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Abstract Background Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. Methods In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients’ cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients’ depressive symptoms at baseline and week 2. Results After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p

IntroductionSleep disorders are common in children with autism spectrum disorder (ASD). Transcranial magnetic stimulation (TMS) can influence the excitability of neuronal cells in stimulated areas, leading to improvements in sleep and other autistic symptoms. However, studies on clinical mechanisms of TMS in treating sleep disorders associated with ASD are limited. Therefore, we aimed to explore the effects of TMS on sleep structure and quality in children with ASD.MethodsBetween January 2020 and December 2021, recruitment was advertised through child and adolescent outpatient clinics and online platforms by the Hangzhou Seventh People’s Hospital and Lishui Second People’s Hospital. Sixty children with ASD who met the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were selected and randomly divided into the active TMS and sham TMS treatment groups. Thirty healthy children of the same age were recruited as controls. The active TMS group received bilateral low-frequency (0.5 Hz) TMS targeting the dorsolateral prefrontal cortex on both sides in children with ASD, whereas the sham TMS group received sham stimulation with the same stimulation time and location as the experimental group. Both groups were treated for 6 weeks, and the participants were assessed using the Sleep Disturbance Scale for Children (SDSC) before treatment, at 3 weeks, and at 6 weeks of intervention. Independent sample t-tests and difference t-tests were used for statistical analysis of the data.ResultsNo significant differences were observed in general demographic variables, such as age and sex, between the ASD and control groups (P>0.05). Independent sample t-test analysis showed that the total SDSC score, difficulty falling asleep, sleep maintenance, awakening disorders, sleep-wake transition disorders, excessive daytime sleepiness, and nocturnal hyperhidrosis scores were significantly higher in the ASD group than in the control group (P0.05). After 15 and 30 treatment sessions, the total SDSC score, difficulty falling asleep, sleep maintenance, sleep-wake transition disorders, and excessive daytime sleepiness scores were significantly higher in the sham TMS group than in the active TMS group (P

Objective: The combined use of transcranial magnetic stimulation and electroencephalography (TMS-EEG), as a powerful technique that can non-invasively probe the state of the brain, can be used as a method to study neurophysiological markers in the field of psychiatric disorders and discover potential diagnostic predictors. This study used TMS-evoked potentials (TEPs) to study the cortical activity of patients with major depressive disorder depression (MDD) and the correlation with clinical symptoms to provide an electrophysiological basis for the clinical diagnosis.Methods: A total of 41 patients and 42 healthy controls were recruited to study. Using TMS-EEG techniques to measure the left dorsolateral prefrontal cortex (DLPFC) ‘s TEP index and evaluate the clinical symptoms of MDD patients using the Hamilton Depression Scale-24 (HAMD-24).Results: MDD subjects performing TMS-EEG on the DLPFC showed lower cortical excitability P60 index levels than healthy controls. Further analysis revealed that the degree of P60 excitability within the DLPFC of MDD patients was significantly negatively correlated with the severity of depression.Conclusion: The low levels of P60 exhibited in DLPFC reflect low excitability in MDD; the P60 component can be used as a biomarker for MDD in clinical assessment tools.

Abstract Background Glioblastoma (GBM) is a highly immunosuppressive and vascular malignant brain tumor. Current therapeutic strategies targeting tumor cells have limited efficacy because of the immunosuppressive microenvironment and vascularization. Glioma-associated mesenchymal stem cells (GA-MSCs) have been identified as important stromal components of the tumor microenvironment, owing to their contribution to tumor angiogenesis and their potential to drive glioma stem cells. However, there are no reports on the effect of oncolytic Ad5-Ki67/IL-15 on programmed death ligand 1 (PD-L1) expression and angiogenesis induced by GA-MSCs. Methods Flow cytometry was respectively performed to detect the PD-L1 of glioma cells and programmed death protein 1 (PD-1), CD3, CD4 and CD8 in lymphocytes, as well as distribution of the cell cycle. CCK-8 assay investigated the proliferation of glioma cells and GA-MSCs in vitro. Tumor-bearing nude mice were established with U87-Luc cells and treated with the viruses, and further the IVIS spectrum was utilized to obtain luciferase images. Finally, the expression of PD-L1 in tumor tissues was also investigated using western blotting. Results We found that GA-MSCs had potential to induce PD-L1 upregulation and involved in vascular mimicry in vitro. Importantly, Ad5-Ki67/IL-15 reduced PD-L1 expression of glioma cells and neovascularization by targeting GA-MSCs. Furthermore, despite the presence of GA-MSCs, the virus has the ability to generate potent antitumor efficacy in vitro and vivo. Conclusions These findings suggest the use of oncolytic Ad5-Ki67/IL-15 targeting GA-MSCs to treat GBM, indicating potential clinical applications.

Abstract Background Glioblastoma (GBM) is an immunosuppressive, highly vascular and devastating malignant brain tumor. Even with progressive combination treatment that includes surgery, radiotherapy, and chemotherapy, the prognosis for GBM patients is still extremely poor. Oncolytic adenovirus (OAd) can specifically replicate in GBM cells, permitting the rapid copy of the therapeutic genes it carries. Moreover, E1A is an essential gene in adenoviral replication and is the first gene expressed upon viral infection. E1A expression can be regulated by the Ki67 promoter, while the CMV promoter drives therapeutic gene expression. However, the efficacy of a double-controlled OAd driven by the Ki67 core promoter and armed with IL-15 against GBM cells has not been investigated. Methods Fluorescence microscopy was performed to evaluate infection ability in the viruses. Cell viability was detected by CCK-8 assay. Levels of cytokines in different supernatants were determined by ELISA, and IL-15 gene expression was measured by RT-PCR. Angiogenic capacity was analyzed by tube formation assay. Results We successfully constructed a double-controlled oncolytic adenovirus driven by the Ki67 core promoter and armed with IL-15 that selectively infected and killed GBM cells while sparing normal cells. The adenoviruses prime IL-15 gene expression to significantly enhance anti-GBM efficacy through effective activation of microglial cells. Moreover, OAd not only directly inhibits angiogenesis but exhibits potent antiangiogenic capacity mediated by the reduction of VEGF secretion. Conclusions These results provide new insight into the effects of a novel double-controlled OAd driven by the Ki67 core promoter and armed with IL-15 in glioblastoma treatment, which may help in the development of novel therapies in solid tumors.

Chimeric antigen receptor T cells (CAR-T) therapy is a prospective therapeutic strategy for blood cancers tumor, especially leukemia, but it is not effective for solid tumors. Glioblastoma (GBM) is a highly immunosuppressive and deadly malignant tumor with poor responses to immunotherapies. Although CAR-T therapeutic strategies were used for glioma in preclinical trials, the current proliferation activity of CAR-T is not sufficient, and malignant glioma usually recruit immunosuppressive cells to form a tumor microenvironment that hinders CAR-T infiltration, depletes CAR-T, and impairs their efficacy. Moreover, specific environments such as hypoxia and nutritional deficiency can hinder the killing effect of CAR-T, limiting their therapeutic effect. The normal brain lack lymphocytes, but CAR-T usually can recognize specific antigens and regulate the tumor immune microenvironment to increase and decrease pro- and anti-inflammatory factors, respectively. This increases the number of T cells and ultimately enhances anti-tumor effects. CAR-T therapy has become an indispensable modality for glioma due to the specific tumor-associated antigens (TAAs). This review describes the characteristics of CAR-T specific antigen recognition and changing tumor immune microenvironment, as well as ongoing research into CAR-T therapy targeting TAAs in GBM and their potential clinical application.

Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs). In this study, the use of a herpes simplex virus carrying endostatin-angiostatin (VAE) as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a) VAE rapidly proliferated in GSCs and expressed endo-angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b) compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c) compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d) MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin-angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development.

Abstract   This paper investigates the problem of setting target finish times (due dates) for project activities with random durations. Using two-stage integer linear stochastic programming, target times are determined in the first stage followed by the development of a detailed project schedule in the second stage. The objective is to balance (1) the cost of project completion as a function of activity target times with (2) the expected penalty incurred by deviating from the specified values. It is shown that the results may be significantly different when deviations are considered, compared to when activities are scheduled as early as possible in the traditional way. For example, the optimal target completion time for a project may be greater than the makespan of the early-start schedules under any scenario. To find solutions, an exact algorithm is developed for the case without a budget constraint and is used as a part of a heuristic when crashing is permitted. All computational procedures are demonstrated on a set of 150 benchmark problems consisting of 90 activities each. [ABSTRACT FROM AUTHOR]

This paper considers the multimode resource-constrained project-scheduling problem (MRCPSP) with a minimum-makespan objective. An exact branch and cut algorithm is presented based on the integer linear programming (ILP) formulation of the problem. In the preprocessing stage, lower bounds on the distance between each pair of precedence-constrained activities are derived. These bounds are used to reduce the number of variables in the model and to generate cuts that tighten the linear programming relaxation. The solution process is accelerated by an adaptive branching scheme in conjunction with a bound-tightening scheme that is called iteratively after branching. To find good feasible solutions in the early stages of the computations, a high-level neighborhood search strategy known as local branching is included. Here, a neighborhood of a feasible solution is defined by the linear inequalities in the ILP model and is searched first. As implemented, the full algorithm is exact rather than heuristic in nature. Numerical results are reported for 20- and 30-activity benchmark problems. These are the largest instances available and are generally viewed to be notoriously difficult. Up until now, there were no confirmed optimal solutions for any of the 552 30-activity instances. We were able to find several better solutions and to show that at least 506 are optimal. [ABSTRACT FROM AUTHOR]

During the last 15 years, the regulatory framework for the wholesale sector of the electricity industry has been replaced in many countries by market competition. In such an environment, electric firms compete through both spot market bidding and bilateral contract trading. Firms have to consider their forward contract positions when they make spot market decisions. In this paper, we propose a linear asymmetric supply function equilibrium (SFE) model with transmission constraints to develop firms' optimal bidding strategies considering forward contracts. The characteristics of firms' behaviors are analyzed under the induced equilibrium conditions. The model is applied to the real-time energy market of the Electric Reliability Council of Texas (ERCOT). The effects of forward contracts on the ERCOT market are evaluated. It is shown that the model is able to capture features of bidding behaviors in the ERCOT market. [ABSTRACT FROM AUTHOR]