative comparative analysis (fsQCA) to reveal the configurations of conditions that lead to high levels of green innovation performance. The results show that the high green technology innovation performance after GMA of heavily polluting enterprises is the outcome of multiple antecedents, and no singular antecedent is sufficient for achieving it. Besides, there are three equivalent configurations of conditions to achieve green transformation: professional buyer, internal leading, and internal-external linkage. Among them, the professional buyer configuration highlights that the combination of M&A experience and M&A scale is of great importance, the internal leading configuration emphasizes that the existence of environmental awareness and organizational resources is the core conditions, and the internal-external linkage configuration requires simultaneous efforts of M&A experience and government environmental regulations. Our research contributes to the understanding of green transformation in heavily polluting enterprises from a configurational perspective, and provides a practice-oriented guide to achieve green transformation for the government and heavily polluting enterprises.

The effect of dissolved natural organic matter on adsorption of phenolic compounds on suspended sediments.

Phenolic compounds have caused different degrees of negative impacts in aquatic environment. Amino acids, humic acids and carbohydrates are the three dominant types of dissolved natural organic matter (DNOM) in natural water bodies. In this research, the influences of dissolved natural organic matter (DNOM) on the adsorption behaviors of phenol, 2,4-dichlorophenol (DCP) and 2,4,6-trichlorophenol (TCP) in Weihe River suspended sediment were studied by using DL-alanine, fulvic acid and glucose as the representatives of the three types of DNOM. The results of batch adsorption experiments showed that, without DNOM, Langmuir and Freundlich had good fitting effects on the three phenolic compounds and their maximum adsorption capacities were 21.580, 27.768 and 24.758 mg/kg respectively. The presence of amino acids increased adsorption capacities of the phenol and TCP on suspended sediments by approximately 13.84% and 11.56% respectively. The existence of fulvic acid and glucose positively affected the adsorption of phenol, DCP and TCP on suspended sediment. The isothermal adsorption in the coexistence of different DNOM were more consistent with the nonlinear adsorption. Other influence factors including pH, ionic strength and temperature can influence the adsorption behavior to different extents. The impact of dissolved natural organic matter (DNOM) on adsorption should be fully considered when mastering environmental migration and transformation behaviors of phenolic compounds in water-sediments environment.

First-in-Human Trial of EphA2-Redirected CAR T-Cells in Patients With Recurrent Glioblastoma: A Preliminary Report of Three Cases at the Starting Dose.

Glioblastoma is the most common primary brain malignancy with limited treatment options. EphA2 is a tumor-associated-antigen overexpressed in glioblastoma. Pre-clinical studies have demonstrated the promise of EphA2-redirected CAR T-cells against glioblastoma. We conduct the first-in-human trial of EphA2-redirected CAR T-cells in patients with EphA2-positive recurrent glioblastoma and report the results of three patients enrolled as the first cohort receiving the starting dosage (1×106 cells/kg). A single infusion of EphA2-redirected CAR T-cells was administrated intravenously, with the lymphodepletion regimen consisting of fludarabine and Cyclophosphamide. In two patients, there was grade 2 cytokine release syndrome accompanied by pulmonary edema, which resolved completely with dexamethasone medication. Except that, there was no other organ toxicity including neurotoxicity. In both the peripheral blood and cerebral-spinal-fluid, we observed the expansion of CAR T-cells which persisted for more than four weeks. In one patient, there was a transit diminishment of the tumor. Among these three patients, one patient reported SD and two patients reported PD, with overall survival ranging from 86 to 181 days. At the tested dose level (1×106 cells/kg), intravenously infusion of EphA2-rediretected CAR T-cells were preliminary tolerable with transient clinical efficacy. Future study with adjusted dose and infusion frequency of CAR T-cells is warranted. TRIAL REGISTRATION NUMBERS: NCT03423992.

Outcomes after semisitting and lateral positioning in large vestibular schwannoma surgery: A single-center comparison.

OBJECTIVE: The semisitting position (SSP) and lateral position (LP) in vestibular schwannoma (VS) surgery each have advantages and disadvantages, and which position is superior overall is debatable. Our objective was to determine the optimal position for surgical treatment of VSs with a diameter ≥3 cm. METHODS: We retrospectively evaluated consecutive patients with a large VS treated between January 2010 and July 2020. Patients were grouped by surgical position and analyzed. RESULTS: We enrolled 259 patients (LP group, n = 156; SSP group, n = 103). The resection extent was not significantly different between the SSP (gross-total resection [GTR], n = 89 [88.1%], near-total resection [NTR], n = 10 [9.9%], subtotal resection [STR], n = 2 [2.0%]) and LP (GTR, n = 125 [80.1%]; NTR, n = 24 [15.4%]; STR, n = 7 [4.5%]) groups. The rate of GTR with facial nerve (FN) functional preservation was higher in the SSP group than in the LP group (P = 0.014) at eight days after the operation. However, during follow-up (SSP group median, 31.5 months; LP group median, 19.5 months), there was no significant between-group difference in FN functional preservation. Two patients in the SSP group required conversion to the LP due to severe intraoperative venous air embolism (VAE). CONCLUSION: Compared with the LP, the SSP did not produce significantly better FN outcomes in patients with a large VS. The duration of surgery was significantly longer in SSP cases than in LP cases. Given the risk of VAE associated with the SSP, the selection of the optimal surgical position should be made with caution on an individual basis.

Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia, promotes insulin secretion, and reduces islet apoptosis.

Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and antiapoptotic mediators. However, the roles of sEH in diabetes and the pancreas are unknown. Our aims were to determine whether sEH is involved in the regulation of hyperglycemia in diabetic mice and to investigate the reasons for the regulation of insulin secretion by sEH deletion or inhibition in islets. We used two separate approaches, targeted disruption of Ephx2 gene [sEH knockout (KO)] and a selective inhibitor of sEH [trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB)], to assess the role of sEH in glucose and insulin homeostasis in streptozotocin (STZ) mice. We also examined the effects of sEH KO or t-AUCB on glucose-stimulated insulin secretion (GSIS) and intracellular calcium levels in islets. Hyperglycemia in STZ mice was prevented by both sEH KO and t-AUCB. In addition, STZ mice with sEH KO had improved glucose tolerance. More important, when insulin levels were assessed by hyperglycemic clamp study, sEH KO was found to promote insulin secretion. In addition, sEH KO and t-AUCB treatment augmented islet GSIS. Islets with sEH KO had a greater intracellular calcium influx when challenged with high glucose or KCl in the presence of diazoxide. Moreover, sEH KO reduced islet cell apoptosis in STZ mice. These results show not only that sEH KO and its inhibition prevent hyperglycemia in diabetes, but also that sEH KO enhances islet GSIS through the amplifying pathway and decreases islet cell apoptosis in diabetes.

The contents and release behavior of heavy metals in construction and demolition waste used in freeway construction.

A large volume (more than 4.0 million m3) of treated construction and demolition waste (CDW) is planned to be used in the construction of the Xi'an-Xianyang north loop line freeway in West China. These CDW were preliminarily separated into broken concretes, bricks, and porcelains in the treatment plants. In this study, a total of 190 CDW samples including 80 concretes, 80 bricks, 20 porcelains, and 10 mixed samples were collected from five treatment plants. Five farmland soil samples near treatment plants were collected as controls. The contents of 10 elements including cadmium (Cd), arsenic (As), copper (Cu), nickel (Ni), zinc (Zn), chromium (Cr), lead (Pb), manganese (Mn), silver (Ag), and mercury (Hg) in these samples were measured. The contents of 8 elements (Cu, Ni, Zn, Cr, Pb, Mn, Ag, and Hg) in all CDW samples were qualified for the third-level criterion of the Standard of Soil Environment (GB15618-2008). However, Cd contents in 37 concretes, 34 bricks, 6 porcelain samples, and 4 mixed CDW samples exceeded the national third-level standards (1 mg/kg) in GB15618-2008. And As contents in 28 concretes, 21 bricks, 5 porcelain samples, and 3 mixed CDW samples were higher than the national third-level standards (40 mg/kg). The total exceeding standard rates (ESRs) of Cd and As were 42.6% and 30%, respectively. The leaching tests for Cd and As were also done due to their higher ESRs. The results showed that the release amounts (µg/kg) of Cd and As from CDW were increased with increasing liquid to solid ratio (0.4-10 l/kg) but decreased with increasing pH (4-7). The leached concentrations of Cd and As from four types of CDW samples were both in a descending order: brick, mixed materials, concrete, and porcelain. The measured concentrations (µg/L) of Cd and As in leachate were all lower than second-grade criteria of Standard for Groundwater Quality (GB3838-2002). By comparing the leached concentrations of Cd and As with the value in European criteria (EU Council Decision 2003/33/EC) for hazardous wastes, all the CDW samples should be classified as inert or non-hazardous wastes. Thus, it could be concluded that heavy metals in these CDW would not pollute surrounding soil, surface water, and groundwater environment when applied in freeway construction.