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A module M over a ring is called simple-direct-injective if, whenever A and B are simple submodules of M with A ≅ B and B ⊆ ⊕ M , we have A ⊆ ⊕ M . Various basic properties of these modules are proved, and some well-studied rings are characterized using simple-direct-injective modules. For instance, it is proved that a ring R is artinian serial with Jacobson radical square zero if and only if every simple-direct-injective right R -module is a C3-module, and that a regular ring R is a right V -ring (i.e., every simple right R -module is injective) if and only if every cyclic right R -module is simple-direct-injective. The latter is a new answer to Fisher's question of when regular rings are V -rings [8] . [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of competing interest No conflict of interest to be disclosed., (Copyright © 2024. Published by Elsevier Inc.)

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 r 2 m 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.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: 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., (© 2024 The Authors.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer YL declared a shared affiliation with the authors to the handling editor at the time of review., (Copyright © 2024 Jin, Lu, Yan, Han, Wei, Zhou, Wang, Shan and Zhao.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Tang, Bu, Tian, Li, Jiang, Qain and Zhou.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 (1×10 6 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 (1×10 6 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., Competing Interests: JH and JL were employed by Hebei Senlang Biotechnology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lin, Ba, Ho, Chen, Cheng, Wang, Xu, Xu, Zhou, Wei, Li and Ling.)

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 (∑PC 11 ) 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 (∑CP 5 ) was significantly higher than that of 6 non-chlorophenols (∑NCP 6 ) 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.

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., Competing Interests: The authors declare no competing interest.

The isocitrate dehydrogenase (IDH1/2) mutations are frequent genetic abnormalities in the majority of WHO grade II/III glioma and secondary GBM. IDH1-mutated (IDH1 Mut ) glioma exhibits distinctive patterns in cancer biology and metabolism. In the present study, we showed that bone morphogenetic proteins (BMP4) are significantly upregulated in IDH1 Mut glioma. Further, we demonstrated that cancer-associated BMP4 is secreted to tumor microenvironment, which enhances the tumor migration and invasion through an autocrine manner. Mechanistically, BMP4 activates its receptor and concomitant SMAD1/5/8 signaling, which potentiates Wnt/β-catenin signaling by enhancing Frizzled receptor expression. LDN-193189, a selective BMP receptor inhibitor, prolonged the overall survival of mice bearing IDH1-mutated intracranial xenografts by limiting BMP/catenin signaling. These findings demonstrate the pivotal role of BMP4 on tumor aggressiveness in IDH1 Mut gliomas, suggesting a possible therapeutic strategy for this type of malignancy., (Published by Elsevier Inc.)

A large volume (more than 4.0 million m 3 ) 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.

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD + metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ( SDHB )-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft. Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423-32. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: Fatty acids (FAs) are essential for membrane lipids biosynthesis and energy consumption in cancer cells. De novo FAs synthesis is catalyzed by fatty acid synthase (FASN), which is overexpressed and correlates with histological grade in glioma. Herein, we focused on the role of FASN in glioma neovascularization., Methods: The expression levels of FASN, Ki67 and CD34 were determined using immunohistochemistry (IHC). FASN specific-targeted shRNA and C75 were applied to evaluate the influence of FASN on glioma stem cell proliferation, migration and tube formation ability in vitro. An intracranial glioma model was established to study the effects of FASN on tumor growth and neovascularization in vivo., Results: IHC staining showed that the expression level of FASN correlated with tumor grade, Ki67 levels and microvessels density (MVD) in human gliomas. Inhibition of FASN using shRNAs or C75 decreased tumor growth, prolonged the overall survival of xenograft mice and decreased MVD in brain tumor sections. Moreover, inhibition of FASN blocked hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGF-A) signaling and upregulated the anti-angiogenic isoform-VEGF 165 b., Conclusion: Our results suggest that FASN plays a pivotal role in glioma neovascularization, and inhibition of FASN may be a potential target for anti-angiogenic therapy for glioma.

Despite the pathophysiological importance of neurohumoral activation in patients with heart failure (HF), the precise underlying mechanisms contributing to elevated vasopressin (VP) activation in HF remains unknown. Carbon monoxide (CO) is a gaseous neurotransmitter in the central nervous system that stimulates VP neuronal firing activity. Recently, we showed that the excitatory effect of CO on VP neurons in the hypothalamic paraventricular nucleus (PVN) was mediated by inhibition of nitric oxide (NO). Given that previous studies showed that VP neuronal activity is enhanced, whereas NO inhibitory signaling is blunted in HF rats, we tested whether an enhanced endogenous CO availability within the PVN contributes to elevated VP neuronal activity and blunted NO signaling in HF rats. We found that both haeme-oxygenase 1 (the CO-synthesizing enzyme) protein and mRNA expression levels were enhanced in the PVN of HF compared with sham rats (∼18% and ∼38%, respectively). We report that in sham rats, bath application of a CO donor (tricarbonyldichlororuthenium dimer) increased the firing activity of identified PVN VP neurons (P < .05), whereas inhibition of endogenous CO production (Tin-protoporphyrin IX [SnPP]) failed to affect neuronal activity. In HF rats, however, SnPP decreased VP activity (P < .05), an effect that was occluded by previous NO synathase blockade NG-nitro-larginine methyl ester. Finally, we found that SnPP increased the mean frequency of γ-aminobutyric acid inhibitory postsynaptic currents in VP neurons in HF (P < .05) but not sham rats. Our results support an enhanced endogenous CO excitatory signaling in VP neurons, which likely contributes to blunted NO and γ-aminobutyric acid inhibitory function in HF rats.

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., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Malignant melanoma causes skin cancer with high rates of mortality. Multinucleated giant cells (MGCs) are frequently observed in tumor pathological analysis, especially in metastasized sites, and are related to poor prognosis. However, the role of MGCs in melanoma development and metastasis is currently unknown. In the present study, we obtained melanoma MGCs (M-MGCs) in vitro using the modified phytohaemagglutinin (PHA)-ECM830 electronic fusion method (fusion efficiency was significantly enhanced by adding PHA to agglutinate cells before electronic fusion). We found that M-MGCs showed decreased proliferation potential but increased pulmonary metastasis ability relative to the parental B16-F10 cells. Microarray and bioinformatics analysis showed that β-tubulin gene group was significantly upregulated in MMGCs. A member of this gene group, TUBB2B, exhibited significantly enhanced expression, indicating that it may play an important role in melanoma metastasis. Our results provide novel insights into the properties of melanoma and they could contribute towards the design of new strategies for rapid diagnosis and treatment of this cancer.

Gliomas are the most frequently occurring primary tumor in the brain. The most malignant form of glioma, glioblastoma multiforme (GBM), is characterized by rapid and invasive growth and is restricted to the central nervous system (CNS). The transforming growth factor β2 (TGFβ2)/small mothers against decapentaplegic (Smad) signaling pathway is important, not only in GBM cell metabolism and invasion, but also in GBM cell proliferation. However, the functions of the downstream mediators of the TGFβ2/Smads signaling pathway remain to be fully elucidated. In the present study, short hairpin (sh)RNA interference was used to specifically inhibit the expression of Smad2 and Smad3 in the TGFβ2/Smad signaling pathway to investigate the effects of shRNA on the proliferation of human GBM cells. The results demonstrated that knockdown of either Smad2 or Smad3 enhanced cellular proliferation. Additionally, the key target genes involved in GBM cell proliferation, induced by TGFβ2, were found to be dependent on Smad3, but not Smad2.

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.

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.

The early stage of diabetic nephropathy (DN) is linked to proteinuria. Transforming growth factor (TGF)-beta1 increases glomerular permeability to albumin (P(alb)), whereas 20-HETE and EETs reduce P(alb). To investigate the impact of hyperglycemia and hyperlipidemia on 20-HETE, EETs, and TGF-beta1 in the glomeruli, rats were divided into four groups: ND rats were fed a normal diet, HF rats were fed a high-fat diet, STZ rats were treated with 35 mg/kg of streptozotocin, and HF/STZ rats were fed a HF diet and treated with STZ. After 10 wk on these regimens, blood glucose, urinary albumin, serum cholesterol, serum triglyceride levels, and the kidney-to-body weight ratio were significantly elevated in STZ and HF/STZ rats compared with HF and ND rats. STZ and HF/STZ rats had histopathologic changes and abnormal renal hemodynamics. Expression of glomerular CYP4A, enzymes for 20-HETE production, was significantly decreased in STZ rats, whereas expression of glomerular CYP2C and CYP2J, enzymes for EETs production, was significantly decreased in both STZ and HF/STZ rats. Moreover, glomerular TGF-beta1 levels were significantly greater in STZ and HF/STZ rats than in HF and ND rats. Five-week treatment of STZ rats with clofibrate induced glomerular CYP4A expression and 20-HETE production, but reduced glomerular TGF-beta1 and urinary protein excretion. These results demonstrate that hyperglycemia increases TGF-beta1 but decreases 20-HETE and EETs production in the glomeruli, changes that may be important in causing glomerular damage in the early stage of DN.

We previously reported that inhibition of nitric oxide (NO) synthesis by N-nitro-L-arginine methyl ester (L-NAME) during late pregnancy leads to increased production of renal vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 (CYP) 4A-derived vasoconstrictor, in pregnant rats. However, the effect of upregulation of vascular 20-HETE production on renal function after NO inhibition is not known. To test the hypothesis that increased gestational vascular 20-HETE synthesis after NO inhibition is involved in mediating blood pressure and renal functional changes, we first determined the IC(50) value of the effect of nitroprusside (SNP), a NO donor, on renal 20-HETE production in cortical microsomes. We then divided pregnant rats and age-matched virgin rats into a vehicle control group, an L-NAME treatment group (0.25 mg/ml in drinking water), and a group treated with L-NAME plus N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; CYP4A-selective inhibitor, 10 mg.kg(-1).day(-1) iv). After 4 days of treatment, we measured blood pressure, renal blood flow (RBF), renal vascular resistance (RVR), and glomerular filtration rate (GFR) in each group. The addition of SNP (IC(50) = 22 microM) decreased renal cortical 20-HETE production. In pregnant rats, L-NAME treatment led to significantly higher mean arterial pressure (MAP) and RVR, and lower RBF and GFR. Combined treatment with DDMS and L-NAME significantly attenuated the increases in MAP and RVR and the decrease in GFR, but not the reduction in RBF induced by L-NAME treatment. L-NAME and L-NAME plus DDMS had no significant impact on renal hemodynamics in virgin rats. In addition, chronic treatment with DDMS selectively inhibited cortical 20-HETE production without a significant effect on CYP4A expression in L-NAME-treated pregnant rats. In conclusion, NO effectively inhibits renal cortical microsomal 20-HETE production in female rats. In pregnant rats, the augmentation of renal 20-HETE production after NO inhibition is associated with increased MAP and RVR, whereas decreased GFR is negated by treatment of a selective and competitive CYP4A inhibitor. These results demonstrate that the interaction between renal 20-HETE and NO is important in the regulation of renal function and blood pressure in pregnant rats.

Epoxyeicosatrienoic acids (EETs), which belong to cytochrome P-450 (CYP)-derived eicosanoids, have been implicated to vasodilate renal arterioles, inhibit sodium transport in the nephron, and regulate blood pressure in several animal models. Because pregnancy is associated with changes of blood pressure, the aim of this study was to examine whether renal EET synthesis is altered and whether EETs are involved in blood pressure regulation during pregnancy in rats. Renal microsomal epoxygenase activity increased by 47, 97, and 63% on days 6, 12, and 19 of gestation, respectively. The elevation of epoxygenase activity during pregnancy was associated with an increase in CYP2C11, CYP2C23, and CYP2J2 protein expression on days 6, 12, and 19 of gestation. Moreover, immunohistochemical analysis showed that renal tubular CYP2C11, CYP2C23, and CYP2J2 expression was significantly increased in pregnant rats on days 6, 12, and 19 of gestation. Administration of 6-(2-propargyloxyphenyl)hexanoic acid (PPOH), a selective epoxygenase inhibitor, caused a dose-dependent inhibition of microsomal expoxygenase activity without a significant effect on omega-hydroxylase activity in female rats. Interestingly, administration of PPOH (20 mg.kg(-1).day(-1) for 4 days starting on day 15 of pregnancy) increased blood pressure by 21 mmHg and caused a significant decrease in the body weight of fetal pups (1.3 +/- 0.08 g in control vs. 1.1 +/- 0.06 g in PPOH). Moreover, PPOH treatment significantly decreased renal microsomal epoxygenase activity and the expression of CYP2C11, CYP2C23, and CYP2J in pregnant rats. This study demonstrates that EET synthesis in the kidney is elevated during pregnancy, and CYP2C11, 2C23, and CYP2J2 are responsible for the change of renal EET synthesis. The inhibition results demonstrate that the downregulation of renal epoxygenase activity by PPOH causes hypertension in pregnant rats. This study suggests that EETs may contribute to the control of blood pressure during pregnancy.