Purpose The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the ...Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments. Methods All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were included. Treatments were grouped into seven categories: RT alone (RT), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). P-score was used to rank the treatments. Fixed- and random-effects frequentist network meta-analysis models were applied. Results The three treatments with the highest probability of benefit on overall survival (OS) were CRT-AC, followed by CRT and IC-CRT, with respective hazard ratios (HRs 95% CIs) compared with RT alone of 0.65 (0.56 to 0.75), 0.77 (0.64 to 0.92), and 0.81 (0.63 to 1.04). HRs (95% CIs) of CRT-AC compared with CRT for OS, progression-free survival (PFS), locoregional control, and distant control (DC) were, respectively, 0.85 (0.68 to 1.05), 0.81 (0.66 to 0.98), 0.70 (0.48 to 1.02), and 0.87 (0.61 to 1.25). IC-CRT ranked second for PFS and the best for DC. CRT never ranked first. HRs of CRT compared with IC-CRT for OS, PFS, locoregional control, and DC were, respectively, 0.95 (0.72 to 1.25), 1.13 (0.88 to 1.46), 1.05 (0.70 to 1.59), and 1.55 (0.94 to 2.56). Regimens with more chemotherapy were associated with increased risk of acute toxicity. Conclusion The addition of AC to CRT achieved the highest survival benefit and consistent improvement for all end points. The addition of IC to CRT achieved the highest effect on DC.
Summary Background A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy ...to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy. Methods We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov , and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis. Findings We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2–11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio HR 0·79, 95% CI 0·73–0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5–9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56–0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70–0·93) but not adjuvant chemotherapy alone (0·87, 0·68–1·12) or induction chemotherapy alone (0·96, 0·80–1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69–0·81), locoregional control (0·73, 0·64–0·83), distant control (0·67, 0·59–0·75), and cancer mortality (0·76, 0·69–0·84). Interpretation Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed. Funding French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.
Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent ...infection. Both primary and recurrent infections can induce diseases, such as encephalitis. In humans, the majority of encephalitis cases occur as a recurrent infection. However, in the past, numerous mouse studies documented that viral reactivation occurs efficiently in the ganglion, but extremely rarely in the brain, when assessed ex vivo by cultivating minced tissue explants. Here, we compare the brains and the trigeminal ganglia of mice latently infected with HSV-1 (strain 294.1 or McKrae) for levels of viral genomes and in vivo reactivation. The numbers of copies of 294.1 and McKrae genomes in the brain stem were significantly greater than those in the trigeminal ganglion. Most importantly, 294.1 and McKrae reactivation was detected in the brain stems earlier than in the trigeminal ganglia of mice treated with hyperthermia to reactivate latent virus in vivo. In addition, the brain stem yielded reactivated virus at a high frequency compared with the trigeminal ganglion, especially in mice latently infected with 294.1 after hyperthermia treatment. These results provide evidence that recurrent brain infection can be induced by the reactivation of latent virus in the brain in situ.
Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. In the past, studies of viral reactivation focused on the ganglion, because efficient viral reactivation was detected in the ganglion but not in the brain when assessed ex vivo by cultivating mouse tissue explants. In this study, we report that the brain contains more viral genomes than the trigeminal ganglion in latently infected mice. Notably, the brain yields reactivated virus early and efficiently compared with the trigeminal ganglion after mice are stimulated to reactivate latent virus. Our findings raise the potential importance of HSV-1 latent infection and reactivation in the brain.
Five Polyporales mushrooms, namely Amauroderma rugosum, Ganoderma lucidum, G. resinaceum, G. sinense and Trametes versicolor, are commonly used in China for managing insomnia. However, their active ...components for this application are not fully understood, restricting their universal recognition.
In this study, we aimed to identify sedative-hypnotic compounds shared by these five Polyporales mushrooms.
A UPLC-Q-TOF-MS/MS-based untargeted metabolomics, including OPLS-DA (orthogonal projection of potential structure discriminant analysis) and OPLS (orthogonal projections to latent structures) analysis together with mouse assays, were used to identify the main sedative-hypnotic compounds shared by the five Polyporales mushrooms. A pentobarbital sodium-induced sleeping model was used to investigate the sedative-hypnotic effects of the five mushrooms and their sedative-hypnotic compounds.
Ninety-two shared compounds in the five mushrooms were identified. Mouse assays showed that these mushrooms exerted sedative-hypnotic effects, with different potencies. Six triterpenes four ganoderic acids (B, C1, F and H) and two ganoderenic acids (A and D) were found to be the main sedative-hypnotic compounds shared by the five mushrooms.
We for the first time found that these six triterpenes contribute to the sedative-hypnotic ability of the five mushrooms. Our novel findings provide pharmacological and chemical justifications for the use of the five medicinal mushrooms in managing insomnia.
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Untargeted metabolomics identified sedative-hypnotic compounds shared by five medicinal Polyporales mushrooms.
The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest ...survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis.
For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524.
The network comprised 28 trials and included 8214 patients (6133 74·7% were men, 2073 25·2% were women, and eight 0·1% had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2–13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59–0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69–0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75–1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%).
The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma.
Institut National du Cancer and Ligue Nationale Contre le Cancer.
A tri-herb formulation comprising Ganoderma (the dried fruiting body of Ganoderma lucidum), Puerariae Thomsonii Radix (the dried root of Pueraria thomsonii) and Hoveniae Semen (the dried mature seed ...of Hovenia acerba) —GPH for short— has been using for treating liver injury; however, the pharmacological basis of this application of GPH is unknown. This study aimed to investigate the liver protective effects and mechanisms of action of an ethanolic extract of GPH (GPHE) in mice.
To control the quality of GPHE, the contents of ganodermanontriol, puerarin and kaempferol in the extract were quantified by ultra-performance liquid chromatography. An ethanol (6 ml/kg, i.g.)-induced liver injury ICR mouse model was employed to investigate the hepatoprotective effects of GPHE. RNA-sequencing analysis and bioassays were performed to reveal the mechanisms of action of GPHE.
The contents of ganodermanontriol, puerarin and kaempferol in GPHE were 0.0632%, 3.627% and 0.0149%, respectively. Daily i.g. administration of 0.25, 0.5 or 1 g/kg of GPHE for 15 consecutive days suppressed ethanol (6 ml/kg, i.g., at day 15)-induced upregulation of serum AST and ALT levels and improved histological conditions in mouse livers, indicating that GPHE protects mice from ethanol-induced liver injury. Mechanistically, GPHE downregulated the mRNA level of Dusp1 (encoding MKP1 protein, an inhibitor of the mitogen-activated protein kinases JNK, p38 and ERK), and upregulated expression and phosphorylation of JNK, p38 and ERK, which are involved in cell survival in mouse liver tissues. Also, GPHE increased PCNA (a cell proliferation marker) expression and reduced TUNEL-positive (apoptotic) cells in mouse livers.
GPHE protects against ethanol-induced liver injury, and this effect of GPHE is associated with regulation of the MKP1/MAPK pathway. This study provides pharmacological justifications for the use of GPH in treating liver injury, and suggests that GPHE has potential to be developed into a modern medication for managing liver injury.
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Enterovirus 71 (EV71) causes death and long-term neurologic sequelae in hundreds of thousands of young children, but its pathogenesis remains elusive. Dendritic cells (DCs) play a crucial role in ...antiviral immunity by functioning as professional antigen-presenting cells to prime T cells and by secreting cytokines to modulate immune responses. Here, we show that EV71 productively infected human immature DCs and expressed viral antigen in DCs. EV71 entry into DCs was partially mediated by DC-SIGN. Further analyses revealed that EV71 increased the viability, activation, release of cytokines, interleukin-6, interleukin-12, and tumor necrosis factor-alpha in DCs. Moreover, EV71 enabled DCs to stimulate T-cell proliferation. Collectively, these findings suggest that EV71 infection of human DCs in vivo is very likely to elicit protective immunity, because in infected mice, both T cells and IL-6 function to reduce mortality.
Borderline personality disorder (BPD) features with affective instability and impulsivity have been shown to correlate with Internet addiction (IA) in cross-sectional studies. Moreover, Internet use ...expectancies were found to be positively associated with IA. Thus, this follow-up study was aimed to examine whether BPD features would increase the risk for IA severity, mediated through the Internet use expectation as a coping method for tension reduction and disinhibition.
1826 Taiwan college students were sampled through a stratified and random clustering in time 1 (T1), and 623 students were followed up one year later (T2). A comprehensive survey was administered.
Structure equation modeling results showed that IA severity (T2) was significantly predicted by BPD features (T1), fully mediated through Internet use expectancy for tension reduction and disinhibition (T2). The model yielded an adequate fit, and was able to explain 43.0% of the variance.
The mediating role of the Internet use expectation for tension reduction and disinhibition in the relationship between BPD features and IA severity were discussed.
•BPD features (T1) was significantly correlated with IA severity (T2).•BPD features (T1) was significantly correlated with IUETRD (T2).•Internet use expectancy fully mediated the relationship between BPD (T1) and IA (T2).
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