SummaryThe ketogenic diet (KD) is an effective treatment for children with drug‐resistant epilepsy and has been widely used in young children. Adult patients with intractable epilepsy would also benefit from this dietary treatment. However, only a few studies have been published, and the use of the KD in intractable epilepsy in adults has been limited. This meta‐analysis summarized the findings of the relevant published studies to identify the efficacy of the KD for the treatment of intractable epilepsy in adults. In this meta‐analysis, PubMed, Embase, and Cochrane Library were used for searching studies concerning the effects of the KD and its major subtypes with intractable epilepsy in adults published up to January 10, 2017. The primary outcomes were seizure freedom, seizure reduction by 50% or more, and seizure reduction by <50%. The quality of the methodology of the observational studies was reviewed by using the Newcastle‐Ottawa Scale. We identified 402 articles, of which, 16 studies including 338 patients met the inclusion criteria. The results of the meta‐analysis showed that the combined efficacy rates of all the symptoms of seizure freedom, seizure reduction by 50% or more, and seizure reduction below 50% in adults with intractable epilepsy were 13%, 53%, and 27%, respectively. The adverse reactions of the KD were mild, whereas low glycemic index diet (LGID) and low‐dose fish oil diet (LFOD) may have fewer side effects. Weight loss, high level of low‐density lipoprotein, and elevated total cholesterol were most frequent. The meta‐analysis indicates that the KD for refractory epilepsy in adults is a well‐tolerated treatment and that its side effects are acceptable, which show that the KD is a promising treatment in adult intractable epilepsy. Further research is needed to assess which type of diet or ratio is more effective in the KD treatment.

BackgroundSmall clinical trials have reported that low-frequency repetitive transcranial magnetic stimulation (rTMS) might improve language recovery in patients with aphasia after stroke. However, no systematic reviews or meta-analyses studies have investigated the effect of rTMS on aphasia. The objective of this study was to perform a meta-analysis of studies that explored the effects of low-frequency rTMS on aphasia in stroke patients.MethodsWe searched PubMed, CENTRAL, Embase, CINAHL, ScienceDirect, and Journals@Ovid for randomized controlled trials published between January 1965 and October 2013 using the keywords “aphasia OR language disorders OR anomia OR linguistic disorders AND repetitive transcranial magnetic stimulation OR rTMS”. We used fixed- and random-effects models to estimate the standardized mean difference (SMD) and a 95% CI for the language outcomes.ResultsSeven eligible studies involving 160 stroke patients were identified in this meta-analysis. A significant effect size of 1.26 was found for the language outcome severity of impairment (95% CI = 0.80 to 1.71) without heterogeneity (I2 = 0%, P = 0.44). Further analyses demonstrated prominent effects for the naming subtest (SMD = 0.52, 95% CI = 0.18 to 0.87), repetition (SMD = 0.54, 95% CI = 0.16 to 0.92), writing (SMD = 0.70, 95% CI = 0.19 to 1.22), and comprehension (the Token test: SMD = 0.58, 95% CI = 0.07 to 1.09) without heterogeneity (I2 = 0%). The SMD of AAT and BDAE comprehension subtests was 0.32 (95% CI = −0.08 to 0.72) with moderate heterogeneity (I2 = 32%,P = 0.22). The effect size did not change significantly even when any one trial was eliminated. None of the patients from the 7 included articles reported adverse effects from rTMS.ConclusionsLow-frequency rTMS with a 90% resting motor threshold that targets the triangular part of the right inferior frontal gyrus (IFG) has a positive effect on language recovery in patients with aphasia following stroke. Further well-designed studies with larger populations are required to ascertain the long-term effects of rTMS in aphasia treatment.

Purpose: By using cDNA microarray analysis, we identified a transcriptional factor, SOX6, was frequently downregulated in esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the role of SOX6 in human esophageal cancer development, and to examine the prevalence and clinical significance of SOX6 downregulation in ESCC.Experimental Design: Expressions of SOX6 mRNA in 50 ESCCs and SOX6 protein in 300 ESCCs were investigated by semiquantitative RT-PCR and immunohistochemistry, respectively. The tumor-suppressive function of SOX6 was characterized by cell growth, foci formation, wound-healing and cell invasive assays, and tumor xenograft experiment. Western blot analysis was applied to detect protein expression levels.Results: SOX6 was frequently downregulated in primary ESCCs in both mRNA level (29/50, 58%) and protein level (149/219, 68.0%), which was significantly associated with the poor differentiation (P ¼ 0.029), lymph node metastases (P ¼ 0.014), advanced TNM stage (P ¼ 0.000), and disease-specific survival (P < 0.001). Multivariate analysis indicated that the downregulation of SOX6 (P ¼ 0.000) was a significant independent prognostic factors for ESCC. Functional studies showed that SOX6 was able to suppress both in vitro and in vivo tumorigenic ability of ESCC cells. The tumor-suppressive mechanism of SOX6 was associated with its role in G1/S cell-cycle arrest by upregulating expressions of p53 and p21 WAF1/CIP1 and downregulating expressions of cyclin D1/CDK4, cyclin A, and b-catenin. Conclusions:We provided the first evidence that SOX6 is a novel tumor-suppressor gene in ESCC development and is a potential prognostic marker in ESCC.

BACKGROUND: PROCEED (), a large registry, evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled mCRPC patients receiving three biweekly sipuleucel-T infusions. Assessments included: overall survival (OS); serious adverse events (SAEs); cerebrovascular events (CVEs); and anticancer interventions (ACIs). Follow-up was ≥3 years, until death, or study withdrawal. RESULTS: 1976 patients (2011–2017) were followed for 46.6 months (median). Median age was 72 years and baseline median prostate-specific antigen was 15.0 ng/ml. 86.7% were Caucasians and 11.6% African American. 1902 patients had ≥1 sipuleucel-T infusion. Median OS was 30.7 (95% confidence interval [CI]: 28.6–32.2) months. Known prognostic factors were independently associated with OS on multivariable analysis. 1255 patients died, 964 (76.8%) from prostate cancer (PC) progression. Median time from first infusion to PC death was 42.7 (95% CI: 39.4–46.2) months. Incidence of sipuleucel-T-related SAEs was 3.9%. Incidence of CVEs was 2.8% and the rate per 100 person-years was 1.2 (95% CI: 0.9–1.6). CVE incidence among 11,972 mCRPC patients from the SEER-Medicare database was 2.8%; 1.5 [95% CI 1.4–1.7]/100 person-years. 77.7% of patients received ≥1 ACI (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium-223) after sipuleucel-T; 32.5% and 17.4% of patients experienced a 1- and 2-year treatment-free interval, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. Safety and tolerability of sipuleucel-T in PROCEED was consistent with previous findings.

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Period1 (PER1) is an important core clock gene, which regulates normal cell proliferations and physiological rhythms of human beings. Recent studies have showed aberrant expressions and altered rhythms of PER1 were highly correlated to the carcinogenesis and development of malignant tumors. However, there is no study on the correlation of aberrant expressions and altered rhythms of PER1 with the growth, proliferation and metastasis of buccal squamous cell carcinoma (BSCC). In this study, PER1 and MMP-2 expression in the cancerous and adjacent noncancerous tissues of 38 patients with BSCC and its correlations with patients' clinical pathologic characteristics were investigated. A mouse model of BSCC was also established and mice were sacrificed at 4 different time points in a period of 24 hours. Xenografted tumor weight, proliferation index (PI), and mitotic index (MI) of tumors in the 4 time groups were detected. Results showed that PER1 expression was significantly down-regulated in cancerous tissues of patients with BSCC (P<0.05). PER1 expression was significantly down-regulated in patients of T3∼T4 staging and those with lymph node metastasis compared to that of T1∼T2 staging and those without lymph node metastasis (P<0.05), respectively. PER1 mRNA expression, MI and tumor weight had significant differences among the 4 time groups, which PI all confirmed to circadian rhythms. MI, PI, MMP-2 mRNA and tumor weight had negative correlation with PER1 mRNA expression. Peak value of PER1 mRNA expression and trough values of MI, PI and tumor weight all appeared in middle activity phase, whereas trough value of PER1 mRNA expression and peak values of MI, PI and tumor weight all occurred in middle rest phase. Our study suggested that aberrant expression of PER1 had significant correlation with the growth, proliferation and metastasis of BSCC and it might act as an anti-oncogene.

Recent studies have demonstrated that abnormal expression of the clock gene PER2 is closely associated with the development of a variety of cancer types. However, the expression of PER2 in oral squamous cell carcinoma (OSCC), a common malignant tumor in humans, and its correlations with the clinicopathological parameters and survival time of OSCC patients and the altered expression of important tumor-related genes remain unclear. In the present study, we detected the mRNA and protein expression levels of PER2, PIK3CA, PTEN, P53, P14ARF and caspase‑8 in OSCC tissues and cancer-adjacent oral mucosa by reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The results showed that the PER2, PTEN, P53, P14ARF and caspase‑8 mRNA and protein expression levels in OSCC were significantly reduced compared with those in cancer-adjacent tissues. Additionally, the PIK3CA protein expression level was significantly increased in OSCC tissues, whereas the mRNA level was not. Decreased expression of PER2 was significantly associated with advanced clinical stage and the presence of lymphatic metastasis in OSCC patients. Patients with PER2‑negative expression had a significantly shorter survival time than those with PER2‑positive expression. PER2 expression was negatively correlated with PIK3CA and P53 levels, and positively correlated with PTEN, P14ARF and caspase‑8 levels. In summary, the results of this study suggest that loss of PER2 expression is closely associated with the genesis and development of OSCC and that PER2 may be an important prognostic biomarker in OSCC. PER2 may serve an antitumor role via the P53/P14ARF, PIK3CA/AKT and caspase‑8 pathways.

Previous studies have shown that the aberrant expression of period circadian clock 2 (Per2) is closely related to the occurrence and development of cancers, but the specific mechanism remains unclear. In the present study, we used shRNA to downregulate Per2 in oral squamous cell carcinoma (OSCC) Tca8113 cells, and then detected the alterations in cell cycle, cell proliferation and apoptosis by flow cytometric analysis and mRNA expression alterations in all the important genes in the cyclin/cyclin-dependent protein kinase (CDK)/cyclin-dependent kinase inhibitor (CKI) cell cycle network by RT-qPCR. We found that in the Tca8113 cells, after Per2 downregulation, the mRNA expression levels of cyclin A2, B1 and D1, CDK4, CDK6 and E2F1 were significantly increased (P<0.05), the mRNA expression levels of p53, p16 and p21 were significantly decreased (P<0.05), cell proliferation was significantly higher (P<0.05), apoptosis was significantly lower (P<0.05) and the number of cells in the G1/G0 phase was significantly decreased (P<0.05). The present study proves that in OSCC, clock gene Per2 plays an important role in cell cycle progression and the balance of cell proliferation and apoptosis by regulation of the cyclin/CDK/CKI cell cycle network. Further research on Per2 may provide a new effective molecular target for cancer treatments.