Low-frequency repetitive transcranial magnetic stimulation alleviates abnormal behavior in valproic acid rat model of autism through rescuing synaptic plasticity and inhibiting neuroinflammation.

Autism is a complex neurodevelopmental disorder with no effective treatment available currently. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising neuromodulation technique to treat autism. However, the mechanism how rTMS works remains unclear, which restrict the clinical application of magnetic stimulation in the autism treatment. In this study, we investigated the effect of low-frequency rTMS on the autistic-like symptoms and explored if this neuroprotective effect was associated with synaptic plasticity and neuroinflammation in the hippocampus. A rat model of autism was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats and male offspring were treated with 1 Hz rTMS daily for two weeks continuously. Behavior tests were performed to identify behavioral abnormality. Synaptic plasticity was measured by in vivo electrophysiological recording and Golgi-Cox staining. Synapse and inflammation associated proteins were detected by immunofluorescence and Western blot analyses. Results showed prenatal VPA-exposed rats exhibited autistic-like and anxiety-like behaviors, and cognitive impairment. Synaptic plasticity deficits and the abnormality expression of synapse-associated proteins were found in the hippocampus of prenatal VPA-exposed rats. Prenatal VPA exposure increased the level of inflammation cytokines and promoted the excessive activation of microglia. rTMS significantly alleviated the prenatal VPA-induced abnormalities including behavioral and synaptic plasticity deficits, and excessive neuroinflammation. TMS maybe a potential strategy for autism therapy via rescuing synaptic plasticity and inhibiting neuroinflammation.

Free radicals removing extracellular polymeric substances to enhance the degradation of intracellular antibiotic resistance genes in multi-resistant Pseudomonas Putida by UV/H2O2 and UV/peroxydisulfate disinfection processes.

UV-based advanced oxidation processes (UV-AOPs) have been recommended to disinfect wastewater treatment plant (WWTP) effluents to control the dissemination of antibiotic resistance, but the mechanism of intracellular antibiotic resistance genes (i-ARGs) degradation by UV-AOPs is still poorly understood. Here we compared the efficacies of UV, UV/H2O2, and UV/PDS in degrading seven i-ARGs carried by a multi-drug resistant P. putida MX-2 isolated from sewage sludge and investigated the roles of free radicals and UV irradiation in degrading the carried i-ARGs in UV-AOPs. The results suggested that although UV/H2O2 and UV/PDS were only slightly superior to UV to inactivate P. putida MX-2, they significantly promoted the degradation of i-ARGs. The generated free radicals mainly reacted with the bacterial extracellular polymeric substances (EPS), increased the cell membrane permeability of bacteria, and consequently facilitated UV irradiation enter into the intracellular environment to damage the i-ARGs, thus enhancing their degradation during UV-AOPs processes. Our findings suggested that the removal of bacterial EPS by free radicals greatly contributed to the degradation of i-ARGs by UV irradiation in UV-AOPs, and more efficient approaches that are capable of removing EPS should be further developed to effectively control the dissemination of antibiotic resistance by UV treatment of wastewater effluent.

A Propensity-Matched Analysis of Survival of Clinically Diagnosed Early-Stage Lung Cancer and Biopsy-Proven Early-Stage Non-Small Cell Lung Cancer Following Stereotactic Ablative Radiotherapy.

PURPOSE: Stereotactic body radiotherapy (SBRT) has been increasingly regarded as a reasonable option for early-stage lung cancer patients without pretreatment pathologic results, but the efficacy and safety in a Chinese population remains unclear. The aim of this study was to compare survival outcomes and toxicities between patients with clinically diagnosed early-stage lung cancer or biopsy-proven early-stage non-small cell lung cancer and to demonstrate the rationality of this treatment. MATERIAL AND METHODS: From May 2012 to December 2018, 56 patients with clinically diagnosed early-stage lung cancer and 60 patients with early-stage biopsy-proven were selected into non-pathological group and pathological group, respectively. Propensity score matching (PSM) was performed to reduce patient selection bias. Survival analysis with log-rank test was used to assess the differences of treatment outcomes, which included local control (LC), progression-free survival (PFS), and overall survival (OS). RESULTS: The median age was 76 (range 47-93) years, and the median follow-up time was 58.3 (range 4.3-95.1) months in the cohort without pathologic results. The median age was 74 (range 57-88) years, and the median follow-up time was 56.3 (range 2.6-94) months in the cohort with pathologic results. 45 matched-pair were analyzed. The 5-year LC, PFS, and OS rates in matched-pair patients with or without pathologic biopsy were 85.5% and 89.8%, 40.6% and 70.9%, and 63.2% and 76.1%, respectively. On Kaplan-Meier survival analysis after PSM analysis, there was no significant difference between patients with pathologic results versus patients with no pathologic results in terms of LC (P= 0.498) and OS (P=0.141). Of the matched-pair patients treated with SBRT, only 1 patient experienced grade 3 or above radiation pneumonitis. CONCLUSION: For early-stage lung cancer patients with medically inoperable or not suitable for invasive diagnosis, SBRT may be a good local treatment.

Application of a radiation pneumonitis prediction model in patients with locally advanced lung squamous cell cancer.

BACKGROUND: The aim of the present study was to establish a new prediction model for radiation pneumonitis (RP) in locally advanced non-small cell lung cancer (LA-NSCLC) patients before and after radiotherapy. METHODS: The study involved 153 patients. Age, arterial partial oxygen pressure (PO2), forced vital capacity, pulmonary emphysema (PE), subclinical interstitial lung disease (sILD), and dosimetric parameters, such as mean lung dose and percentage of lung volume, and a dose >5/20 Gy (V5/V20), were considered candidate RP predictors. RESULTS: Of the 153 eligible patients, 33 (21.6%) developed RP, 68 had PE (43.8%), and 24 (15.7%) had sILD. Grades 2, 3, and 5 RP were scored in 17 (11.1%), 15 (9.8%), and 1 (0.7%) patient/s, Grade 4 RP was not observed. Grades 1, 2, and 3 PE were scored in 45 (29.4%), 22 (14.4%), and 1 (0.7%) patient/s. Grades 0 and 1 sILD were observed in 129 (84.3%) and 24 (15.7%) patients. Univariate analysis found age, PE, and sILD to be significantly correlated with grade ≥2 RP. Multivariate analysis revealed age >68 years, PE grade >1, and sILD grade ≥1 as independent risk factor for grade ≥2 RP in LA-NSCLC with squamous cell carcinoma (SCC). Finally, a new predictive risk score (PRS) comprised of these factors was developed. The PRS score was 0, 3-5, and 6-11 when the cumulative incidence of grade ≥2 RP was 8.8% (5 patients), 13% (3 patients), and 84.6% (13 patients) (P=<0.001). CONCLUSIONS: Age, PE, and sILD could independently and significantly predict RP in LA-NSCLC with SCC.

Risk factors for radiation pneumonitis in lung cancer patients with subclinical interstitial lung disease after thoracic radiation therapy.

BACKGROUND: Previous studies have found that patients with subclinical interstitial lung disease (ILD) are highly susceptible to developing radiation pneumonitis (RP) after thoracic radiation therapy. In the present study we aimed to evaluate the incidence of and risk factors for RP after thoracic intensity-modulated radiation therapy in lung cancer patients with subclinical ILD. METHODS: We retrospectively analyzed data from lung cancer patients with subclinical ILD who were treated with thoracic intensity-modulated radiation therapy with a prescribed dose of ≥ 50 Gy in our institution between January 2016 and December 2017. RESULTS: Eighty-seven consecutive lung cancer patients with subclinical ILD were selected for the study. The median follow-up period was 14.0 months. The cumulative incidence of grades ≥ 2 and ≥ 3 RP at one year was 51.0% and 20.9%, respectively. In the multivariate analysis, a mean lung dose ≥ 12 Gy was a significant risk factor for grade ≥ 2 RP (p = 0.049). Chemotherapy with gemcitabine in the past, V5 ≥ 50%, and subclinical ILD involving ≥ 25% of the lung volume were significantly associated with grade ≥ 3 RP (p = 0.046, p = 0.040, and p = 0.024, respectively). CONCLUSION: Mean lung dose is a significant risk factor for grade ≥ 2 RP. Lung cancer patients who have received chemotherapy with gemcitabine in the past, V5 ≥ 50%, and those with subclinical ILD involving ≥ 25% of lung volume have an increased risk of grade ≥ 3 RP in lung cancer patients with subclinical ILD.

miR-338-5p inhibits cell growth and migration via inhibition of the METTL3/m6A/c-Myc pathway in lung cancer.

Lung cancer is a common type of cancer that causes a very large public health burden worldwide. Achieving a better understanding of the molecular mechanism underlying the progression of lung cancer is of benefit for the diagnosis, prognosis, and treatment of lung cancer. Here, we first identified dramatically decreased expression of miR-338-5p in lung cancer tissues and cells using quantitative polymerase chain reaction (qPCR) analysis. We then revealed that miR-338-5p inhibited the cell growth and migration of lung cancer cells using cell counting kit 8 (CCK8), EdU, and Transwell analysis. Furthermore, we demonstrated that miR-338-5p inhibited METTL3 expression by qPCR, western blot analysis, and luciferase reporter assay, while upregulation of METTL3 alleviated the role of miR-338-5p in lung cancer cells. We also showed that METTL3 promoted c-Myc expression by increasing the m6A modification of c-Myc, and overexpression of c-Myc restored the inhibition of cell growth and migration of lung cancer cells induced by METTL3 silencing. Ultimately, this research illustrated that modification of the miR-338-5p/METTL3/c-Myc pathway affected cellular progression in lung cancer cells. Collectively, our study revealed the underlying mechanism of miR-338-5p in lung cancer, providing a novel regulatory pathway in lung cancer. There is potential for this pathway to serve as a diagnostic, prognostic, and therapeutic biomarker for lung cancer.

Prenatal stress impairs memory function in the early development of male-offspring associated with the gaba function.

Prenatal stress (PS) induces cognitive deficits, abnormal behavior patterns and physical impairments in offspring, which disturbs the developmental process. GABA systems play a key role in the brain development. The developmental trajectories are less understood although PS increases the expression of GABAAR in young offspring. In the present study, we aimed to examine if the long-lasting effects on memory function and hippocampal synaptic plasticity induced by PS were associated with the GABA function throughout developmental process. Thus, a PS rat model was established by using restraint stress three 45-min periods per day from gestational day 15 until delivery. PS-exposed offspring exhibited the memory function deficits, LTP and depotentiation inhibitions in young and puberty offspring, but the disorder resolved at adult offspring. Meanwhile, the hippocampal spine density was decreased by PS in offspring. Additionally, we found that the balance of excitatory and inhibitory receptors was significantly disturbed after PS. The immunostaining of parvalbumin level was increased in the PS group. Overall, these all results suggest that the PS induces negative effects in memory and hippocampal synaptic plasticity in the early developmental stage, which could be an underlying mechanism of the disturbed GABA function.

Carbon emissions in the transportation sector of Yangtze River Economic Belt: decoupling drivers and inequality.

Carbon emissions in the transportation sector are of great concern, since they are the third leading contributor to China's carbon emissions. This research examines the decoupling relationship between economic outputs and carbon emissions of 11 provinces in 2000-2016 by focusing on Yangtze River Economic Belt (YREB), which is the densest traffic and economic corridor in China. Although many studies have focused on the decoupling state and its driving forces between economic outputs and carbon emissions, few studies further addressed the microscale analysis for decoupling drivers. This paper reveals the characteristic, inequality contribution ratio, and dynamic evolution of the drivers by integrating Dagum's Gini ratio with kernel density estimation in YREB. Results are as follows: (1) The decoupling states presented weak decoupling state at the whole belt in the majority of the latter observed sub-periods. The decoupling states at the provincial level turned more satisfactory during the four observed sub-periods, especially for Shanghai and Zhejiang. (2) The energy intensity (EI) effect is the predominant driver for promoting the decoupling state in the vast majority of provinces, whereas value added per capita effect is the major role for inhibiting the decoupling state. (3) During the four observed sub-periods, the Gini inequality and transvariation intensity of the EI effect between sub-regions are the main sources of the provincial differences in YREB. The driving force of EI effect is increasing, but the provincial differences are expanding in the upstream and downstream regions by analyzing its dynamic evolution. Understanding the temporal and spatial microscale inequality of the decoupling drivers provides governments with differentiated and forward-looking suggestions towards coordinating regional economic growth and carbon emissions reduction.

Inhibitory effects of Dulcitol on rat C6 glioma by regulating autophagy pathway.

In the study, we treated C6 rat glioma cells with 25 mg/ml Dulcitol for 24 h. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to detect cellular growth. The measurements of the superoxide dismutase (SOD), malondialdehyde (MDA) and catalase (CAT) were used to assess oxidative stress level. Western was performed to detect the autophagy and apoptosis expression. The data showed that Dulcitol significantly decreased the cell viability, upregulated the Bax level in mitochondria and the Cytochrome C level in cytoplasm, and downregulated anti-apoptotic protein Bcl-xl. Moreover, it enhanced MDA level, reduced CAT and SOD activities, decreased LC3-II/LC3-I ratio, and increased P62 expression. However, rapamycin increased autophagy level and cell viability, and decreased ROS in Dulcitol treated C6 cells. Moreover, Dulcitol inhibited the glioma growth and enhanced survival in vivo. These results suggest that Dulcitol evidently increase cellular ROS levels and apoptosis in glioma cells, which can be significantly regulated by autophagy.

Anti-inflammatory treatment with ß-asarone improves impairments in social interaction and cognition in MK-801 treated mice.

The aim of this study investigates whether ß-asarone can improve cognition deficits in dizocilpine (MK-801) treated mice. Six-week-old male C57BL/6 mice were divided into four groups: control group (CON), MK-801-treated group (MK-801), MK-801 plus ß-asarone group (MK-801+ß-asa) and ß-asarone group (ß-asa). Behavioral tests, including sociability test, open field test (OPT) and Morris water-maze (MWM), were performed. Extracellular field excitatory postsynaptic potentials were recorded in the hippocampal dentate gyrus (DG) region. Western blot was employed to measure the expression of cognitive function-associated proteins and pro-inflammatory cytokines in the hippocampus. Immunofluorescence was performed to assess the microglial activation in the hippocampus DG region. The data show that social interactions and spatial learning and memory were impaired by MK-801. However, ß-asarone significantly mitigated the impairments. Furthermore, it was found that MK-801 aggravated the hyperactivity and anxiety-like behavior, but ß-asarone alleviated them. Moreover, ß-asarone alleviated the impairments of hippocampal synaptic plasticity and enhanced the expression of hippocampal synaptophysin (SYP) and postsynaptic density protein 95 (PSD95) in MK-801-treated mice. In addition, it suppressed the expression of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (i-Nos) and cyclo-oxygenase-2 (COX-2) expression in MK-801-treated mice. The results suggest that ß-asarone improved the impairment of cognition and synaptic plasticity possibly through modulating the excess release of pro-inflammatory cytokines and microglia activation in MK-801-treated mice.

rTMS Ameliorates Prenatal Stress-Induced Cognitive Deficits in Male-Offspring Rats Associated With BDNF/TrkB Signaling Pathway.

BACKGROUND: Growing evidences suggest that brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) plays a key role in the regulation of hippocampal synaptic plasticity in a prenatal stress (PNS) rat model. Repetitive transcranial magnetic stimulation (rTMS) is currently being acknowledged to affect attention and memory in both preclinical and clinical studies, although the mechanism is still unclear. OBJECTIVE: The current study aimed to explore whether a whole brain rTMS (5 Hz, 14 days) could ameliorate cognitive dysfunction-induced PNS in male offspring, and examine if the positive effect of rTMS was associated with the BDNF/TrkB signaling in the hippocampus. METHODS: The rats were randomly divided into 5 groups: CON, PNS, PNS + rTMS, PNS + rTMS + DMSO (dimethyl sulfoxide), and PNS + rTMS + K252a. Spatial cognition was evaluated by using Morris water maze test. Following behavioral assessment, both paired-pulse facilitation and long-term potentiation were recorded from Schaffer collaterals to CA1 region in the hippocampus. Synaptic, apoptotic, and BDNF/TrkB signaling proteins were measured by Western blot. RESULTS: PNS-exposed offspring exhibited cognitive deficits, long-term potentiation inhibition in the hippocampus, the decrease of synaptic and BDNF/TrkB signaling proteins expression, apoptosis, and reduced number of cells in the CA1 region. Five-hertz rTMS significantly alleviated the PNS-induced abnormalities. However, the effect of rTMS was antagonized by intracerebroventricular infusion of K252a (a TrkB inhibitor). CONCLUSIONS: The findings suggest that 5-Hz rTMS significantly improves the impairment of spatial cognition and hippocampal synaptic plasticity, which is possibly associated with the activation of BDNF/TrkB signaling.

Preexisting radiological interstitial lung abnormalities are a risk factor for severe radiation pneumonitis in patients with small-cell lung cancer after thoracic radiation therapy.

BACKGROUND: Previous studies reported that patients with preexisting radiological interstitial lung abnormalities (ILAs) were more susceptible to developing radiation pneumonitis (RP) after thoracic radiation therapy (TRT). The present study aimed to evaluate the incidence and predictors of RP after TRT in patients with small-cell lung cancer (SCLC) with or without preexisting radiological ILAs. METHODS: A total of 95 consecutive patients with SCLC between January 2015 and December 2015, who were treated with thoracic intensity-modulated radiation therapy at Shanghai Pulmonary Hospital,Tongji University School of Medicine, were analyzed. The diagnosis of ILAs was reviewed by two experienced thoracic radiologists based on the pretreatment high-resolution computed tomography imaging, such as honeycombing, subpleural reticular opacities, ground-glass opacity, and traction bronchiectasis. Univariate and multivariate analyses were used to assess the correlation of clinical factors, preexisting radiological ILAs, and dose-volume histogram-based dosimetric parameters with RP. RESULTS: Fifteen (15.8%) patients had preexisting radiological ILAs. The incidence of ≥ grade 2 and 3 RP at 1 year was 27.1% and 12.7% in the entire cohort, respectively. Preexisting radiological ILAs were associated with an increased risk of ≥grade 2 RP (50.0% in ILAs + vs 23.3% in ILAs-, P = 0.017) and ≥ grade 3 RP (35.8% in ILAs + vs 8.9% in ILAs-, P = 0.005) at 1 year. Preexisting radiological ILAs and smoking history (≥40 pack-years of smoking) were significant predictors of ≥grade 3 RP in multivariate analysis (P = 0.023 and 0.012, respectively). CONCLUSIONS: Preexisting radiological ILAs and smoking history (≥40 pack-years of smoking) are associated with an increased risk of ≥grade 3 RP after TRT in patients with SCLC.

Rapamycin relieves anxious emotion and synaptic plasticity deficits induced by hindlimb unloading in mice.

This study examined whether increasing autophagy could improve cognitive deficits in hindlimb unloaded (HU) mice, which was used as an animal model of synaptic plasticity impairment. Male C57BL/6 mice were randomly divided into three groups: control, HU and HU + rapamycin groups. Hindlimb unloading treatment was used to establish the animal model for 2 weeks. Rapamycin was intraperitoneally injected at a dose of 0.5 mg/kg/day along with hindlimb unloading procedure. The open field test and the elevated plus maze test showed that rapamycin considerably prevented the level of anxiety and increased exploratory behaviour in HU mice. Afterwards, long-term potentiation (LTP) recorded in the hippocampal dentate gyrus (DG) region was effectively reduced by rapamycin, which was significantly inhibited by HU procedure. In addition, rapamycin further increased the autophagy level, which was already elevated in HU mice. Meanwhile, the expression of NMDA receptor 2A and 2 B was modified by rapamycin in HU mice. Moreover, rapamycin noticeably increased the total superoxide dismutase (T-SOD) activity and reduced the malondialdehyde (MDA) as well as the level of carbonylated proteins in HU mice's hippocampus. The results show that increasing autophagy may pacificate the anxious emotion, and partly alleviate the hippocampal synaptic plasticity deficits.

[Observation of endovascular stent insertion for non-small cell lung cancer patients with superior vena cava syndrome].

OBJECTIVE: To evaluate the effectiveness and safety of endovascular stent insertion for non-small cell lung cancer patients with superior vena cava syndrome. METHODS: We retrospectively studied 123 patients referred to our hospital for the treatment of non-small cell lung cancer presenting with superior vena cava syndrome. Patients were devided in two groups according to the use of endovascular stent insertion in superior vena cava syndrome or not. 64 patients underwent endovascular stent insertion was designed as the stenting group and 59 without stenting as control group. The differences between the two groups in complete response, complication and survival were analyzed. RESULTS: The complete response rate of superior vena cava obstruction was 92.0% for the stenting group, and 42.0% for the control group, showing a significant difference between the two groups (P < 0.001). The median time to complete response was (3.76 ± 2.83) days in the stenting group, significantly shorter than that of the control group (28.08 ± 16.06) days (P < 0.001). The relapse rate after complete response was 12.0% in the stenting group and 16.0% in the control group, showing a non-significant difference between the two groups (P = 0.607). The median time to relapse was 2.7 months in the stenting group and 1.1 months in the control group (P = 0.533). In the stenting group, stent stenosis occurred in 1 case and thrombosis was observed in 3 cases. The incidence rate of complications was 6.3%. Thrombosis occurred in 1 case of the control group, with an incidence rate of complications of 1.7%, showing a non-significant difference between the two groups (P = 0.201). Seven among the 123 patients were still alive at the endpoint of following up. The median survival time was 8.0 months (stenting group) and 5.5 months (control group) (P = 0.382). CONCLUSIONS: Endovascular stent insertion is effective and safe for non-small lung cell cancer patients with superior vena cava syndrome, and it may be recommended as the first choice for palliative treatment of superior vena cava obstruction.