Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an effective chemotherapeutic agent that specifically impairs cancer cells while sparing normal cells; however, some cancer cells develop resistance to TRAIL.Here, we identified Andrographolide, a diterpenoid lactone derived from a traditional herbal medicine Andrographis paniculata, as an ideal sensitizer for TRAIL to overcome bladder cancer.Our results showed that combination treatment of Andro and TRAIL retarded growth, attenuated proliferation, decreased colony formation, inhibited migration and promoted caspases-mediated apoptosis in T24 cells.Additionally, the sensitization by Andro is achieved through up-regulation of death receptors (DR4 and DR5) of TRAIL in a p53-dependent manner.Crucially, Andro is also capable of inactivating NF-κB signaling pathway via transcriptional down-regulation p65/RelA, which is further contributed to enhancement of TRAIL-mediated cytotoxicity.These results indicated that non-toxic doses of Andrographolide sensitized bladder cancer cells to TRAIL-mediated apoptosis, suggesting it as an effective therapeutic agent for TRAIL resistant human bladder cancers.
Omentin is a novel adipokine, which is expressed in and released from omental adipose tissue. In the present study, the effect of omentin on neural stem cells (NSCs) was investigated. NSCs are a subtype of stem cell in the nervous system, which are able to self‑renew and generate neurons and glia for repairing neural lesions. Mouse NSCs were isolated and cultured in vitro. Treatment with recombinant omentin for 3 and 5 days significantly increased the size of NSC neurospheres (P<0.01) and enhanced NSC cell viability in normal conditions. In addition, omentin protected against the decrease in cell viability induced by the pro‑inflammatory cytokine tumor necrosis factor‑α. In the NSCs, incubation of omentin for 2, 4, 6, 8 and 16 h enhanced the phosphorylation of Akt at the Thr308 site and of AS160 at the Ser318 site, peaking 6 h after treatment. Additionally, treatment with LY294002 (10 µM), a specific inhibitor of phosphatidylinositol 3‑kinase/Akt signaling, eliminated the omentin‑induced increase in neurosphere size and cell viability. Overall, the present study provided the first evidence, to the best of our knowledge, that omentin promotes the growth and survival of NSCs in vitro through activation of the Akt signaling pathway. These results may contribute to the understanding of the role of omentin in the nervous system.
The objective of the present study was to investigate the incidence of and possible risk factors associated with sarcopenia among cancer patients. Patients with cancer were examined through the use of lumbar magnetic resonance imaging, and clinical data was collected between September and December, 2012, at Jilin Province Tumor Hospital (Changchun, China). The data was subsequently compared between patients with and without sarcopenia. Of the 113 treated cancer patients, 96 patients [39 males (L3 index, <52.4 cm2/m2) and 57 females (L3 index, <38.5 cm2/m2)] suffered from sarcopenia. Overall, the development of sarcopenia was not significantly associated with patient age or treatment, including surgery, chemotherapy or radiotherapy (P>0.05). The frequency of treatment‑associated complications did not differ significantly between patients with or without sarcopenia. However, males were more inclined to develop sarcopenia than females (P=0.02). Patients with sarcopenia had significantly less lymphocytes than patients without sarcopenia (P=0.03). This was confirmed through multiple logistic regression analyses (P=0.046), which also identified that patients with cancer with an Eastern Cooperative Oncology Group score >2 had a significantly increased risk of developing sarcopenia. Finally, the serum albumin level in sarcopenia patients was 36.18±4.65 g/l, which was not significantly less than that of patients without sarcopenia (39.67±3.69 g/l; P=0.11). The incidence of sarcopenia among patients with cancer is high, particularly for males. Further research with larger sample sizes would be beneficial, with the aim of verifying the results obtained in the present study. During the treatment of patients with sarcopenia, precaution should continue to be taken to prevent associated complications, including infection, diarrhea and myelosuppression.
Tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, with minimal toxicity to normal tissues. However, accumulating evidence suggests that certain cancer types are insensitive to TRAIL signaling. The aim of this study was to identify an effective combination regimen, which can overcome TRAIL resistance in renal cancer cell. Herein, we found that human renal carcinoma cells (RCCs) are widely resistant to TRAIL‑mediated growth inhibition and subsequently identified that andrographolide (Andro), a major constituent of Andrographis paniculate, an annual herbaceous plant in the family Acanthaceae, counteracts TRAIL resistance in RCCs. Combined treatment with TRAIL and Andro suppressed cell viability as determined by MTS and proliferation as determined by EdU in a dose‑dependent manner and inactivated the clonogenic and migration ability of RCCs. Andro significantly enhances TRAIL‑mediated cell cycle arrest at the G2/M phase as determined by flow cytometry and senescence. Moreover, Andro restored TRAIL signaling, which in turns activated pro‑apoptosis caspases as determined by immunoblot assay. The TRAIL receptor, death receptor (DR)4, but not DR5, was found to be significantly upregulated in Andro‑treated RCC cells, which contributed to the role of Andro as a TRAIL sensitizer. The present study demonstrated that the combined treatment of Andro and TRAIL has potential therapeutic value against renal cancer.
Objective: To investigate risk factors for early mortality (EM) in patients with newly diagnosed multiple myeloma (NDMM) and to build an EM-predictive model. Methods: In a cohort of 275 patients with NDMM, risk factors for EM at 6, 12, and 24 months after diagnosis (EM6, EM12, and EM24, respectively) were determined to establish a model to predict EM. Results: The rates of EM6, EM12, and EM24 were 5.5% , 12.7% , and 30.2% , respectively. The most common cause for EM was disease progression/relapse, accounting for 60.0% , 77.1% , and 84.3% of EM6, EM12, and EM24, respectively. EM6 was associated with corrected serum calcium >2.75 mmol/L and platelet count <100×10(9)/L, whereas risk factors for EM12 included age >75 years, ISS Ⅲ, R-ISS Ⅲ, corrected serum calcium >2.75 mmol/L, serum creatinine >177 µmol/L, platelet count <100×10(9)/L, and bone marrow plasma cell ratio ≥ 60% . In addition to the risk factors for EM12, EM24 was also associated with male sex and 1q21 gain. By multivariate analysis, age >75 years, platelet count <100×10(9)/L, and 1q21 gain were independent risk factors for EM24 but there were no independent risk factors significantly associated with EM6 and EM12. Using a scoring system including these three risk factors, a Cox model for EM24 was generated to distinguish patients with low (score<3) and high (score ≥ 3) risk. The sensitivity and specificity of the model were 20.7% and 99.2% , respectively. Further, an internal validation performed in a cohort of 183 patients with NDMM revealed that the probability of EM24 in high-risk patients was 26 times higher than that in low-risk patients. Moreover, this model was also able to predict overall survival. The median overall survival of patients with scores of 0, 1, 2, 3, 4, and 5 were 59, 41, 22, 17.5, and 16 months, respectively. Conclusion: In the study cohort, the EM6, EM12, and EM24 rates were 5.5% , 12.7% , and 30.2% , respectively, and disease progression or relapse were main causes of EM. An EM24-predictive model built on three independent risk factors for EM24 (age>75 years, platelet count<100×10(9)/L, and 1q21 gain) might predict EM risk and overall survival.目的： 分析影响初治多发性骨髓瘤（NDMM）患者早期死亡（EM）的因素，建立其预测模型，以期识别EM风险。 方法： 回顾性分析2009年5月至2017年1月吉林大学白求恩第一医院收治的275例NDMM患者，对6个月（EM6）、12个月（EM12）及24个月（EM24）内死亡患者初诊时基线特征进行单因素分析，并根据多因素分析结果建立EM的预测模型。 结果： 本研究中EM6、EM12及EM24的发生率分别是5.5%、12.7%和30.2%；最常见的死亡原因为疾病复发/进展，在EM6、EM12及EM24中分别占60.0%、77.1%及84.3%。影响EM6的因素包括经白蛋白校正的血清钙（校正钙）>2.75 mmol/L和PLT<100×10(9)/L；影响EM12的因素包括年龄>75岁、国际分期系统（ISS） Ⅲ期、修订版国际分期系统（R-ISS） Ⅲ期、校正钙>2.75 mmol/L、血清肌酐>177 μmol/L、PLT<100×10(9)/L及骨髓浆细胞比例≥60%；影响EM24的因素中，除上述影响EM12的因素外，还包括男性和染色体核型1q+。多因素分析尚未发现EM6和EM12的独立预后因素。在EM24的多因素分析中，年龄>75岁、PLT<100×10(9)/L和染色体核型1q+是EM24的独立预后因素。根据Logistic回归系数赋分：年龄>75岁：1分；PLT<100×10(9)/L：2分；染色体核型1q+：1分，建立EM24预测模型，ROC曲线下面积为0.709（95%CI 0.626~0.793）。积分≥3分的患者24个月内死亡风险是0~2分患者的26倍，积分0~4分的NDMM患者中位总生存期分别为59、41、22、17.5及16个月（P<0.001）。 结论： 年龄>75岁、PLT<100×10(9)/L和染色体核型1q+为EM24的独立预后因素，依据上述变量构建的EM24预测模型有助于识别EM风险和预测生存，具有较好标准度与区分度。.
Human MOF (males absent on the first), as a histone acetyltransferase, is responsible for histone H4K16 acetylation in human cells. Recent studies have shown that the abnormal gene expression of hMOF is involved in certain primary cancers. Here, we first report the involvement of hMOF expression in clinically diagnosed primary colorectal carcinoma (CRC) and gastric cancer. Simultaneously, the correlation of hMOF expression and clinicopathological features in CRC, gastric cancer and renal cell carcinoma (RCC) was analyzed. The hMOF mRNA expression was assessed in 44 CRC, 16 gastric cancer and 47 RCC human tissue samples by quantitative PCR (qPCR). Statistical analysis of qPCR data revealed a significant reduction (>2-fold decrease) of hMOF gene expression in CRC, 57% (25/44), 94% (15/16) in gastric cancer and 74% (35/47) in RCC tissues of the patients. In patients with CRC, lymph node metastasis and tumor stage were associated with hMOF expression patterns. However, no significant association between hMOF expression and tumor types emerged (p>0.05). Interestingly, in patients with gastric cancer, although no statistically significant difference was found between adjacent (<2 cm away from the cancer tissue) and normal tissues (>5 cm away from the cancer tissue), >2-fold reduction of hMOF expression in adjacent tissues had already appeared in 35% of patients. In addition, low expression of hMOF was strongly correlated with tumor differentiation (p<0.05) and survival of patients with gastric cancer (p<0.001). While in patients with RCC, downregulation of hMOF was connected to ccRCC and tissues with T1 tumor status. Our results suggest that downregulation of hMOF may be common in cancer tissues, and may represent a novel biomarker for tumor diagnosis.
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