BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL), nasal-type, is a distinct entity of lymphoid tissue. ENKTL is sensitive to radiotherapy (RT), but the prognosis is poorer than for other types of early lymphoma. The treatment schedule is controversial. METHODS: A phase 2 study was conducted of ''sandwich'' protocols, with earlier RT after an initial 2 to 3 cycles of LVP (L-asparaginase, vincristine, and prednisone), followed by further ''consolidation'' cycles. Patients aged 18 years and older who had previously untreated ENKTL and localized lesions in the upper aerodigestive tract were enrolled. The primary endpoints were objective response rate and complete remission rate. The secondary endpoints were 2-year overall survival, 2-year progression-free survival, and toxicity. This study is registered with www.Chictr.org, number ChicTR-TNC-00000394, and is ongoing for long-term follow-up. RESULTS: Twenty-six patients completed total therapy, which resulted in 88.5% response that included 21 patients (80.8%) with complete response (CR) and 2 patients (7.7%) with partial response. Three (11.5%) of 26 patients progressed during therapy. With a median follow-up of 27 months (range, 4-35 months), the 2-year overall survival was 88.5%, and the 2-year progression-free survival was 80.6%. Patients with CR had better prognosis than patients without CR. Only 2 patients (7.7%) experienced grade 3 leukocytopenia. No grade 4 toxicity or treatment-related deaths were observed. CONCLUSIONS: The research showed that the ''sandwich'' protocol of LVP combined with RT was a safe and effective treatment for localized nasal natural killer/T-cell lymphoma, and the results warrant further investigation into this protocol. Cancer 2012;118:3294-

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BackgroundPrevious study demonstrated that miR-133a was released into blood from injured myocardium in cardiovascular diseases. However, the dynamic change of circulating miR-133a level in the early phase of acute myocardial infarction (AMI) and the correlation between miR-133a and severity of coronary stenosis in coronary heart disease (CHD) patients are not clear.Methods and resultsThree different cohorts (including 13 AMI patients, 176 angina pectoris patients and 127 control subjects) were enrolled to investigate the expression levels of circulating miR-133a in patients with myocardial ischemia and also the relationship between plasma miR-133a and severity of coronary stenosis. Plasma miR-133a levels of participants were examined by real-time quantitative PCR. Simultaneously, plasma cardiac troponin I (cTnI) concentrations were measured by ELISA assays. The results showed that circulating miR-133a level was significantly increased in AMI patients in time-dependent manner, and achieved a 72.1 fold peak at 21.6 ± 4.5 hours after the onset of AMI symptoms and exhibited a similar trend to plasma cTnI level. We also found that plasma miR-133a levels were higher in CHD patients than control group. Importantly, the levels of circulating miR-133a positively correlated with the severities of the coronary artery stenosis. Receiver operating characteristic (ROC) analysis revealed that circulating miR-133a had considerable diagnostic accuracy for CHD with an AUC of 0.918 (95% confidence interval 0.877-0.960).ConclusionsCirculating miR-133a may be a new biomarker for AMI and as a potential diagnostic tool. And increased miR-133a level may be used to predict both the presence and severity of coronary lesions in CHD patients.

BackgroundThere is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen injection (CKI), and its anti-HCC efficiency in combination with low-dose sorafenib.MethodsGrowth of two murine HCC cells was evaluated in an orthotopic model, a subcutaneous model, two postsurgical recurrence model, and a tumor rechallenge model with CKI and low-dose sorafenib combination treatment. In vivo macrophage or CD8+T cell depletion and in vitro primary cell coculture models were used to determine the regulation of CKI on macrophages and CD8+T cells.ResultsCKI significantly enhanced the anticancer activity of sorafenib at a subclinical dose with no obvious side effects. CKI and sorafenib combination treatment prevented the postsurgical recurrence and rechallenged tumor growth. Further, we showed that CKI activated proinflammatory responses and relieved immunosuppression of tumor-associated macrophages in the HCC microenvironment by triggering tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated NF-κB and p38 MAPK signaling cascades. CKI-primed macrophages significantly promoted the proliferation and the cytotoxic ability of CD8+T cells and decreased the exhaustion, which subsequently resulted in apoptosis of HCC cells.ConclusionsCKI acts on macrophages and CD8+T cells to reshape the immune microenvironment of HCC, which improves the therapeutic outcomes of low-dose sorafenib and avoids adverse chemotherapy effects. Our study shows that traditional Chinese medicines with immunomodulatory properties can potentiate chemotherapeutic drugs and provide a promising approach for HCC treatment.

BackgroundThe dysregulated expressions of circulating miRNAs have been detected in various cardiovascular diseases. In our previous experiments, the altered expressions of circulating miRNA-21-5p, miRNA-361-5p and miRNA-519e-5p were confirmed in patients with coronary atherosclerosis by miRNA microarrays. However, the expression levels of these circulating miRNAs in the early phase of acute myocardial infarction (AMI) are still unknown. In the present study, our aims were to examine the expressions of circulating miR-21-5p, miR-361-5p and miR-519e-5p in AMI patients, and assess their clinical applications for diagnosing and monitoring AMI.ResultsTwo different cohorts were enrolled in this study. The first cohort included 17 AMI patients and 28 healthy volunteers, and the second cohort included 9 AMI patients, 9 ischemic stroke patients, 8 patients with pulmonary embolism, and 12 healthy volunteers. Quantitative real-time PCR and ELISA assays were preformed to detect the concentrations of plasma miRNAs and cardiac troponin I (cTnI), respectively. The results showed that the plasma levels of miR-21-5p and miR-361-5p were significantly increased in AMI patients, whereas the concentration of circulating miR-519e-5p was reduced. Interestingly, the levels of these circulating miRNAs correlated with the concentrations of plasma cTnI. Receiver operating characteristic (ROC) analysis revealed that these three circulating miRNAs had considerable diagnostic accuracy for AMI with high values of area under ROC curve (AUC). Importantly, combining the three miRNAs significantly increased the diagnostic accuracy. Furthermore, cell experiments demonstrated that these plasma miRNAs may originate from injured cardiomyocytes induced by hypoxia. In addition, the levels of all the three circulating miRNAs in ischemic stroke (IS) and pulmonary embolism (PE) were elevated, whereas the decreased level of plasma miR-519e-5p was only detected in AMI. ROC analysis demonstrated that circulating miR-519e-5p may be a useful biomarker for distinguishing AMI from other ischemic diseases.ConclusionsCirculating miRNAs may be novel and powerful biomarkers for AMI and they could be potential diagnostic tool for AMI.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

Renal miR-214-3p plays a functional and potentially genetic role in the development of hypertension, which might be mediated in part by targeting eNOS.

The detrimental effects of oxidative stress on the skeletal system have been documented, and understanding the mechanisms is important to design a therapeutic strategy. As an antioxidant and anti-inflammatory agent, the active ingredient of turmeric curcumin has been used as medication for numerous complications including bone loss. However, it is unclear if curcumin could influence the osteogenic potential of mesenchymal stem cells (MSCs), particularly in oxidative injuries. Here we demonstrate that curcumin treatment protects cell death caused by hydrogen peroxide (HO) exposure in human adipose-derived MSCs in vitro. Importantly, curcumin is able to enhance the osteoblast differentiation of human adipose-derived MSCs that is inhibited by HO. Notably, both oxidative stress and the inhibition of Wnt/β-catenin signaling are attenuated by curcumin treatment. These results suggest that curcumin can promote osteoblast differentiation of MSCs and protect the inhibitory effect elicited by oxidative injury. The findings support potential use of curcumin or related antioxidants in MSC-based bone regeneration for disease related with oxidative stress-induced bone loss.