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Electroacupuncture (EA) is a clinically useful physiological therapy that has been recently adopted to treat several brain disorders. However, the potential role of early EA intervention in the prevention of posttraumatic stress disorder (PTSD) as well as its potential cellular and molecular mechanism has never been investigated previously. In the present study, we used an enhanced single prolonged stress (ESPS) model to access the effects of early EA intervention on the prevention of anxiety-like and fear learning behaviors, as well as the influence of the expression of post-synaptic density protein 95 (PSD95), synaptophysin (Syn), brain derived neurotrophic factor (BDNF), diacylglycerol lipase alpha (DAGLα) and cannabinoid type 1 receptor (CB1R) in the hippocampus with or without DAGLα or CB1R knockdown by a short hairpin RNA (shRNA) in the hippocampus. Moreover, the effects of electrical stimulation with different parameters on the expression of DAGLα and CB1R in the hippocampal astrocytes were also observed. The results showed that Early EA intervention improved hippocampal synaptic plasticity and ameliorated PTSD-like behaviors and also increased expression of BDNF, DAGLα and CB1R. However, either DAGLα or CB1R knockdown by a short hairpin RNA (shRNA) eliminated the neuroprotective effects of early EA intervention. Furthermore, electrical stimulation with 2/15 Hz 1 mA elevated the expression of DAGLα and CB1R. Altogether, our findings provide new insights regarding the possibility of using early EA intervention in the prevention of PTSD, and the protective effects of EA is involving the activation of DAGLα and CB1R.

The antipsychotic effect of Quetiapine (Que) has been extensively studied and growing evidence suggests that Que has a beneficial effect, improving cognitive functions and promoting myelin repair. However, the effects of Que on the brain lipidome and the association between Que-associated cognitive improvement and changes in lipids remain elusive. In the present study, we assessed the cognitive protective effects of Que treatment and used a mass spectrometry-based lipidomic approach to evaluated changes in lipid composition in the hippocampus, prefrontal cortex (PFC), and striatum in a mouse model of cuprizone (CPZ)-induced demyelination. CPZ induces cognitive impairment and remarkable lipid changes in the brain, specifically in lipid species of glycerophospholipids and sphingolipids. Moreover, the changes in lipid classes of the PFC were more extensive than those observed in the hippocampus and striatum. Notably, Que treatment ameliorated cuprizone-induced cognitive impairment and partly normalized CPZ-induced lipid changes. Taken together, our data suggest that Que may rescue cognitive behavioral changes from CPZ-induced demyelination through modulation of the brain lipidome, providing new insights into the pharmacological mechanism of Que for schizophrenia.

Background The association between abnormal gut microbiome composition and depression is well established. However, the composition and functional capacity of the gut microbiota regarding depressed women has been poorly addressed. Methods Stool samples from 62 female patients with major depressive disorder (MDD) and 46 healthy controls (Con) were analyzed by 16S rRNA gene sequencing; Twenty fecal samples from the patient group and 21 fecal samples from the Con group were further analyzed by shotgun metagenomic sequencing. Psychiatric symptoms and psychological, social, and professional functioning was also assessed. Results Phylum Bacteroidetes, proteobaeteria, and Fusobacteria were greatly enriched in patients with MDD, while the Firmicutes and Actinobacteria phyla were consistently higher in Con. Notably, 18 microbial markers were identified on a random forest model and achieve an area under the curve of 0.92 between patients with MDD and the Con group. Forty-five species and their associated function were identified with statistically significant differences between patients with MDD and the Con group. Limitations The number of recruited samples, especially samples enrolled for shotgun metagenomic sequencing was relatively small, and the stool samples were collected only at baseline, making it difficult to establish a causal association between changes in gut microbiota compositions and disease remission. Conclusions This study characterizes the gut microbiota and their related function in female MDD. The gut microbiota-based biomarkers may be helpful in diagnosis and the altered gut microbial metabolites may contribute to the pathogenesis of MDD in women, representing potential microbial targets.

Purpose: This study aims to investigate the prognostic value and dosimetric impact of paranasal sinus invasion (PSI) in patients with nasopharyngeal carcinoma (NPC), and further to explore the feasibility of an integrative prognostic model based on anatomic, volumetric, and dosimetric features.Methods: Two hundred six patients with T3 NPC receiving intensity-modulated radiation therapy (IMRT) were retrospectively analyzed. Dosimetric parameters were calculated from dose–volume histograms. Primary gross tumor volume (GTV-P) and dosimetric parameters were categorized using optimal cutpoints determined by R. Local recurrence-free survival (LRFS) was estimated using Kaplan–Meier method. Independent risk factors for LRFS were identified through univariable and multivariable analyses by Cox proportional hazards models.Results: The incidence of PSI was 10.7% (22/206). Patients with PSI had significantly inferior 5-year LRFS (77.3 vs. 93.8%, P = 0.006). IMRT plans for patients with PSI had larger dose heterogeneity, higher frequency of underdosing, and higher maximum dose to optic structures. When categorized by optimal cutpoints, GTV-P > 38.67 cm3 (5-year LRFS, 84.8 vs. 97.4%, P = 0.008), and V66.88 < 89.87% (5-year LRFS, 67.1 vs. 94.5%, P < 0.001) were associated with significantly worse local outcome. Multivariable analyses showed that PSI, GTV-P > 38.67 cm3, and V66.88 < 89.87% were independent risk factors for local relapse, either in patients with or without concurrent chemotherapy. An integrative prognostic model was then established upon the cumulative score of risk factors. Subgroups with score of 0, 1–2, and 3 had distinctive local outcomes; the 5-year LRFS was 96.6, 84.7, and 58.3%, respectively (P < 0.001).Conclusions: Paranasal sinus invasion jeopardized local control in T3 NPC patients due to large tumor burden and inadequate radiation dose in GTV-P. The presence of PSI, GTV-P, and radiation underdosing combined are critical for the risk stratification of local failure.

Epstein-Barr virus (EBV) is a B-lymphocytes herpes virus and can transform B lymphocytes to malignant tumor cells if infected. Nasopharyngeal carcinoma (NPC) is strongly associated with EBV. Circulating EBV DNA in plasma has been recognized as an important biomarker of NPC. Much work has been done to validate the ability of circulating EBV DNA for screening, diagnosis, risk stratification, monitoring, and predicting prognosis. This chapter reviews the clinical progress of circulating cell-free EBV DNA in NPC.

Objective To observe the local regression and control in T1‐2 nasopharyngeal carcinoma (NPC) patients treated with intensity‐modulated radiotherapy (IMRT) and to analyze the related influencing factors. Methods Between January 2006 and June 2014, 247 consecutive T1‐2 NPC patients treated with IMRT were retrospectively analyzed, with 126 (51.0%) N0‐1 disease and 121 (49.0%) N2‐3 disease. Among them, 72.9% received platinum‐based chemotherapy. The prescribed dose to gross tumor volume was 66 Gy/30 fractions. Results By the end of IMRT, the chemoradiotherapy (CRT) group had higher local complete response (CR) rate compared with IMRT alone group (92.2% vs 74.6%, P

Repetitive transcranial magnetic stimulation (rTMS) is a useful monotherapy for depression or adjunctive therapy for resistant depression. However, the anti-depressive effects of different parameters and the underlying mechanisms remain unclear. Here, we aimed to assess the effect of rTMS with different parameters (1/5/10 Hz, 0.84/1.26 T) on the depressive-like behaviors, 5-hydroxytryptamine (5-HT), 5-HIAA (5-hydroxyindoleacetic acid) and DA and NE levels, and monoamine oxidase A (MAO-A) activity in chronic unpredictable stress-treated rats, along with the expression of sirtuin 1 (Sirt1) and MAO-A in the prefrontal cortex (PFC) and cortex-derived astrocytes from new-born rats. Moreover, the depressive-like behaviors were monitored following the transcranial injection of the Sirt1 inhibitor EX527 (1 mM) daily for 1 week. We found that rTMS treatment (5/10 Hz, 0.84/1.26 T) ameliorated depressive-like behaviors, increased 5-HT, DA and NE levels, decreased the 5-HIAA level and Sirt1 and MAO-A expression, and reduced MAO-A activity in the PFC. The depressive-like behaviors were also ameliorated after the transcranial injection of EX527. Importantly, rTMS (5/10 Hz, 0.84/1.26 T) inhibited Sirt1 and MAO-A expressions in astrocytes and Sirt1 knockdown with short hairpin RNA decreased MAO-A expression in astrocytes. These results suggest that the inhibition of Sirt1/MAO-A expression in astrocytes in the PFC may contribute to the different anti-depressive effects of rTMS with different parameters, and may also provide a novel insight into the mechanisms underlying major depressive disorder.

Fen Xue,1,2 Chaosu Hu,1,2 Xiayun He1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China Purpose: A common problem in stage T3–4 nasopharyngeal carcinoma (NPC) is the narrow gap between the primary tumor and neurological structures, which makes dose optimization difficult. Considering that significant tumor shrinkage may occur during induction chemotherapy (IC), this study explored the efficacy of intensity-modulated radiotherapy (IMRT) using reduced gross tumor volume (GTV) in the treatment of T3–4 NPC.Patients and methods: Between January 2009 and April 2014, 103 patients with non-metastatic stage T3–4 NPC were prospectively recruited. They were assigned to accept IC, followed by reduced-volume IMRT and adjuvant chemotherapy. GTV was based on the post-IC volume of intracavity tumors and lymph nodes, and the pre-IC volume of the remaining involved structures.Results: For all treated patients, the 3-year local failure-free survival (LFFS) was 91.9%. After IC, 91 (88.3%) patients achieved local objective response (OR), and their 3-year LFFS rates were significantly better than in patients who failed to achieve local OR (94.1% vs 75.0%, P=0.023). A multivariate analysis demonstrated the prognostic value of tumor response to IC for LFFS. Dosimetric analysis showed good homogeneity, and the dose constraints were stringent. Asymptomatic temporal lobe necrosis in the ipsilateral side of tumor occurred in one patient.Conclusion: IMRT using a reduced GTV delineation delivered satisfactory doses to the target volumes and avoided overdosing of critical neurological structures. Results showed satisfactory survival outcomes with few treatment-related toxicities. Tumor response to IC could facilitate selection of patients with stage T3–4 NPC eligible for treatment with this method. Keywords: nasopharyngeal carcinoma, intensity-modulated radiotherapy, induction chemotherapy, target delineation

Neonatal isoflurane exposure in rodents disrupts hippocampal cognitive functions, including learning and memory, and astrocytes may have an important role in this process. However, the molecular mechanisms underlying this disruption are not fully understood. The present study investigated the role of TWIK‑related K+ channel (TREK‑1) in isoflurane‑induced cognitive impairment. Lentiviruses were used to overexpress or knockdown TREK‑1 in astrocytes exposed to increasing concentrations of isoflurane or O2 for 2 h. Subsequently, the mRNA and protein expression of brain‑derived neurotrophic factor (BDNF), caspase‑3, Bcl‑2‑associated X (Bax) and TREK‑1 was measured by reverse transcription‑ quantitative polymerase chain reaction and western blot analysis, respectively. In addition, cell viability was assessed by a 2‑(4‑Iodophenyl)‑3‑(4‑nitrophenyl)‑5‑(2,4‑disulfophenyl)‑ 2H‑tetrazolium monosodium salt assay. The results demonstrated that, prior to manipulating TREK‑1, isoflurane significantly decreased the cell viability and BDNF expression, and increased Bax, caspase‑3 and TREK‑1 expression was observed. However, TREK‑1 overexpression in astrocytes significantly downregulated BDNF expression, and upregulated Bax and caspase‑3 expression. Furthermore, lentiviral‑mediated short hairpin RNA knockdown of TREK‑1 effectively inhibited the isoflurane‑induced changes in BDNF, Bax and caspase‑3 expression. Taken together, the results of the present study indicate that isoflurane‑induced cell damage in astrocytes may be associated with TREK‑1‑mediated inhibition of BDNF and provide a reference for the safe use of isoflurane anesthesia in infants and children.

Purpose To analyze the long-term patterns of regional failure following intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). Methods From January 2005 to December 2010, 275 non-metastatic NPC patients treated with IMRT were retrospectively enrolled. Patients staged as II (lymph nodes measuring 4 or more cm in diameter), III or IV also received chemotherapy. Failures were assessed as in-field or out-field relative to the pretreatment planning computed tomography data sets. Univariate and multivariate analyses were performed with Cox proportional hazards model to analyze the effect of various prognostic factors on regional failure-free survival (RFFS) and overall survival (OS). Results During a median follow-up of 71 months, the RFFS and OS rates were 94.3% and 83.9%, respectively. Seventeen patients developed regional failures, of which 16 were in-field; one patient showed an out-field failure in the parotid gland, and no recurrences were seen for level Ib. Failures in level II and in the retropharyngeal area accounted for 70.6% (12/17) and 52.9% (9/17) of all failures, respectively. The 5-year RFFS rates for patients with classifications of N0-1 and N2-3 were 98.5% and 90.2%, respectively (p = 0.001). Multivariate analysis showed that N stage was the only independent prognostic predictor of RFFS (HR 7.363, 95% CI 1.516-35.756, p = 0.013). Conclusions The regional failure of NPC after treatment with IMRT is uncommon but is significantly higher in N2-3 patients than in N0-1 patients. In-field failures represent the main pattern of regional recurrence and are most often detected in level II and in the retropharyngeal area, while out-field failure is rare. Close attention should be directed to NPC patients with advanced N stages.

This study aimed to explore the prognostic value of extensive invasion of primary tumor volume for local control in patients with T3-4 NPC receiving intensity-modulated radiotherapy (IMRT).Between January 2009 and December 2015, initial volume of GTV-P, the confined and extensive invasion part of GTV-P (GTV-C and GTV-E) were obtained from 159 prospectively enrolled non-metastatic T3-4 NPC patients. GTV-E included the tumor with infiltration of bony structures at skull base, cervical vertebra, paranasal sinuses or with intracranial extension. GTV-C was calculated by the subtraction of GTV-E from GTV-P. The effects of tumor volume levels on local control rate (LC) were evaluated by Kaplan-Meier method and multivariate analysis.GTV-P (P = 0.015) and GTV-E (P = 0.001) were significantly correlated with local failure, while GTV-C (P = 0.494) was not. Then optimal cut-off values of GTV-P (43 mL) and GTV-E (22 mL) were determined by receiver operating characteristic curve analysis. Patients with small (22 mL) GTV-E achieved better 5-year LC rate than those with large (≥22 mL) GTV-E (96.3% vs.76.1%, P 0.001), but no significant difference was found between patients with small (43 mL) and large (≥43 mL) GTV-P (95.9% vs. 85.5%, P = 0.094). Multivariate analysis also demonstrated large (≥22 mL) GTV-E to be an independent unfavorable prognostic factor for LC (hazard ratio [HR], 3.805; 95% CI, 1.100-13.166; P = 0.035).GTV-E is an independent prognostic factor for LC in T3-4 NPC and may further assist in the optimization of treatment strategies.

To explore the temporal profile of the peripheral neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced nasopharyngeal carcinoma (LANPC) and the potential prognostic value of its dynamic changes.Complete blood count of 112 patients from a previous phase II study were retrospectively collected at the timepoints of the initiation of induction chemotherapy (pre-IC), within 1 week before radiotherapy started (pre-RT), and within 1 week after radiotherapy finished (post-RT). Data of 103 patients were fully recorded and Cox regression analysis was used to analyze the correlations of potential risk factors with 5‑year overall survival (OS). The performance of the prognostic factor was validated in another independent cohort of 103 matched (by T and N stage) patients selected from 236 consecutive NPC patients treated with IC and concurrent chemoradiation.Multivariate analysis (MVA) identified patient age50 years old (hazard ratio [HR] = 3.4, p = 0.02), weight loss during RT7.5% (HR = 3.2, p = 0.03), and post-RT peripheral NLR7.05 (vs. NLR ≤7.05, HR = 2.5, p = 0.04, 5‑year OS 71.4% vs. 87.8%) as unfavorable prognostic factors for OS. There was also a non-significant trend in the MVA that patients with post-RT peripheral NLR7.05 showed worse progression-free survival (PFS; HR = 1.9, p = 0.06, 5‑year PFS 64.1% vs. 81.8%). Post-RT NLR had a good prognostic performance in the validation cohort (concordance index = 0.73, standard error 0.10; p = 0.02, Wilcoxon test).Post-RT NLR is an independent prognostic factor for OS in LANPC patients. The dynamic change of the routinely tested inflammatory variable could help selection of appropriate treatment options and follow-up strategies.ZWECK: Untersuchung des zeitlichen Verlaufs der peripheren NLR („neutrophil-to-lymphocyte ratio“) bei Patienten mit lokal fortgeschrittenem Nasopharynxkarzinom (LANPC) und des potenziellen prognostischen Werts seiner dynamischen Veränderungen.Das vollständige Blutbild von 112 Patienten aus einer früheren Phase-II-Studie wurde zum Zeitpunkt des Beginns der Induktionschemotherapie (Pre-IC), innerhalb einer Woche vor Beginn der Strahlentherapie (Pre-RT) und innerhalb einer Woche nach beendeter Strahlentherapie (post-RT) retrospektiv erhoben. Die Daten von 103 Patienten wurden vollständig aufgezeichnet und die Cox-Regressionsanalyse wurde verwendet, um die Korrelationen des potenziellen Risikofaktors mit dem 5‑Jahres-Gesamtüberleben (OS) zu analysieren. Die Leistung des Prognosefaktors wurde in einer anderen unabhängigen Kohorte von 103 (nach T‑ und N‑Stadium) passenden Patienten validiert, die aus 236 konsekutiven NPC-Patienten ausgewählt wurden, die mit IC und gleichzeitiger Radiochemotherapie behandelt wurden.Die multivariate Analyse (MVA) identifizierte ein Patientenalter50 Jahre (Hazard Ratio [HR] = 3,4; p = 0,02), einen Gewichtsverlust während RT7,5% (HR = 3,2; p = 0,03) und eine periphere NLR nach RT7,05 (NLR ≤7,05; HR = 2,5; p = 0,04; 5‑Jahres-OS 71,4% vs. 87,8%) als ungünstige Prognosefaktoren für das OS. Es gab auch einen nichtsignifikanten Trend in der MVA, dass Patienten mit peripherer NLR nach RT7,05 ein schlechteres progressionsfreies Überleben (PFS) zeigten (HR = 1,9; p = 0,06; 5‑Jahres-PFS 64,1% vs. 81,8%). Post-RT-NLR zeigte eine gute Prognoseleistung in der Validierungskohorte (Konkordanzindex = 0,73, Standardfehler 0,10; p = 0,02, Wilcoxon-Test).Post-RT-NLR ist ein unabhängiger Prognosefaktor für das OS bei LANPC-Patienten. Die dynamische Änderung der routinemäßig getesteten entzündlichen Variablen könnte dazu beitragen, geeignete Behandlungsoptionen und Follow-up-Strategien zu entwickeln.

The anti-depressant effect of repetitive transcranial magnetic stimulation (rTMS), a clinically-useful treatment for depression, is associated with changes to the endocannabinoid system (ECS). However, it is currently unknown whether different frequencies of rTMS alter the ECS differently. To test this, rats exposed to chronic unpredictable stress (CUS) were treated with rTMS at two different frequencies (5 (high) or 1 Hz (low), 1.26 Tesla) for 7 consecutive days. Twenty-four hours after the final rTMS treatment, we evaluated depressive-like behaviors and the expression of several synaptic proteins and ECS-related proteins in the hippocampus. In addition, we knocked-down diacylglycerol lipase alpha (DAGLα) and cannabinoid type 1 receptor (CB1R), two important components of the ECS, and measured depressive-like behaviors and synaptic protein expression following rTMS. Furthermore, we measured the expression levels of several components of the ECS system in hippocampal-derived astrocytes and neurons exposed to repetitive magnetic stimulation (rMS) with different parameters (5 or 1 Hz, 0.84 or 1.26 Tesla). Interestingly, we found that only high-frequency rTMS ameliorated depressive-like behaviors and normalized the expression of hippocampal synaptic proteins in CUS-treated rats; this effect was eliminated by knockdown of DAGLα or CB1R. Moreover, we found that rMS at 5 Hz increased the expression of DAGLα and CB1R in hippocampal astrocytes and neurons. Collectively, our results suggest that high-frequency rTMS exerts its anti-depressant effect by up-regulating DAGLα and CB1R.

Electroacupuncture (EA) pretreatment is a clinically useful therapy for several brain disorders. However, whether and via which exact molecular mechanisms it ameliorates post-traumatic stress disorder (PTSD) remains unclear. In the present study, rats received EA stimulation for seven consecutive days before exposure to enhanced single prolonged stress (ESPS). Anxiety-like and fear learning behaviors; hippocampal neurogenesis; the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (keap1), and heme oxygenase 1 (HO-1); and the activity of AMP-activated kinase (AMPK) were evaluated at 14 days after ESPS. EA pretreatment improved hippocampal neurogenesis and ameliorated anxiety-like behaviors in ESPS-treated rats. EA pretreatment also increased the expression of Nrf2 and HO-1 and the activity of AMPK. Furthermore, Nrf2 knockdown by a short hairpin RNA affected anxiety-like behaviors and expression of neuroprotective markers (BDNF, DCX) in a manner similar to ESPS alone and dampened the neuroprotective effects of EA pretreatment. In contrast, Keap1 knockdown increased the expression of HO-1, improved hippocampal neurogenesis, and alleviated PTSD-like behaviors. Altogether, our results suggest that EA pretreatment ameliorates ESPS-induced anxiety-like behaviors and prevents hippocampal neurogenesis disruption in a rat model of PTSD possibly through regulation of the keap1/Nrf2 antioxidant defense pathway.

// Fen Xue 1 , Duanshu Li 2 , Chaosu Hu 1 , Zhuoying Wang 2 , Xiayun He 1 and Yi Wu 2 1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China Correspondence to: Xiayun He, email: // Yi Wu, email: // Keywords : unresectable poorly differentiated thyroid carcinoma; intensity modulated radiotherapy; chemotherapy; locoregional control; distant metastases Received : July 10, 2016 Accepted : October 13, 2016 Published : October 20, 2016 Abstract Poorly differentiated thyroid carcinoma (PDTC) is a rare and aggressive malignancy with high rates of invasion and distant metastasis. This study was to explore the ability of intensity-modulated radiotherapy (IMRT) combined with chemotherapy to manage unresectable PDTC. Between February 2011 and April 2012, 5 patients with unresectable PDTC were treated by IMRT at our institution and were included in this analysis. The median radiotherapy dose to the gross tumor volume (GTV) was 66 Gy/33 fractions/6.4 weeks. All patients received chemotherapy, and one patient with tumor compression symptoms had a tracheotomy before treatment. The mean survival time of the 5 patients was 41.6 months. The direct causes of death were distant metastases (40%) and progression of the locoregional disease (20%). In conclusion, IMRT combined with chemotherapy for unresectable PDTC might be beneficial to improve locoregional control. Further new therapies are needed to control metastases.

To compare the treatment outcomes between young and adult patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT).We conducted a retrospective case-matched analysis of all patients with non-metastatic NPC ≤20 years treated in our institution between January 2010 and July 2016. Adult patients ≥35 years treated over the same time period were included and matched at a ratio of 1:1 according to N classification, T classification, treatment modality, year of diagnosis, and gender. Survival outcomes and late toxicities were compared between the two groups.Overall 112 young patients with NPC were included, and 112 out of 3105 consecutive patients with NPC aged ≥35 years were matched. The 5-year overall survival (OS), progression-free survival, locoregional control and distant control of young and control cohorts were 89.1% vs. 79.3% (p = 0.03), 80.3% vs. 67.0% (p = 0.02), 96.4% vs. 84.3% (p 0.01), and 82.9% vs. 82.8% (p = 0.94), respectively. Multi-variate analysis showed that age ≤20 years was the only significant factor predicting for better OS (HR = 0.5, CI 0.3-0.97, p = 0.04). A trend of higher rate of hypothyroidism (grade 1-2) was observed in the young cohort (67.9% vs. 46.2%, p = 0.08).Young patients with NPC treated with modern multimodality therapy have better survival outcomes. Age was an independent favorable prognostic factor for NPC in the IMRT era. Further prospective studies are needed to establish optimal management for the young population to minimize and manage long-term side-effects without compromising survival.

The antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) has been extensively studied; growing evidence suggests that changes in lipid composition may be involved in the pathogenesis of depression and may be a targeted mechanism for treatment. However, the influence of rTMS on lipid composition and the differences between these effects compared to antidepressants like fluoxetine (Flx) have never been investigated. Using a chronic unpredictable stress (CUS) model in rats, we assessed the antidepressive effects of rTMS and Flx treatments and evaluated changes in lipid composition in the hippocampus and prefrontal cortex (PFC) using a mass spectrometry-based lipidomic approach. Both rTMS and Flx treatments ameliorated depressive-like behaviors induced by CUS. Moreover, changes in lipid composition, especially glycerophospholipids, sphingolipids, and glycerolipids induced by CUS in the hippocampus were more robust than those observed in the PFC. CUS led to decreased levels of 20 carbon-containing fatty acyls and polyunsaturated fatty acyls in the PFC, and decreased levels of acyl carnitines (AcCa) in both the hippocampus and PFC. Notably, rTMS treatment had higher impact than Flx on composition of glycerophospholipids and sphingolipids in the hippocampus that were altered by CUS, while Flx attenuated CUS-induced changes in the PFC to a greater extent than rTMS. However, neither was able to restore fatty acyls and AcCa to baseline levels. Altogether, modulation of the brain lipidome may be involved in the antidepressant action of rTMS and Flx, and the degree to which these treatments induce changes in lipid composition within the hippocampus and PFC might explain their differential antidepressant effects.

Computerized cognitive remediation therapy (CCRT) has been found to generally improve cognition among patients with schizophrenia, but its effect on functioning has not been extensively studied. This study addressed this gap in the literature by investigating the effect of CCRT and its long-term efficacy among community-dwelling patients with schizophrenia. 157 Chinese patients with schizophrenia were recruited from communities and randomized to CCRT (n = 78) or treatment as usual (TAU; n = 79) groups for 12 weeks with 4–5 sessions per week. Neurocognition, functioning, and symptoms of participants were assessed at baseline, after treatment, and at the 6 month follow-up. The CCRT group showed significantly greater improvements than the TAU group regarding the MATRICS Consensus Cognitive Battery (MCCB) total score and social cognition score. Significant cognitive benefits for functioning were observed (Personal and Social Performance scale, PSP). Moreover, improvement of the MCCB total score mediated a positive effect on functional capacity (UCSD Performance-based Skills Assessment, UPSA), and mediated decreases in negative symptoms across both groups. CCRT improved social functioning and general cognitive functioning among community-dwelling patients with schizophrenia. These improvements persisted for 6 months after treatment. CCRT also led to improvements in functioning and symptom severity by modulating cognitive functioning.

Background We aim to explore the relationship between minimum point dose (Dmin) to the primary gross tumor volume (GTV_P) and local control in treating T3-4 nasopharyngeal carcinoma (NPC). Methods Ninety-six non-metastatic T3-4 NPC patients were enrolled between January 2009 and November 2013. Intensity-modulated radiation therapy (IMRT) plus docetaxel, cisplatin and fluorouracil (TPF) chemotherapy was administered. The prescribed dose was 66-70.4 Gy to the GTV_P while maintaining all the critical neurologic organs within dose constraints. Results The local response rate was 88.6% after induction chemotherapy. With a median follow-up of 48.5 months, the 3-year local failure-free survival (LFFS) and overall survival (OS) rates were 92.4% and 89.6%, respectively. The average Dmin to the GTV_P was 59.4 Gy (range, 48.3-70.4 Gy). Additionally, 54.0 Gy was identified as the optimal cut-off Dmin to the GTV_P, and the Dmin ≥54.0 Gy group had a better local complete response rate after IMRT (52.4% vs. 81.3%, χ2 = 7.335, P = 0.007), a better 3-year LFFS (95.9% vs. 78.4%, P = 0.005) and a better OS (93.3% vs. 75.9%, P = 0.003). Furthermore, a multivariate analysis found the Dmin to the GTV_P ≥54.0 Gy to be prognostically important for LFFS and OS. One patient (1%) developed asymptomatic temporal lobe necrosis, but no other neurological dysfunctions were observed. Conclusions For T3-4-stage NPC treated with IMRT plus TPF chemotherapy, excellent local control with few late toxicities was achieved. A Dmin ≥54.0 Gy to the GTV_P may confer better local control. New ways to increase the Dmin to the GTV_P as far as possible without increasing late toxicities are urgently required.

Antipsychotic agents have been reported to promote hippocampal neurogenesis and improve cognitive deficits; yet, the molecular mechanisms underlying these actions remain unclear. In the present study, we used a murine model of schizophrenia induced by 5-day intraperitoneal injection with the non-competitive N-methyl-d-aspartate receptor antagonist MK801 (0.3mg/kg/day) to assess cognitive behavioral deficits, changes in Notch signaling, and cellular proliferation in the hippocampus of adult male C57BL/6 mice after 2-week administration of risperidone (Rip, 0.2mg/kg/day) or vehicle. We then utilized in vivo stereotaxic injections of a lentivirus expressing a short hairpin RNA (shRNA) for Notch1 into the dentate gyrus to examine the role of Notch1 in the observed actions of Rip. We found that Rip ameliorated cognitive deficits and restored cell proliferation in MK801-treated mice in a manner associated with the up-regulation of Notch signaling molecules, including Notch1, Hes1, and Hes5. Moreover, these effects were abolished by pretreatment with Notch1 shRNA. Our results suggest that the ability of Rip to improve cognitive function in schizophrenia is mediated in part by Notch signaling.

Background To protect neurological tissues, underdosing occurs in most cases of T4 nasopharyngeal carcinoma (NPC) with intracranial extension. In this study, we aimed to evaluate the effect of dosimetric inadequacy on local control and late neurological toxicities for patients treated with intensity-modulated radiotherapy (IMRT) plus chemotherapy. Methods We prospectively enrolled patients who had non-metastatic T4 NPC with intracranial extension treated between January 2009 and November 2013. The prescribed dose was 66.0–70.4 Gy to the primary planning target volume (primary gross tumor volume [GTVp; i.e., the nasopharyngeal tumor] + 5.0 mm). Dose–volume histogram parameters were calculated, including minimum point dose (Dmin) and dose to 95% of the target volume (D95). All patients received chemotherapy with the cisplatin, 5-fluorouracil, and docetaxel regimen. Survivals were estimated using the Kaplan–Meier method and compared using the log-rank test. Results In total, 41 patients were enrolled. The local partial response rate was 87.8% after induction chemotherapy. With a median follow-up of 51 months, 7 patients experienced failure in the nasopharynx; the 3-year local failure-free survival and overall survival rates of the 41 patients were 87.4% and 90.2%, respectively. The actual mean Dmin to the GTVp was 55.2 Gy (range 48.3–67.3 Gy), and D95 was 61.6 Gy (range 52.6–69.0 Gy). All doses received by neurological organs remained well within their dose constraints. No patients developed temporal lobe necrosis or other neurological dysfunctions. Conclusions With relative underdosed IMRT plus effective chemotherapy, the patients achieved satisfactory local control with few late toxicities of the central nervous system. Determining the acceptable extent of dosimetric inadequacy requires further exploration.

Sirtuin 1 (Sirt1) is a class III histone deacetylase involved in neuroprotection induced by hyperbaric oxygen preconditioning (HBO-PC) in animal models of ischemia. However, the underlying mechanisms remain to be illustrated. In the present study, rats exposed to middle cerebral artery occlusion (MCAO) were used to establish an ischemic stroke model. The infarct volume ratio, neurobehavioral score, and expressions of Sirt1, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and superoxide dismutase 1 (SOD1) were evaluated at 7 days after reperfusion, and the level of malondialdehyde (MDA) was used to assess oxidative stress. HBO-PC increased the expression of Sirt1 and reduced infarct volume ratio and neurobehavioral deficit in MCAO rats. Meanwhile, HBO-PC also increased expression of Nrf2, HO-1, and SOD1 and decreased MDA content. Furthermore, either Sirt1 or Nrf2 knockdown by short interfering RNA (siRNA) inhibited the expression of Nrf2, HO-1, and SOD1 and eliminated the neuroprotective effects of HBO-PC. Taken together, the results suggest that the Nrf2/antioxidant defense pathway is involved in the long lasting neuroprotective effects of Sirt1 induced by HBO-PC against transient focal cerebral ischemia.

Background: White matter disturbances and myelin impairment are key features of schizophrenia. The antipsychotic drug quetiapine can promote the maturation of oligodendrocytes, but the molecular mechanisms remain largely unknown. Methods: The schizophrenia-like behaviors, degrees of demyelination, and levels of Notch signaling molecules in forebrains of adult male C57BL/6 mice were examined after fed with cuprizone (0.2% wt/wt) in the presence or absence of 10mg/kg/d quetiapine for 6 weeks. These parameters were also observed after the transcranial injection of Notch signaling inhibitor MW167 (1mM) daily during the last week of the treatment period. Results: Quetiapine ameliorated the schizophrenia-like behaviors and decreased expression of myelin basic protein and inhibition of Notch signaling molecules, such as Notch1, Hes1, and Hes5, in the forebrain that induced by cuprizone. These beneficial effects of quetiapine were abolished by MW167. Conclusions: The antipsychotic and myelin protective effects of quetiapine are mediated by Notch signaling in a mouse model of cuprizone-induced demyelination associated with schizophrenia-like behaviors. The Notch pathway might therefore be a novel target for the development of antipsychotic drugs.