Prognosis of laparoscopic surgery for colorectal cancer in middle-aged patients.

Background: The prognosis of middle-aged patients with colorectal cancer (CRC) treated by laparoscopic resection (LR) is unclear. This study aimed to evaluate the survival outcomes of LR compared with open resection (OR) for middle-aged patients with CRC. Patients and Methods: This retrospective cohort study used the data from a database of all consecutive colorectal resections performed between January 2009 and December 2017. Propensity score matching (PSM) was performed to handle the selection bias based on age, gender, body mass index, tumour location, AJCC stage and admission year. Univariate and multivariate COX regression model was used to identify risk factors of overall survival (OS) and disease-free survival (DFS). Results: After PSM, 154 patients were included in each group. Compared with the OR group in the total cohort, there were better survival outcomes in the LR group for 5-year OS and 5-year DFS (both P < 0.001). These differences were observed for Stage II and III diseases and for all CRC, irrespective of location. The multivariate analysis showed that tumour ≥5 cm (hazard ratio [HR] = 1.750, 95% confidence interval [CI]: 1.026-2.986, P = 0.040), Stage III (HR = 14.092, 95% CI: 1.894-104.848, P = 0.010) and LR (HR = 0.300, 95% CI: 0.160-0.560, P < 0.001) were independently associated with OS. Pre-operative carcinoembryonic antigen ≥5 ng/ml (HR = 3.954, 95% CI: 1.363-11.473, P = 0.011), Stage III (HR = 6.206, 95% CI: 1.470-26.200, P = 0.013) and LR (HR = 0.341, 95% CI: 0.178-0.653, P = 0.001) were independently associated with DFS. Conclusions: In middle-aged patients with CRC, LR achieves better survival than OR. Complications are similar, except for less blood loss and shorter post-surgical hospital stay with LR.

Stanford type a aortic dissection with cerebral infarction: a rare case report.

BACKGROUND: Aortic dissection (AoD) is a disease with a high mortality rate. Its clinical manifestations are diverse and covert, which makes diagnosis and treatment challenging. Here, we report a very rare case of aortic dissection leading to bilateral cerebral cortex ischaemia and epilepsy. CASE PRESENTATION: A 54-year-old man was admitted to the hospital with acute onset of right limb weakness accompanied by slurred speech. He had a history of hypertension as well as tobacco and alcohol use. The patient was found to have aphasia and right hemiplegia on physical examination. No bleeding was seen on the skull CT. Acute cerebral infarction was considered after admission, and rt-PA was administered for intravenous thrombolysis. During intravenous thrombolysis, the patient suddenly developed epilepsy, and diazepam was given immediately by intravenous injection to control the symptoms. Emergency skull diffusion-weighted imaging (DWI) was performed, and the results showed a small, patchy, high signal that was scattered throughout the left brain hemisphere, right frontal parietal lobe and centrum semiovale. Head and neck CT angiography (CTA) was performed; dissection was found in the ascending aorta, aortic arch, bilateral common carotid artery, proximal part of the internal carotid artery, and initial segment of the left external carotid artery. The laceration was located in the upper part of the ascending aorta. AoD complicated by acute cerebral infarction and epilepsy was considered, and the patient was immediately transferred to the cardiovascular surgery specialist hospital for surgical treatment. CONCLUSIONS: Some aortic dissections have no typical manifestations of chest pain, and the onset is covert. Atypical clinical manifestations of epilepsy secondary to bilateral cerebral hemisphere infarction may appear. AoD with cerebral infarction is a contraindication for intravenous thrombolysis; surgical treatment is the best way to reduce mortality.

Neoadjuvant chemotherapy as a comprehensive treatment in patients with laryngeal and hypopharyngeal carcinoma.

Background: Neoadjuvant chemotherapy is important for advanced laryngeal and hypopharyngeal carcinoma (LHC).Aims/objectives: To determine the efficacy and toxicity of the combination of docetaxel, nedaplatin, and 5-fluorouracil in induction treatment of advanced LHC.Material and methods: A total of 157 cancer patients were included. The primary endpoints of this study were overall response rate, pathological complete response rate, the safety of induction treatment, progression-free survival (PFS), and overall survival (OS).Results: After two-cycle induction treatment, 17(10.8%) patients experienced complete remission, 76 (48.4%) experienced partial remission, 47 (30.0%) had stable disease, and 17 (10.8%) had progressive disease. The TNM stage decreased by two or more in 17 cases, decreased by one in 71 cases, increased in 15 cases, and did not change in 54 cases after induction treatment. Most of the adverse chemotherapy responses were alleviated by symptomatic management. After the induction treatment, 29 patients continued receiving chemotherapy followed by radiotherapy, and 112 underwent surgical management depending on tumor site followed by radiotherapy. The median PFS was 13.00 ± 2.10 months and the median OS was 14.20 ± 0.29 months.Conclusions and significance: Combination of docetaxel, nedaplatin, and 5-fluorouracil plays an important role in the comprehensive treatment of advanced LHC.

Validation of the 8th edition of AJCC/UICC staging system for nasopharyngeal carcinoma: Results from a non-endemic cohort with 10-year follow-up.

OBJECTIVES: This study aimed to validate the 8th edition of American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM staging system for nasopharyngeal carcinoma (NPC) in non-endemic region. MATERIALS AND METHODS: We recruited 607 patients with histology-proven, previously untreated, non-metastatic NPC treated by intensity-modulated radiotherapy (IMRT) at our center. Harrell's concordance index (c-index) and Akaike information criterion (AIC) were applied to compare the prognostic discrimination between the 7th and 8th edition staging system. RESULTS: For T category, the local recurrence-free survival (LRFS) Kaplan-Meier curves of T1, T2 and T3 were well separated in the 8th edition; however, LRFS did not significantly differ between T3 and T4 (P = 0.166). Moreover, the 7th edition achieved higher c-index (0.702 [95% CI, 0.618-0.787] vs. 0.685 [95% CI, 0.604-0.767]) and lower AIC (766.1 vs. 770.8) than 8th edition for LRFS. With regard to N category, the 8th edition achieved higher c-index (0.796 [95% CI, 0.749-0.843] vs. 0.751 [95% CI, 0.696-0.805]) and lower AIC (1439.4 vs. 1471.9) for distant metastasis-free survival. In terms of overall stage, the 8th edition also had higher c-index (0.798 [95% CI, 0.753-0.844] vs. 0.721 [95% CI, 0.672-0.770]) and lower AIC (1963.9 vs. 2007.2) compared with the 7th edition for overall survival. Furthermore, interval validation by bootstrapping the sample randomly for ~100-1000 times also validated above findings. CONCLUSION: The 8th edition of AJCC/UICC TNM staging system achieved significantly better prognostic discrimination than the 7th edition with regard to N category and overall stage but not T category.

Five serum microRNAs for detection and predicting of ovarian cancer.

OBJECTIVE: Ovarian cancer (OC) was one of the deadliest gynecological malignancy among women in global. Serum microRNAs (miRNAs) could serve as promising diagnostic biomarkers for patients with OC. STUDY DESIGN: Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) based Exiqon panel, we identified 27 differentially expressed miRNAs from one normal control (NC) pool and two OC pool samples in the initial screening stage. We further verified the miRNAs in the training (30 OC VS. 36 NCs) and validation stages (80 OC VS. 80 NCs) based on qRT-PCR. Later, the expression levels of the identified miRNAs were also evaluated in exosomes and tissues. RESULTS: We found a serum microRNA signature including five overexpressed miRNAs (miR-200c-3p, miR-346, miR-127-3p, miR-143-3p and miR-205-5p) in OC in comparison with NCs. The areas under the receiver operating characteristic (ROC) curve (AUC) of the five-miRNA panel were 0.783 for the training stage and 0.745 for the validation stage. The diagnostic sensitivity and specificity of the combined five-miRNA panel was 0.818 and 0.609 when the cut-off value was 0.636. The levels of miR-200c-3p, miR-346 and miR-127-3p in serum were related to tumor grade and distant metastasis of OC. The expression levels of the five miRNAs were also significantly up-regulated in serum exosomes (32 OC VS. 32 NCs). Furthermore, miR-200c-3p was significantly elevated in OC tissues (22 OC VS. 22 NCs). But the levels of the miR-346 and miR-143-3p were significantly lower in OC tissues. CONCLUSION: Our findings showed a five-miRNA panel in serum for the detection of OC. Moreover, serum expression levels of miR-200c-3p, miR-346 and miR-127-3p were concerned with tumor grade and distant metastasis of OC.

ZNF488 is an independent prognostic indicator in nasopharyngeal carcinoma and promotes cell adhesion and proliferation via collagen IV/FAK/AKT/Cyclin D1 pathway.

Background: ZNF488 acts as an oncogene which promotes cell invasion and endows tumor cells stem cell capacity in nasopharyngeal carcinoma (NPC), but its correlation with clinicopathologic characteristics and patients' survival in NPC remain undefined. Methods: In this study, 158 cases of confirmed NPC were subjected to immunohistochemistry staining for evaluating endogenous expression. Kaplan-Meier method and log-rank test were used to estimate the survival rates. The relationship between ZNF488 and clinicopathological characteristics was statistically calculated by chi-squared test, univariate and multivariate analysis. In addition, adhesion assay, MTT and colony formation assays were performed for measuring adhesion and proliferation capacity. Cell cycle analysis via flow cytometry was conducted to explore cell cycle distribution. Western blot was used to detect pathway protein levels, and the pFAK (Y397) kit was used for focal adhesion kinase (FAK) activation. Results: We demonstrated that high expression of ZNF488 was significantly correlated with locoregional failure (P=0.018) and distant metastasis (P=0.001). Patients with high ZNF488 expression had poorer overall survival (P<0.001), loco-regional recurrence-free survival (P<0.001), distance metastasis-free survival (P<0.001) and progression-free survival (P<0.001) than those with low ZNF488 group. Multivariate analysis showed that ZNF488 expression was an independent prognostic indicator for predicting NPC patients' survival (HR, 3.314; 95% CI, 1.489-7.386; P=0.003). Additionally, ZNF488-induced collagen IV/FAK/AKT to enhance adhesion ability meanwhile led to the upregulation of Cyclin D1 to facilitate cell proliferation through promoting cell cycle progression and inhibition of apoptosis through caspase-independent way. Conclusion: These results reveal that ZNF488, as an independent prognostic indicator, promotes cell adhesion and proliferation through collagen IV/FAK/AKT/Cyclin D1 pathway in NPC.

Effectiveness of Cetuximab in Combination with Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A 1:2 Propensity Score-matched Analysis.

Background: This study aimed to compare concurrent chemoradiotherapy (CCRT) plus cetuximab (C) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma(NPC). Methods: A total of 682 locoregionally advanced NPC patients who had undergone chemoradiotherapy with or without cetuximab were included. Propensity score-matching method was used to match patients. Progression-free survival (PFS), overall survival (OS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were compared between the two treatment arms. Results: After matching, 225 patients were identified for the analysis. Compared to CCRT, CCRT plus C was associated with significantly improved 3-year PFS (83.7% vs 71.9%, P = 0.036), LRFS (98.6% vs 90.2%, P = 0.034) but not OS (91.4% vs 85.4%, P = 0.117). Among patients with T4 and/or N3 category, CCRT plus C significantly prolonged 3-year PFS (81.0% vs 61.4%, P = 0.022) and increased 3-year OS (88.0% vs 77.9%, P = 0.086). No significant differences were observed between CCRT plus C and CCRT alone groups with regard to 3-year PFS, OS, LRFS and DMFS rates in stage III patients. Acute oral and oropharyngeal mucositis during radiotherapy were more common in the CCRT plus C than that in CCRT, but late toxicities were comparable. Conclusions: This study reveals that patients with locoregionally advanced NPC could benefit from the addition of cetuximab to CCRT, and this therapeutic gain mainly originated from T4 and/or N3 subgroup although suffering more acute moderate to severe toxicities.

Comparing the efficacy of induction-concurrent with concurrent-adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma: a propensity score matching analysis.

PURPOSE: This study aimed to compare the efficacy of induction-concurrent (IC-CCRT) with concurrent-adjuvant (CCRT-AC) chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated by intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Data on 834 patients with newly diagnosed, non-metastatic stage III-IVA (except T3N0) NPC receiving either IC-CCRT or CCRT-AC between July, 2004 and December, 2014 were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes of matched patients between IC-CCRT and CCRT-AC were compared. RESULTS: The median follow-up duration is 45.2 months (range, 1.07-145.4 months). Overall, 309 pairs were selected by PSM. Univariate analysis revealed the CCRT-AC group achieved significantly higher 3-year DFS (83.9% vs. 78.7 %; P = 0.014) and OS (87.6% vs. 87.0%; P = 0.031). Multivariate analysis also identified treatment group (IC-CCRT vs. CCRT-AC) as an independent prognostic factor for 3-year DFS (HR, 1.546; 95% CI, 1.113-2.149; P = 0.009) and OS (HR, 1.487; 95% CI, 1.035-2.136; P = 0.032). Subgroup analysis revealed IC-CCRT was a protective factor for DMFS (HR, 0.145; 95% CI, 0.043-0.488; P = 0.002) in stage III disease; however, it could adversely affected DFS (HR, 2.009; 95% CI, 1.316-3.065; P = 0.001), OS (HR, 1.671; 95% CI, 1.060-2.636; P = 0.027) and DMFS (HR, 1.986; 95% CI, 1.155-3.416; P = 0.013) in stage IVA disease. CONCLUSIONS: CCRT-AC may be a more effective treatment modality in patients with stage IVA NPC disease, while IC-CCRT was superior in stage III disease.

Prognostic value of chemotherapy in addition to concurrent chemoradiotherapy in T3-4N0-1 nasopharyngeal carcinoma: a propensity score matching study.

PURPOSE: The objective of this study is to evaluate the contribution of induction (IC) or adjuvant (AC) chemotherapy additional to concurrent chemoradiotherapy (CCRT) for patients with T3-4N0-1 nasopharyngeal carcinoma (NPC) in the era of intensity-modulate radiotherapy (IMRT). METHOD AND MATERIALS: We retrospectively reviewed the data on 685 patients with newly diagnosed T3-4N0-1 NPC. Propensity score matching (PSM) method was used to match patients. Survival outcomes between different groups were calculated by Kaplan-Meier method and compared using log-rank test. Cox proportional hazard model was adopted to establish independent prognostic factors. RESULTS: In total, 236 pairs were selected from the primary cohort. Univariate analysis revealed 3-year overall survival (OS) (90.8% vs. 90.3%, P = 0.820), distant failure-free survival (DFFS) (87.3% vs. 89.4%, P = 0.896) and locoregional failure-free survival (LRFFS) (95.4% vs. 93.0%, P = 0.311) rates were comparable between CCRT plus IC/AC and CCRT alone groups. Multivariate analysis found that treatment group was not an independent prognostic factors for OS (HR, 0.964; 95% CI, 0.620-1.499; P = 0.869), DFFS (HR, 1.036; 95% CI, 0.626-1.714; P = 0.890) and LRFFS (HR, 0.670; 95% CI, 0.338-1.327; P = 0.250). Further subgroup analysis according to overall stage also obtained similar results. CONCLUSION: Patients with T3-4N0-1 NPC receiving CCRT could not benefit from additional induction or adjuvant chemotherapy in the era of IMRT.

Vinpocetine alleviate cerebral ischemia/reperfusion injury by down-regulating TLR4/MyD88/NF-κB signaling.

Inflammatory responses play crucial roles in cerebral ischemia/reperfusion injury. Toll-like receptor 4 (TLR4) is an important mediator of the neuroinflammatory response to cerebral ischemia/reperfusion injury. Vinpocetine is a derivative of the alkaloid vincamine and exerts an anti-inflammatory effect by inhibiting NF-κB activation. However, the effects of vinpocetine on pathways upstream of NF-κB signaling, such as TLR4, have not been fully elucidated. Here, we used mouse middle cerebral artery occlusion (MCAO) and cell-based oxygen-glucose deprivation (OGD) models to evaluate the therapeutic effects and mechanisms of vinpocetine treatment. The vinpocetine treatment significantly reduced mice cerebral infarct volumes and neurological scores. Moreover, the numbers of TUNEL+ and Fluoro-Jade B+ cells were significantly decreased in the ischemic brain tissues after vinpocetine treatment. In the OGD model, the vinpocetine treatment also increased the viability of cultured cortical neurons. Interestingly, vinpocetine exerted a neuroprotective effect on the mouse MCAO model and cell-based OGD model by inhibiting TLR4-mediated inflammatory responses and decreasing proinflammatory cytokine release through the MyD88-dependent signaling pathway, independent of TRIF signaling pathway. In conclusion, vinpocetine exerts anti-inflammatory effects to ameliorate cerebral ischemia/reperfusion injury in vitro and in vivo. Vinpocetine may inhibit inflammatory responses through the TLR4/MyD88/NF-κB signaling pathway, independent of TRIF-mediated inflammatory responses. Thus, vinpocetine may be an attractive therapeutic candidate for the treatment of ischemic cerebral injury or other inflammatory diseases.

Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage-Induced Blood-Brain Barrier Disruption by Inhibiting Vesicular Transcytosis.

BACKGROUND: Blood-brain barrier (BBB) disruption aggravates brain injury induced by intracerebral hemorrhage (ICH); however, the mechanisms of BBB damage caused by ICH remain elusive. Mfsd2a (major facilitator superfamily domain containing 2a) has been known to play an essential role in BBB formation and function. In this study, we investigated the role and underlying mechanisms of Mfsd2a in BBB permeability regulation after ICH. METHODS AND RESULTS: Using ICH models, we found that Mfsd2a protein expression in perihematomal brain tissues was significantly decreased after ICH. Knockdown and knockout of Mfsd2a in mice markedly increased BBB permeability, neurological deficit score, and brain water contents after ICH, and these were rescued by overexpressing Mfsd2a in perihematomas. Moreover, we found that Mfsd2a regulation of BBB permeability after ICH correlated with changes in vesicle number. Expression profiling of tight junction proteins showed no differences in Mfsd2a knockdown, Mfsd2a knockout, and Mfsd2a overexpression mice. However, using electron microscopy following ICH, we observed a significant increase in pinocytotic vesicle number in Mfsd2a knockout mice and decreased the number of pinocytotic vesicles in mouse brains with Mfsd2a overexpression. Finally, using multiple reaction monitoring, we screened out 3 vesicle trafficking-related proteins (Srgap2, Stx7, and Sec22b) from 31 vesicle trafficking-related proteins that were markedly upregulated in Mfsd2a knockout mice compared with controls after ICH. CONCLUSIONS: In summary, our results suggest that Mfsd2a may protect against BBB injury by inhibiting vesicular transcytosis following ICH.

Ten-year survival outcomes for patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: An analysis of 614 patients from a single center.

OBJECTIVES: Intensity-modulated radiotherapy (IMRT) has been applied in nasopharyngeal carcinoma (NPC) for nearly twenty years, while little is known about the ten-year survival outcomes. This study aimed at evaluating the 10-year survival outcomes for patients with NPC receiving IMRT. MATERIALS AND METHODS: Data on 614 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2004 and 2008 were retrospectively reviewed. Survival outcomes stratified by tumor stage were compared. RESULTS: The median follow-up duration was 112.7months (range, 7.6-156.8months) for the entire cohort. The 10-year local relapse-free survival rates for T1, T2 and T3 were 94.2%, 92.5% and 91.4% (P>0.05), respectively, and significantly higher than that of T4 disease (79.3%, P<0.05 for all rates). As N category increased from N0 to N3, the 10-year distant metastasis-free survival rates significantly decreased accordingly (P<0.01 for all rates). Furthermore, the 10-year overall survival rates were 100%, 87.1%, 75.5% and 55.6% for stage I, II, III and IV, respectively (P<0.05 except stage I and II). Multivariate analysis established tumor stage and age as independent prognostic factors. Late toxicities were assessable for 495 (80.6%) patients and most were Grade I/II damages. Xerostomia (387 of 489, 79.1%) and hearing impairment (212 of 495, 42.8%) remained the most troublesome. CONCLUSION: IMRT could achieve satisfactory survival outcomes for NPC patients with acceptable late toxicities. However, distant control still remains poor, especially for patients with N3 disease.

Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3ß/PTEN axis.

Inflammation mediated by the peripheral infiltration of inflammatory cells plays an important role in intracerebral hemorrhage (ICH) induced secondary injury. Previous studies have indicated that regulatory T lymphocytes (Tregs) might reduce ICH-induced inflammation, but the precise mechanisms that contribute to ICH-induced inflammatory injury remain unclear. Our results show that the number of Tregs in the brain increases after ICH. Inducing Tregs deletion using a CD25 antibody or Foxp3DTR-mice increased neurological deficient scores (NDS), the level of inflammatory factors, hematoma volumes, and neuronal degeneration. Meanwhile, boosting Tregs using a CD28 super-agonist antibody reduced the inflammatory injury. Furthermore, Tregs depletion shifted microglia/macrophage polarization toward the M1 phenotype while boosting Tregs shifted this transition toward the M2 phenotype. In vitro, a transwell co-culture model of microglia and Tregs indicated that Tregs changed the polarization of microglia, decreased the expression of MHC-II, IL-6, and TNF-α and increased CD206 expression. IL-10 originating from Tregs mediated the microglia polarization by increasing the expression of Glycogen Synthase Kinase 3 beta (GSK3ß), which phosphorylates and inactivates Phosphatase and Tensin homologue (PTEN) in microglia, TGF-ß did not participate in this conversion. Thus, Tregs ameliorated ICH-induced inflammatory injury by modulating microglia/macrophage polarization toward the M2 phenotype through the IL-10/GSK3ß/PTEN axis.

Study on diagnosis criteria of fire-heat syndrome based on receiver operating characteristic curve and principal component analysis.

OBJECTIVE: To establish the diagnostic quantitative criteria for fire-heat syndrome (FHS) of Chinese medicine (CM) based on the receiver operating characteristic (ROC) curve and principal component analysis (PCA). METHODS: The symptoms and signs of FHS cases and healthy subjects from Guangzhou, Henan and Hunan of China were collected through questionnaire, and the diagnostic quantitative score tables were established for the three regions, respectively, with the method of maximum likelihood analysis. The homogeneity test was then performed on the diagnostic score tables for the three regions with ROC curve, and the diagnostic efficiency of diagnostic score tables for the three regions was compared with the prospective test and retrospective test. The method of PCA was adopted to obtain the analysis matrix for classifying the tapes of FHS. RESULTS: Twenty-seven elements of FHS were confirmed through Chi-square test, and the diagnostic score tables for the three regions were established with the method of maximum likelihood analysis on the basis of the collected case data. According to the ROC curve test, the areas under ROC curve of Guangzhou diagnostic score table assessment with candidates in Guangzhou, Henan and Hunan were 0.998, 0.961 and 0.956, respectively. It showed that the diagnostic efficiency of Guangzhou diagnostic score tables was the highest one. With the prospective test, the area under ROC of Guangzhou diagnostic score table was 0.949, and more than any other diagnostic score table. By PCA, FHS was classified into excess fire and deficiency fire, and then classified into syndrome of flaring up of Heart (Xin) fire, syndrome of Lung (Fei)-Stomach (Wei) excess fire, syndrome of deficiency of Liver (Gan)-yin and Kidney (Shen)-yin, and syndrome of deficiency of Lung-yin from the view of viscera. In the retrospective test, the consistency with clinicians' diagnosis was 69.4%, and in the prospective test, it was 70.1%. CONCLUSIONS: The Guangzhou diagnostic score table could be used as the recommended criteria for the diagnosis of FHS. The classification of FHS was basically in conformity with the clinical situation.

Silencing of miR-21 sensitizes CML CD34+ stem/progenitor cells to imatinib-induced apoptosis by blocking PI3K/AKT pathway.

BCR-ABL tyrosine kinase inhibitor imatinib fails to eradicate leukemia stem cells (LSCs), the underlying mechanisms maintaining CML LSCs remain poorly understood. Here, we showed that transient inhibition of miR-21 by antagomiR-21 markedly increased imatinib-induced apoptosis in CML, but not normal CD34+ stem/progenitor cells. Furthermore, PI3K inhibitors also significantly sensitized CML CD34+ cells to imatinib-induced apoptosis. MiR-21 or PI3K inhibitor in combination with imatinib treatment significantly decreased AKT phosphorylation and c-Myc expression than either agent did alone, but did not affect Bim and Bcl-6 expresssion. These findings indicate that miR-21 is required for maintaining the imatinib-resistant phenotype of CML CD34+ cells through PI3K/AKT signaling pathway, thus providing the basis for a promising therapeutic approach to eliminate CML LSCs.

Targeting miR-21 sensitizes Ph+ ALL Sup-b15 cells to imatinib-induced apoptosis through upregulation of PTEN.

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) cells are insensitive to BCR-ABL tyrosine kinase inhibitor imatinib, the underlying mechanisms remain largely unknown. Here, we showed that imatinib treatment induced significant upregulation of miR-21 and downregulation of PTEN in Ph+ ALL cell line Sup-b15. Transient inhibition of miR-21 resulted in increased apoptosis, PTEN upregulation and AKT dephosphorylation, whereas ectopic overexpression of miR-21 further conferred imatinib resistance. Furthermore, knockdown of PTEN protected the cells from imatinib-induced apoptosis achieved by inhibition of miR-21. Additionally, PI3K inhibitors also notably enhanced the effects of imatinib on Sup-b15 cells and primary Ph+ ALL cells similar to miR-21 inhibitor. Therefore, miR-21 contributes to imatinib resistance in Ph+ ALL cells and antagonizing miR-21 demonstrates therapeutic potential by sensitizing the malignancy to imatinib therapy.

[Prevention of atherosclerotic plaque development by modulating heme oxygenase-1-endogenous carbon monoxide system in rabbit model].

OBJECTIVE: To investigate the effect of heme oxygenase/carbon monoxide (HO-1/CO) system on lipid deposition at aortic intima and the mechanism involved in hyperlipidemic rabbits. METHODS: Totally 32 rabbits, were divided into four groups. One group as control. Three groups for the following treatments: 1.5% cholesterol ration (Ch group, n = 8); 1.5% cholesterol ration plus HO-1 inducer hemin (Hm group, n = 8); and instead of hemin, the HO-1 inhibitor, zinc protoporphyrin IX (Zn group, n = 8) was given by injection into the abdominal cavity. Experiments were lasted for 12 weeks. Rabbit aortas were then isolated as the samples for histopathologic and ultrastructural examination. The protein expressions of HO-1 and endothelin-1 (ET-1) were investigated by immunohistochemical staining and Western blot analysis. RESULTS: Comparing with the Ch group, rabbits of the Hm group showed a remarkably less extent of lipid deposition at the aortic intima [(17.9 ± 3.0)% vs (54.0 ± 4.2)%], and rabbits of the Zn group had a marked extent of lesion development [(61.1 ± 3.5)%]. Lipid deposition, endothelial damage and neo-intimal formation were less severe in rabbits of the Hm group than those in the Zn or Ch group, respectively. Comparing with the control group, rabbits of the Ch group showed a significant decrease of aortic NO production and cNOS activity. However, there were an enhancement of CO production and HO-1 activity (P < 0.01). Compared with Ch group, rabbits of the Hm group showed a remarkable elevation of aortic HO activity and CO production, whereas rabbits of the Zn group showed a marked decrease of both parameters. Compared with the Ch group, rabbits of the Hm group demonstrated a marked reduction of aorta ET-1 expression, whereas Zn group had a significantly higher ET-1 expression. CONCLUSIONS: Modulation of HO-1/CO system may improve vascular endothelial function and inhibit smooth muscle cell proliferation in hypercholesterolemic rabbits, likely through a compensatory mechanism and a reduction of ET-1 expression, eventually leading to an inhibition of atherosclerotic plaque development.

Effect of the haeme oxygenase-1/endogenous carbon monoxide system on atherosclerotic plaque formation in rabbits.

BACKGROUND: To investigate the effect of the haeme oxygenase-1/carbon monoxide (HO-1/CO) system on atherosclerotic plaque formation and its possible mechanism. METHODS: For 12 weeks, rabbits were given a 1.5% cholesterol diet (Ch group, n = 8) or a 1.5% cholesterol diet plus an HO-1 inducer, haemin (Hm group, n = 8), or an HO-1 inhibitor, zinc protoporphyrin IX (Znpp-IX, Zn group, n = 8) by intraperitoneal injection. RESULTS: Compared with the normal control group (C group, n = 8), serum levels of lipids and oxidised low-density lipoproteins (ox-LDL) increased significantly in all experimental groups (p < 0.01). However, no significant differences were observed among the three experimental groups (p > 0.01). Compared with the control group, aortic nitric oxide (NO) production and nitric oxide synthase (cNOS) activity decreased markedly, whereas carbon monoxide (CO) production and HO-1 activity increased markedly in the Ch group (p < 0.01). This was associated with an increase in the area of aortic plaque of 54.00 ± 4.16%. Compared with the Ch group, CO production and HO-1 activity increased markedly, while aortic HO activity and CO production decreased significantly in the Hm group. The area of aortic plaque was significantly reduced in the Hm group (17.88 ± 3.01%), whereas the area of aortic plaque was significantly increased in the Zn group (61.13 ± 3.50%). Compared with the Ch group, aortic endothlin-1 expression in the Hm group reduced significantly, while in the Zn group it was significantly higher than in the Ch group (p < 0.01). CONCLUSION: The HO-1/CO system plays an inhibitory role in atherosclerotic plaque formation. This role was not mediated by regulating serum lipids and ox-LDL, but was related to the reciprocal relationship between the HO-1/CO and NOS/NO systems in atherosclerosis and the down-regulated expression of endothlin-1 (ET-1), which inhibits the proliferation of vascular smooth muscle cells.

[Epidemiological study of high risk human papillomavirus infection in 25 to 54 years old married women in Beijing.].

OBJECTIVE: To investigate high risk human papillomavirus (HR-HPV) prevalence among married women in Beijing and to study the high risk factors. METHODS: During March 2007 to September 2008, a total of 6185 married women sampled from 137 communities in 12 districts were screened by HR-HPV DNA test and cytological test. The interview was carried out with unified questionnaires. The database was set up and twice entered in EpiData 3.0. After checked up, the data were analyzed in SPSS 15.0. RESULTS: (1) The HR-HPV infection rate was 9.89%. The HR-HPV infection rate of the city zone, the suburb and the exurb were 9.34%, 10.51% and 9.51% (P > 0.05). The HR-HPV infection rate of the native and the outlander were 9.53%, 11.30% (P < 0.05). (2) The age distribution of HR-HPV infection was that the rate was around 10% among 25 to 44 age groups, which was the highest (11.21%) in 30 to 34 age group; then the rate was descended as the age raising, the rate of 50 to 54 age group was the lowest (7.78%). (3) Multiple logistic regression showed that the related risk factors of HR-HPV infection mainly included 1000 RMB and above of family income per person per month, possessing more than 1 sexual partner of her husband, outlander and high levels of education. (4) The prevalence of cervical intraepithelial neoplasia (CIN) in HR-HPV positive group was significantly higher than that in HR-HPV negative group (29.76% vs 3.32%, P < 0.01). CONCLUSIONS: (1) The HR-HPV infection rate among aged 25 to 54 years was 9.9% and there was no significant difference in area distribution. (2) The high risk population which should strengthen screening was the married bearing-age women with high level of family income, outlander, high levels of education and her husband possessing more than 1 sexual partner. (3) HR-HPV infection is the main risk factor for CIN and cervical cancer, while does not provide a causal relationship with them. The high risk population should be checked regularly to understand the development of HR-HPV infection and CIN incidence.