Search

Acute ischemic stroke has become the major cause of mortality and disability worldwide. Following ischemic stroke, the reperfusion injury is mainly mediated by the burst of reactive oxygen and nitrogen species (RONS). Therefore, blocking the excessive production or removing RONS holds great promise as a potential therapeutic strategy. Herein, we developed a Co-doped Fe3O4 nanozyme that is capable of scavenging H2O2, O2•-, •NO, and ONOO- in vitro and in vivo and provides neuroprotection against ischemic stroke. In vitro experiments showed that pre-incubation with the Co-Fe3O4 nanozyme could prevent neurotoxicity and neuroinflammation induced by H2O2 or lipopolysaccharide, respectively, in HT22 cells. After intravenous administration, the Co-Fe3O4 nanozyme showed no signs of toxicity in peripheral organs of C57BL/6J mice, even after prolonged delivery for 4 weeks. In permanent photothrombotic stroke model and transient middle cerebral artery occlusion stroke model, the Co-Fe3O4 nanozyme specifically accumulated in the infarct rim at 72 h post-stroke and was endocytosed by neurons, astrocytes, microglia, and endothelial cells. Importantly, the Co-Fe3O4 nanozyme delivery reduced the infarct volume in both stroke models. The observation that the Co-Fe3O4 nanozyme was efficacious in two well-characterized ischemic stroke models provides strong evidence that it represents a powerful tool for targeting oxidative and nitrosative stress in the ischemic brain.

Cisplatin is used in a wide variety of malignancies, but cisplatin-induced ototoxicity remains a major issue in clinical practice. Experimental evidence indicates that ferroptosis plays a key role in mediating the unwanted cytotoxicity effect caused by cisplatin. However, the role of ferroptosis in cisplatin-induced ototoxicity requires elucidation. Ferrostatin-1 (Fer-1) was identified as a potent inhibitor of ferroptosis and radical-trapping antioxidant with its ability to reduce the accumulation of lipid peroxides and chain-carrying peroxyl radicals. In the current study, we investigated the effects of Fer-1 in cisplatin-induced ototoxicity in in vitro, ex vivo, and in vivo models. We found, for the first time that Fer-1 efficiently alleviated cisplatin-induced cytotoxicity in HEI-OC1 cells via a concentration-dependent manner. Furthermore, Fer-1 mitigated cisplatin cytotoxicity in transgenic zebrafish sensory hair cells. In HEI-OC1 cells, Fer-1 pretreatment not only drastically reduced the generation of intracellular reactive oxygen species but also remarkably decreased lipid peroxidation levels induced by cisplatin. This was not only ascribed to the inhibition of 4-hydroxynonenal, the final product of lipid peroxides, but also to the promotion of glutathione peroxidase 4, the protein marker of ferroptosis. MitoTracker staining and transmission electron microscopy of mitochondrial morphology suggested that in HEI-OC1 cells, Fer-1 can effectively abrogate mitochondrial damage resulting from the interaction with cisplatin. In addition, Fer-1 pretreatment of cochlear explants substantially protected hair cells from cisplatin-induced damage. Therefore, our results demonstrated that ferroptosis might be involved in cisplatin ototoxicity. Fer-1 administration mitigated cisplatin-induced hair cell damage, further investigations are required to elucidate the molecular mechanisms of its otoprotective effect.

Cutaneous wound healing requires intricate synchronization of several key processes. Among them, local nerve regeneration is known to be vitally important for proper repair. However, the underlying mechanisms of local nerve regeneration are still unclear. Fibroblasts are one of the key cell types within the skin whose role in local nerve regeneration has not been extensively studied. In our study, we found skin fibroblasts were in tight contact with regenerated nerves during wound healing, while rare interactions were shown under normal circumstances. Moreover, skin fibroblasts surrounding the nerves were shown to be activated and reprogrammed to exhibit neural cell‐like properties by upregulated expressing inhibitor of DNA binding 1 (ID1) and ID3. Furthermore, we identified the regulation of integrin α6 (Itga6) by ID1/ID3 in fibroblasts as the mechanism for axon guidance. Accordingly, transplantation of the ID1/ID3‐overexpressing fibroblasts or topical injection of ID1/ID3 lentivirus significantly promoted local nerve regeneration and wound healing following skin excision or sciatic nerve injury. Therefore, we demonstrated a new role for skin fibroblasts in nerve regeneration following local injury by directly contacting and guiding axon regrowth, which might hold therapeutic potential in peripheral nerve disorders and peripheral neuropathies in relatively chronic refractory wounds., Skin fibroblasts contribute to local nerve regeneration by directly guiding axon regrowth, which suggests a potential therapeutic strategy for peripheral nerve disorders and relatively chronic refractory wounds.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF., Graphical abstract Image 1, Highlights • Glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts lead to lung fibrosis. • Succinate contributes to metabolic dysregulation of fibroblasts by stabilizing HIF-1α. • Succinate dehydrogenase is an exciting new therapeutic target to treat IPF. • IR-780 can be a promising agent to control lung fibrosis by targeting succinate dehydrogenase.

Background: The MYC-expressing diffuse large B-cell lymphoma (DLBCL) is one of the refractory lymphomas. The pathogenesis of MYC-expressing DLBCL is still unclear, and there is a lack of effective therapy. In this study, we have explored the clinical significance and the molecular mechanisms of transcription co-activator 4 (PC4) in MYC-expressing DLBCL.Methods: We investigated PC4 expression in 54 cases of DLBCL patients’ tissues and matched normal specimens, and studied the molecular mechanisms of PC4 in MYC-expressing DLBCL both in vitro and in vivo.Results: We reported for the first time that targeting c-Myc could induce autophagic cell death in MYC-expressing DLBCL cell lines. We next characterized that PC4 was an upstream regulator of c-Myc, and PC4 was overexpressed in DLBCL and was closely related to clinical staging, prognosis and c-Myc expression. Further, our in vivo and in vitro studies revealed that PC4 knockdown could induce autophagic cell death of MYC-expressing DLBCL. And inhibition of c-Myc mediated aerobic glycolysis and activation of AMPK / mTOR signaling pathway were responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Through the CHIP, DLRTM and EMSA assay, we also found that PC4 exerted its oncogenic functions by directly binding to c-Myc promoters.Conclusions: PC4 exerts its oncogenic functions by directly binding to c-Myc promoters. Inhibition of PC4 can induce autophagic cell death of MYC-expressing DLBCL. Our study provides novel insights into the functions and mechanisms of PC4 in MYC-expressing DLBCL, and suggests that PC4 might be a promising therapeutic target for MYC-expressing DLBCL.

Diabetic bladder dysfunction (DBD) afflicts nearly half of diabetic patients, but effective treatment is lacking. In this study, IR-61, a novel heptamethine cyanine dye with potential antioxidant effects, was investigated to determine whether it can alleviate DBD. Rats were intraperitoneally injected with IR-61 or vehicle after diabetes was induced with streptozotocin. Before evaluating the effects of IR-61 in improving DBD by filling cystometry, we detected its distribution in tissues and subcellular organelles by confocal fluorescence imaging. Near infrared (NIR) imaging showed that IR-61 could accumulate at high levels in the bladders of diabetic rats, and confocal images demonstrated that it was mainly taken up by bladder smooth muscle cells (BSMCs) and localized in mitochondria. Then, filling cystometry illustrated that IR-61 significantly improved the bladder function of diabetic rats. The histomorphometry results showed that IR-61 effectively mitigated the pathological changes in bladder smooth muscle (BSM) in diabetic rats. Furthermore, IR-61 remarkably reduced the number of apoptotic BSMCs and the unfavorable expression of proteins related to the mitochondrial apoptotic pathway (Bcl-2, BAX, Cytochrome C, and cleaved Caspase-9) in diabetic rats. Moreover, the frozen section staining and transmission electron microscopy results proved that IR-61 significantly reduced the reactive oxygen species (ROS) levels and prevented the mitochondrial mass and morphology damage in the BSM of diabetic rats. In addition, IR-61 upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its associated antioxidant proteins in the BSM of diabetic rats. Together, these results indicate that IR-61 can improve the voiding function of rats with DBD by protecting the mitochondria of BSMCs from oxidative stress, which is possibly mediated through the activation of the Nrf2 pathway.

Background and purpose There is an urgent but unmet need for mitigating radiation-induced intestinal toxicity while radio sensitising tumours for abdominal radiotherapy. We aimed to investigate the effects of metformin on radiation-induced intestinal toxicity and radiosensitivity of colorectal tumours. Experimental approach Acute and chronic histological injuries of the intestine from mice were used to assess radioprotection and IEC-6 cell line was used to investigate the mechanisms in vitro. The fractionated abdominal radiation model of HCT116 and HT29 tumour grafts was used to determine the effects on colorectal cancer. Key results Metformin alleviated radiation-induced acute and chronic intestinal toxicity by optimising mitophagy which was AMPK-dependent. In addition, our data indicated that metformin increased the radiosensitivity of colorectal tumours with P53 mutation both in vitro and in vivo. Conclusion and implications Metformin may be a radiotherapy adjuvant agent for colorectal cancers especially those carrying P53 mutation. Our findings provide a new strategy for further precise clinical trials for metformin on radiotherapy.

// Chuntao Li 1 , Zhixiong Liu 1 , Kui Yang 1 , Xin Chen 1 , Yu Zeng 1 , Jinfang Liu 1 , Zhenyan Li 1 , Yunsheng Liu 1 1 Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, 410008 Hunan, China Correspondence to: Zhixiong Liu, email: zxliu_csu@sina.com Keywords: glioma, microRNA-133b, silent information regulator 1, proliferation, invasion Received: November 16, 2015 Accepted: April 16, 2016 Published: May 06, 2016 ABSTRACT MicroRNAs (miRs) are a class of small non-coding RNAs that function as mediators of gene expression. Dysregulations of miRs have been implicated in the development and progression of glioma. In the present study, we investigated the role of miR-133b in mediating the proliferation and invasion of glioma cells, and the potential mechanism. Real-time RT-PCR results showed that miR-133b expression was significantly decreased in glioma tissues compared with normal brain tissues. Luciferase reporter assay further identified silent information regulator 1 (Sirt1) as a novel direct target of miR-133b in glioma U87 cells. Overexpression of miR-133b suppressed Sirt1 expression and reduced the proliferation and invasion of U87 cells, which could be partly rescued by forced expression of Sirt1. In addition, the Sirt1 mRNA level was significantly higher in glioma tissues than in normal brain tissues, and was inversely correlated with miR-133b level in glioma tissues. In summary, our study sheds light on the regulatory mechanism of miR-133b in glioma growth and metastasis via direct mediation of Sirt1 expression, and suggests that Sirt1 may serve as a potential therapeutic target for glioma.

Stress is an important risk factor of Alzheimer’s disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.

Non-functioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. The elucidation of the mechanisms of aggressive NFPAs in bone destruction is required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, we investigated the differential proteomics of fibroblasts isolated from clinical specimens of NFPAs with or without bone destruction. Proteomic analysis revealed a group of molecules associated with cytoskeleton organization, including caldesmon, were differentially expressed between fibroblasts isolated from bone destruction NFPAs (BD-NFPAs) and fibroblasts isolated from non-bone destruction NFPAs (NBD-NFPAs). The secreted proteins analysis found that osteopontin was significantly upregulated in BD-NFPAs fibroblasts. Furthermore, immunohistochemical staining of the NFPAs clinical samples showed that the expression of caldesmon in stromal cells and the expression of osteopontin in both tumor cells and stroma were significantly increased in BD-NFPAs. Taken together, our results indicate a possible way that osteopontin secreted from both NFPA cells and surrounding fibroblasts modify caldesmon expression and polymerization in fibroblasts, which may contribute to bone destruction in NFPA patients.

Podocalyxin (PODXL) has been found to increase the aggressive phenotype of a number of cancers, including astrocytoma. In addition, the progression of astrocytoma has been associated with sperm‑associated antigen 9 (SPAG9), a recently characterized oncoprotein. In the present study, the association between SPAG9 and PODXL in human astrocytoma invasion and the underlying mechanisms were investigated for the first time, to the best of our knowledge. Overexpression and knockdown of SPAG9 were performed in SW1783 (grade III astrocytoma) and U87 (grade IV astrocytoma; glioblastoma) cells, respectively. PODXL expression at both the mRNA and the protein level, as well as the PODXL gene promoter activity, were significantly increased and decreased in parallel with the overexpression and knockdown of SPAG9 in astrocytoma cells; these effects were blocked by the selective c‑Jun N‑terminal kinase (JNK) inhibitor SP600125 (5 µM) and restored by the JNK agonist anisomycin (25 ng/ml), respectively. SPAG9 overexpression significantly increased cell invasion and matrix metalloproteinase‑9 (MMP‑9) expression in SW1783 cells, and this effect was reversed by knockdown of PODXL. In U87 cells, knockdown of SPAG9 markedly decreased cell invasion and MMP‑9 expression, which was completely restored by overexpression of PODXL. In conclusion, it was demonstrated in the present study that SPAG9 upregulates PODXL expression in human astrocytoma cells at the PODXL gene promoter/transcriptional level through a JNK‑dependent mechanism and that PODXL is a critical mediator of the promoting effect of SPAG9 on astrocytoma cell invasion, possibly through upregulation of MMP‑9 expression. This study provides novel insights into the molecular mechanisms involved in astrocytoma invasion.

Insulin-like growth factor 1 (IGF1)(CA)19 and insulin-like growth factor-binding protein-3 (IGFBP-3)-202A/C gene polymorphisms had been focused by many epidemiological studies recently, which were associated with common cancer risk including colorectal, breast, prostate, and lung cancer. However, the findings of epidemiological investigations are not coincident. We did a systematic review and meta-analysis of case–control studies, including studies nested in cohorts, of the association between IGF1(CA)19 and IGFBP-3-202A/C gene polymorphism and prostate, colorectal, premenopausal and postmenopausal breast cancer. We identified 17 eligible studies (24 datasets), which included 9,744 cases and 11,332 controls. The result displays that individuals carrying (CA)19 allele had a subtly decreased risk of all cancer sites [OR(95 % CI) 0.92(0.87,0.97); 0.882(0.809,0.962); 0.902(0.849,0.958)] and postmenopausal breast cancer [OR(95 % CI) 0.893(0.832,0.959); 0.834(0.719,0.968); 0.862(0.776,0.958)] in allele contrast model, CA19/CA19 vs. non-CA19/non-CA19 model, and recessive genetic model. In subgroup analysis according to ethnicities, (CA)19 repeat polymorphism had an increased risk of common cancers in Asian [OR (95 % CI) of allele contrast model: 1.105(1.000,1.224); additive model: 1.103(0.844,1.441), 1.197(1.013,1.413); recessive model: 1.039(0.831,1.300); and dominant model: 1.191(1.030,1.376)]. On the other hand, IGFBP-3-202A/C gene polymorphism did not seem to be associated with all the cancer sites in any genetic model and ethnicity. In conclusion, the result of this meta-analysis indicates that the IGF1(CA)19 polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors, especially in Asian.

Background The synthetic peptide solnatide is a novel pharmacologic agent that reduces extravascular lung water, blunts reactive oxygen species production, and improves lung function due to its ability to directly activate the epithelial sodium channel. The goal of this study was to investigate the effect of solnatide in pulmonary edema induced by acute hypobaric hypoxia and exercise in rats, which is considered a model for high-altitude pulmonary edema. Methods Sprague-Dawley rats were assigned to low-altitude control and eight treatment groups. Animals of all groups were subjected to exhaustive exercise in a hypobaric hypoxic environment simulating an altitude of 4,500 meters, followed by simulated ascent to 6,000 meters. After 48 h at 6,000 meters, rats were given sodium chloride, dexamethasone, aminophylline, p38 mitogen activated protein kinase inhibitor, and NOD-like receptor containing a pyrin domain 3 inhibitor, or one of three different doses of solnatide, once daily for 3 consecutive days. After 3 days, arterial blood gas, BAL fluid, lung water content, and histologic and ultra-microstructure analyses were performed. Tight junction protein occludin was assayed by using immunohistochemistry. Results Rats treated with solnatide had significantly lower BAL fluid protein and lung water content than high-altitude control rats. Lungs of solnatide-treated rats were intact and showed less hemorrhage and disruption of the alveolar-capillary barrier than those of high-altitude control animals. Occludin expression was significantly higher in solnatide-treated animals, compared with high-altitude control, dexamethasone-, and aminophylline-treated animals. Conclusions Solnatide reduced pulmonary edema, increased occludin expression, and improved gas-blood barrier function during acute hypobaric hypoxia and exercise in rats. These results provide a rationale for the clinical application of solnatide to patients with pulmonary edema and exposure to a high-altitude hypoxic environment.

The endoplasmic reticulum (ER) stress signaling or unfolded protein response (UPR) is a common feature of many human diseases, including cancer. Excessive activation of ER stress directly induces cell death, holding a new promising strategy for the therapeutic intervention of cancer. Current ER-stress-inducing agents mainly target UPR components or proteasomes, which exert limited treatment efficacy and undesired side effects due to unselective ER stress and poor tumor-specific distribution. In this study, a unique near-infrared (NIR) fluorophore, IR-34, is synthesized and identified to selectively and efficiently trigger tumoricidal ER stress by targeting the mitochondrial protein NDUFS1. IR-34 is demonstrated to specifically accumulate in living cancer cells for tumor NIR imaging and drastically inhibit tumor growth and recurrence without causing apparent toxicity. Thus, this multifunctional NIR fluorophore may represent a novel theranostic agent for tumor imaging-guided treatment and also strengthens the idea that mitochondria could be a useful target for therapeutic ER stress in cancer cells.

The preoperative diagnosis of cavernous sinus invasion remains difficult and controversial, and there are currently no reliable histological or molecular markers that predict pituitary tumour behaviour and response to treatment. We evaluated 45 patients with pituitary adenoma. The results have shown that the sensitivity of MRI for indicating cavernous sinus invasion in this prospective study was 60%, specificity 85%, positive predictive value 83.33%, negative predictive value 62.96%. Forty-five specimens of pituitary adenomas were analyzed for expression of F8, VEGF, Ki-67, c-myc, bcl-2, nm23 and MMP-9 immunoreactivity using immunoperoxidase staining. MVD was assessed using F8-related antigen. The results have shown that MVD of invasive pituitary adenomas was significantly higher than that of noninvasive (P < 0.001). There was an association between the invasion of pituitary adenomas and Ki-67 LI (P = 0.039) or the expression of VEGF (P < 0.001) and MMP-9 (P < 0.001). But c-myc LI and bcl-2 expression have no association with invasiveness of pituitary adenomas (P = 0.061 vs. P = 0.201). On the other hand, there is an inverse relationship between nm23 expression and tumor invasion (P < 0.001). In conclusion, parasellar extension of pituitary adenomas through the medial wall of the cavernous sinus diagnosed at surgery, can be determined by radiology with sensitive gadolinium-enhanced MRI. Although our study has shown that MVD and the expression of VEGF, Ki-67, nm23 and MMP-9 have associations with invasiveness of pituitary adenomas, they are lack of specificity. These markers can only provide some useful informations on the therapeutic strategy of pituitary adenomas.

The associations of SNPs rs11614913, rs2292832, and rs2910164 in miRNAs have been exploded in several independent studies and meta-analyses, but the small sample sizes and incomplete data precluded well-defined roles of the miRNA SNPs in the development of CRC. The aim of this study was to combine all available data to comprehensively assess the unclear association. A meta-analysis of nine studies included 2,209 cancers and 2,803 controls, 2,349 cases and 2,663 controls, and 1,409 cases and 1,115 controls for SNP rs11614913, SNP rs2910164, and SNP rs2292832, respectively. The true effect size was estimated by an odds ratio (OR) and 95 % confidence intervals (CI) with the fixed effects model. For SNP rs11614913, the risk of CRC was more pronounced in the C allele carriers as compared with the T allele carriers among the subjects of Asian decent (CC vs. TT: OR = 1.18, 95 % CI 1.01–1.38, P = 0.734; CC vs. TC + TT: OR = 1.18, 95 % CI 1.02–1.36, P = 0.573; C vs. T: OR = 1.08, 95 % CI 1.00–1.17, P = 0.775). SNP rs2910164 and SNP rs2292832 were not found to be significantly associated with CRC risk. This meta-analysis reveals that SNP rs11614913, but not SNP rs2910164 and SNP rs2292832, may contribute to susceptibility to CRC in an Asian-specific manner.

The objective of this study was to confirm the biological role of p38γ in human gliomas. The expression profiles of p38γ and hTERT in human glioma samples were detected by Western Blot and immunohistochemistry. RNA interference was performed in U251 cells by p38γ silencing. Cell proliferation and apoptosis were assayed by CCK-8 and flow cytometric analysis, and then RNA and protein expression levels were measured by real-time RT-PCR and Western Blot, respectively. Telomerase activity assays and Caspase-3,-9 activation assays were also conducted. The results showed p38γ had a positive correlation with the glioma's malignancy grade and that the treatment of U251 cells with p38γ-siRNA inhibited proliferation and induced apoptosis. Correspondingly, hTERT expression and telomerase activity were down regulated and Caspase-3 and -9 activities were elevated. In conclusion, p38γ may serve as an oncogenic factor promoting the growth and progression of gliomas and may become a useful therapeutic target.

The aim of this study was to evaluate the application of phase-contrast cine magnetic resonance imaging (MRI) in endoscopic aqueductoplasty (EA) for patients with obstructive hydrocephalus. The clinical diagnosis of hydrocephalus caused by aqueduct obstruction in 23 patients was confirmed by phase-contrast cine MRI examination. The patients were treated with EA and MRI was repeated during the follow-up. The cerebrospinal fluid (CSF) flow velocity in the aqueduct was measured to determine whether the aqueduct was obstructed. The results of phase-contrast cine MRI examinations indicated that there was no CSF flow in the aqueduct for all patients prior to surgery. Aqueductoplasty was successfully performed in all patients. The results of phase-contrast cine MRI examinations performed a week after surgery demonstrated an average CSF flow velocity of 4.74±1.77 cm/sec. During the follow-up, intracranial hypertension recurred in two patients in whom CSF flow was not observed in the aqueduct by the phase-contrast cine MRI scan. Aqueduct re-occlusion was revealed by an endoscopic exploration. By measuring the CSF flow velocity, phase-contrast cine MRI accurately identifies aqueduct obstruction. Cine MRI is a nontraumatic, simple and reliable method for determining whether the aqueduct is successfully opened following aqueductoplasty.

Concurrent chemoradiotherapy (CCRT) showed a significant improvement in disease control and clinical outcome in patients with intermediate and locoregionally advanced nasopharyngeal carcinoma (NPC) (stage II, III and IVA+B). However, there has been debate about the contribution and application of additional adjuvant chemotherapy (AC) to a CCRT regime. This study aims to evaluate the additional value of AC in the treatment of intermediate and locally advanced NPC with regard to toxicity and clinical outcomes. A total of 189 patients with American Joint Committee on Cancer (AJCC) stage II to stage IVB NPC were retrospectively identified. Patient characteristics, toxicity, compliance with treatment and clinical outcomes, including response to treatment, overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), freedom from local recurrence (FLR) and freedom from distant metastasis (FDM), were analyzed. The overall response rate of CCRT and CCRT/AC groups was 97.92 % and 97.83 %, respectively (P=0.643). The 5-year OS rate was 68.2 % in the CCRT group and 75.9 % in the CCRT/AC group (P=0.53). The 5-year PFS rate was 66.7 % and 71.4 % in CCRT and CCRT/AC groups, respectively (P=0.96). This study showed no evidence of an additional value of AC in CCRT treatment in disease control and clinical outcomes in patients with locally advanced NPC in endemic regions. Moreover, three additional cycles of AC after CCRT appeared to be poorly tolerated in patients. Therefore, AC should not be routinely used for treatment, although clinical trials may be justified.

Background It has been suggested that pituitary adenoma results from accumulation of multiple genetic and/or epigenetic aberrations, which may be identified through association studies. As pituitary tumor transforming gene-1 (PTTG1)/securin plays a critical role in promoting genomic instability in pituitary neoplasia, the present study explored the association of PTTG1 haplotypes with the risk of pituitary adenoma. Methods We genotyped five PTTG1 haplotype-tagging SNPs (htSNP) by PCR-RFLP assays in a case-control study, which included 280 Han Chinese patients diagnosed with pituitary adenoma and 280 age-, gender- and geographically matched Han Chinese controls. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of the htSNPs. Results No significant differences in allele and genotype frequencies of the htSNPs were observed between pituitary adenoma patients and controls, indicating that none of the individual PTTG1 SNPs examined in this study is associated with the risk of pituitary adenoma. In addition, no significant association was detected between the reconstructed PTTG1 haplotypes and pituitary adenoma cases or the controls. Conclusions Though no significant association was found between PTTG1 haplotypes and the risk of pituitary adenoma, this is the first report on the association of individual PTTG1 SNPs or PTTG1 haplotypes with the risk of pituitary adenoma based on a solid study; it will provide an important reference for future studies on the association between genetic alterations in PTTG1 and the risk of pituitary adenoma or other tumors.

Pituitary adenomas are frequently invasive of surrounding tissues, which adversely affects the surgical outcome and the disease-free survival of patients. In the present study, Interleukin 4 receptor (IL-4R) complex has been investigated to figure out whether the three subunits are overexpressed in human invasive pituitary adenomas. Reverse transcription-polymerase chain reaction (RT-PCR) analysis for interleukin 4 receptor alpha (IL-4Ralpha), interleukin 13 receptor alpha1 (IL-13Ralpha1), interleukin 2 receptor gammac (IL-2Rgammac) were performed on total RNA extracted from 10 non-invasive pituitary adenomas, 30 invasive pituitary adenomas, one glioblastoma multiforme, one normal human pituitary tissue sample and one normal human brain tissue sample. Quantitative real-time PCR and in situ immunofluorescence assay were performed in five invasive functioning pituitary adenoma samples and five invasive nonfunctioning pituitary adenoma samples. RT-PCR analysis for IL-4Ralpha, IL-13Ralpha1 and IL-2Rgammac chains were overexpressed in invasive pituitary adenomas. The transcripts for three subunits were not/weakly expressed in normal pituitary tissue and normal brain tissue. The quantitative real-time PCR and in situ immunofluorescence assay confirmed the results of the RT-PCR analysis. Our results indicate that human invasive pituitary adenomas express type III IL-4R complex. These receptors may serve as a novel target for immunotoxin therapy in patients with invasive pituitary adenomas who are not amenable to total surgical resection or for recurrent cases.