Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and ∼10% of gastric cancer (GC) worldwide. Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC. However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC. High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified. Further characterization of the epigenomes (genome-wide CpG methylation profile—methylome) of NPC and EBVaGC shows that these EBV-associated tumors display a unique high CpG methylation epigenotype with more extensive gene methylation accumulation, indicating that EBV acts as a direct epigenetic driver for these cancers. Mechanistically, oncogenic modulation of cellular CpG methylation machinery, such as DNA methyltransferases (DNMTs), by EBV-encoded viral proteins accounts for the EBV-induced high CpG methylation epigenotype in NPC and EBVaGC. Thus, uncovering the EBV-associated unique epigenotype of NPC and EBVaGC would provide new insight into the molecular pathogenesis of these unique EBV-associated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.
Epstein-Barr virus; CpG methylation; DNA methyltransferase; tumor suppressor gene; naso-pharyngeal carcinoma; gastric cancer
Background. Contrast-induced nephropathy (CIN) limits the outcome of percutaneous coronary intervention (PCI). Objective. To investigate whether pretreatment with Compound Danshen Dripping Pills (CDDP) will decrease the incidence of CIN after PCI. Methods. A total of 229 patients with acute coronary syndrome (ACS) undergoing PCI were divided into the control group (n = 114) and the CDDP (containing salvia miltiorrhiza and sanqi) group (n = 115; given 20 CDDP pills, three times daily before PCI). Serum creatinine, creatinine clearance (CrCl), high-sensitivity C-reactive protein (hsCRP), P-selectin, and intercellular adhesion molecule-1 (ICAM-1) were measured at admission and 24 and 48 h after PCI. Results. CrCl decreased after PCI but recovered after 48 h. In the CDDP group, CrCl recovered more rapidly (P < 0.05). The procedure increased the hsCRP, P-selectin, and ICAM-1 levels, but these levels were less in the CDDP group (P < 0.05). Conclusions. Pretreatment with CDDP can decrease the occurrence of CIN in patients undergoing PCI, suggesting that the early use of CDDP is an appropriate adjuvant pharmacological therapy before PCI.
AIM: To compare the efficacy of different chemotherapeutic agents during conventional transarterial chemoembolization (cTACE) in the treatment of unresectable hepatocellular carcinoma (HCC).
METHODS: A retrospective review was undertaken of patients with unresectable HCC undergoing cTACE from May 2003 to November 2011. A total of 107 patients were treated with at least one cTACE session. Irinotecan (CPT-11) was used as a chemotherapeutic agent in 24 patients, gemcitabine (GEM) in 24 and doxorubicin in 59.
RESULTS: The time to progression and overall survival rates were significantly superior in patients treated with CPT-11 compared with the GEM or doxorubicin treated groups (11.4, 8.2, 9.5 mo, P = 0.02 and 21.7, 12.7, 14.5 mo, P = 0.004, respectively). Subgroup analysis showed that for intermediate-stage HCC, CPT-11 resulted in a significantly longer time to progression and overall survival compared with the GEM or doxorubicin treated groups (P = 0.022; P = 0.003, respectively). There were no significant differences in adverse events among the three groups (P > 0.05).
CONCLUSION: For patients treated with cTACE, the chemotherapeutic agent CPT-11 was significantly associated with improved overall survival and delayed tumor progression compared with GEM or doxorubicin. There were no significant differences in clinical adverse events between the three agents. CPT-11 thus appears to be a promising agent when combined with cTACE for the treatment of HCC.
Irinotecan; Gemcitabine; Transarterial chemoembolization; Hepatocellular carcinoma; Overall survival
This study aimed to evaluate the accuracy of surgical outcomes in free iliac crest mandibular reconstructions that were carried out with virtual surgical plans and rapid prototyping templates.
This study evaluated eight patients who underwent mandibular osteotomy and reconstruction with free iliac crest grafts using virtual surgical planning and designed guiding templates. Operations were performed using the prefabricated guiding templates. Postoperative three-dimensional computer models were overlaid and compared with the preoperatively designed models in the same coordinate system.
Compared to the virtual osteotomy, the mean error of distance of the actual mandibular osteotomy was 2.06 ± 0.86 mm. When compared to the virtual harvested grafts, the mean error volume of the actual harvested grafts was 1412.22 ± 439.24 mm3 (9.12% ± 2.84%). The mean error between the volume of the actual harvested grafts and the shaped grafts was 2094.35 ± 929.12 mm3 (12.40% ± 5.50%).
The use of computer-aided rapid prototyping templates for virtual surgical planning appears to positively influence the accuracy of mandibular reconstruction.
Mandibular tumor; Mandible reconstruction; Virtual surgical planning
The expression of genes encoding proteins involved in triacyglyceride and fatty acid synthesis and storage in cattle muscle are correlated with intramuscular fat (IMF)%. Are the same genes also correlated with IMF% in sheep muscle, and can the same set of genes be used to estimate IMF% in both species?
The correlation between gene expression (microarray) and IMF% in the longissimus muscle (LM) of twenty sheep was calculated. An integrated analysis of this dataset with an equivalent cattle correlation dataset and a cattle differential expression dataset was undertaken. A total of 30 genes were identified to be strongly correlated with IMF% in both cattle and sheep. The overlap of genes was highly significant, 8 of the 13 genes in the TAG gene set and 8 of the 13 genes in the FA gene set were in the top 100 and 500 genes respectively most correlated with IMF% in sheep, P-value = 0. Of the 30 genes, CIDEA, THRSP, ACSM1, DGAT2 and FABP4 had the highest average rank in both species. Using the data from two small groups of Brahman cattle (control and Hormone growth promotant-treated [known to decrease IMF% in muscle]) and 22 animals in total, the utility of a direct measure and different estimators of IMF% (ultrasound and gene expression) to differentiate between the two groups were examined. Directly measured IMF% and IMF% estimated from ultrasound scanning could not discriminate between the two groups. However, using gene expression to estimate IMF% discriminated between the two groups. Increasing the number of genes used to estimate IMF% from one to five significantly increased the discrimination power; but increasing the number of genes to 15 resulted in little further improvement.
We have demonstrated the utility of a comparative approach to identify robust estimators of IMF% in the LM in cattle and sheep. We have also demonstrated a number of approaches (potentially applicable to much smaller groups of animals than conventional methods) to using gene expression to rank animals for IMF% within a single farm/treatment, or to estimate differences in IMF% between two farms/treatments.
Cattle; Gene expression phenotype; IMF%; Sheep
The diatom Phaeodactylum tricornutum can accumulate eicosapentaenoic acid (EPA) up to 30% of the total fatty acids. This species has been targeted for isolating gene encoding desaturases and elongases for long-chain polyunsaturated fatty acid (LC-PUFA) metabolic engineering. Here we first report the cloning and characterization of Δ5-elongase gene in P. tricornutum. A full-length cDNA sequence, designated PhtELO5, was shown to contain a 1110 bp open reading frame encoding a 369 amino acid polypeptide. The putative protein contains seven transmembrane regions and two elongase characteristic motifs of FLHXYHH and MYSYY, the latter being typical for microalgal Δ5-elongases. Phylogenetic analysis indicated that PhtELO5 belongs to the ELO5 group, tightly clustered with the counterpart of Thalassiosira pseudonana. Heterologous expression of PhtELO5 in Pichia pastoris confirmed that it encodes a specific Δ5-elongase capable of elongating arachidonic acid and eicosapentaenoic acid. Co-expression of PhtELO5 and IsFAD4 (a ∆4-desaturase from Isochrysis sphaerica) demonstrated that the high-efficiency biosynthetic pathway of docosahexaenoic acid was assembled in the transgenic yeast. Substrate competition revealed that PhtELO5 exhibited higher activity towards n-3 PUFA than n-6 PUFA. It is hypothesized that Phaeodactylum ELO5 may preferentially participate in biosynthesis of transgenic LC-PUFA via a n-3 pathway in the yeast host.
diatom fatty acids metabolites; Phaeodactylum Δ5-elongase; functional stacking of ELO5 and FAD4
Objective: To quantify the radiation dose in the thyroid attributable to different CT scans and to estimate the thyroid cancer risk in pediatric patients. Methods: The information about pediatric patients who underwent CT scans was abstracted from the radiology information system in one general hospital between 1 January 2012 and 31 December 2012. The radiation doses were calculated using the ImPACT Patient Dosimetry Calculator and the lifetime attributable risk (LAR) of thyroid cancer incidence was estimated based on the National Academies Biologic Effects of Ionizing Radiation VII model. Results: The subjects comprised 922 children, 68% were males, and received 971 CT scans. The range of typical radiation dose to the thyroid was estimated to be 0.61–0.92 mGy for paranasal sinus CT scans, 1.10–2.45 mGy for head CT scans, and 2.63–5.76 mGy for chest CT scans. The LAR of thyroid cancer were as follows: for head CT, 1.1 per 100,000 for boys and 8.7 per 100,000 for girls; for paranasal sinus CT scans, 0.4 per 100,000 for boys and 2.7 per 100,000 for girls; for chest CT scans, 2.1 per 100,000 for boys and 14.1 per 100,000 for girls. The risk of thyroid cancer was substantially higher for girls than for the boys, and from chest CT scans was higher than that from head or paransal sinus CT scans. Conclusions: Chest CT scans caused higher thyroid dose and the LAR of thyroid cancer incidence, compared with paransal sinus or head CT scans. Therefore, physicians should pay more attention to protect the thyroid when children underwent CT scans, especially chest CT scans.
cancer risk; pediatric CT; radiation dose
Cluster of differentiation 8 (CD8) is expressed in cytotoxic T cells, where it functions as a co-receptor for the T-cell receptor by binding to major histocompatibility complex class I (MHCI) proteins, which present peptides on the cell surface. CD8A is critical for cell-mediated immune defense and T-cell development. CD8A transcription is controlled by several cis-acting elements and trans-acting elements and is also regulated by DNA methylation. However, the epigenetic regulation of CD8A in the duck and its relationship with virus infection are still unclear.
We investigated the epigenetic transcriptional regulatory mechanisms, such as DNA methylation, for the expression of the CD8A and further evaluated the contribution of such epigenetic regulatory mechanisms to DHV-I infection in the duck. Real-time quantitative polymerase chain reaction (RT-qPCR) revealed the highest level of CD8A expression to be in the thymus, followed by the lungs, spleen, and liver, and the levels of CD8A expression were very low in the kidney, cerebrum, cerebellum, and muscle in the duck. RT-qPCR also demonstrated that the CD8A mRNA was down-regulated significantly in morbid ducklings treated with DHV-1 and up-regulated significantly in non-morbid ducklings in all the tissues tested. In addition, hypermethylation of CD8A was detected in the morbid ducklings, whereas relatively low methylation of CD8A was evident in the non-morbid ducklings. The CD8A mRNA level was negatively associated with the CpG methylation level of CD8A and global methylation status.
We concluded that the mRNA level of the CD8A was negatively associated with the CpG methylation level of CD8A and global methylation status in the duck, suggesting that the hypermethylation of CD8A may be associated with DHV-1 infection. The first two CpG sites of the CD8A promoter region could be considered as epigenetic biomarkers for resistance breeding against duckling hepatitis disease in the duck.
Aim. To evaluate the predictive value of RRM1, ERCCl, and BRCA1 expression in Chinese NSCLC patients treated with gemcitabine and cisplatin. Methods. Real-time fluorescent quantitative PCR was used to determine the RRM1, ERCC1, and BRCA1 mRNA expression levels of peripheral blood in late-stage NSCLC patients. The relationship between peripheral blood and mRNA expression in tumor tissues was analyzed further.
Results. In terms of the tumor susceptibility to chemotherapy, the response rate in the low-RRM1-expression group was significantly greater than in the high-expression group (52.9% versus 5.9%, χ2 test, P = 0.007). Subjects with low peripheral blood RRM1 expression survived longer than those with high RRM1 expression (15.5 versus 12.0 months, logrank 3.980, P = 0.046). Linear correlations were observed between peripheral blood and tumor tissue expression levels for RRM1 (R2 = 0.045, P = 0.048) and BRCA1 (R2 = 0.021, P = 0.001). Conclusion. Our study demonstrates increased survival and superior efficacy of gemcitabine and cisplatin combination chemotherapy in the treatment of NSCLC patients with low peripheral blood RRM1 expression. The linear correlations of the relative expression of mRNA were observed between peripheral blood and tumor tissue expression levels for RRM1 and BRCA1. RRM1 gene expression may contribute to chemotherapy sensitivity and may be an indicator of survival. It was significant to individual chemotherapy of patients with advanced NSCLC who do not have sufficient tumor tissue.
This study aimed to examine HIF-2α, TWIST, and CXCR4 expression in papillary thyroid carcinoma (PTC) and assesses the association of their expression with clinicopathological indicators. HIF-2α, TWIST, and CXCR4 protein expression in 129 PTCs, 61 nodular hyperplasia, and 118 normal thyroid tissue specimens was analyzed using immunohistochemistry. The protein expression levels of these three molecules were upregulated in PTCs. High protein expression of HIF-2α, TWIST, and CXCR4 was significantly correlated with lymph node metastasis (LNM) (P < 0.001). Furthermore, HIF-2α, TWIST, and CXCR4 protein expression was correlated with one another. Concomitant high expression of these molecules had stronger correlation with LNM than did each alone (P = 0.032 for HIF-2α/TWIST, P < 0.001 for HIF-2α/CXCR4, P = 0.018 for TWIST/CXCR4, and P < 0.001 for HIF-2α/TWIST/CXCR4). Additionally, HIF-2α, TWIST, and CXCR4 mRNA expression were assessed in 30 PTCs, 10 nodular hyperplasia, and 10 normal thyroid tissue specimens using real-time RT-PCR. TWIST and CXCR4 mRNA expression levels were up-regulated in PTCs, and high mRNA expression of TWIST and CXCR4 was significantly correlated with LNM (P = 0.005 and P = 0.010, resp.). These results demonstrated that the evaluation of HIF-2α, TWIST, and CXCR4 expression in PTC may be useful in predicting the risk of LNM.
Cofilin is a member of the actin depolymerizing factor (ADF)/cofilin family, which regulates actin dynamics. Increasing evidence suggests that mitochondrial translocation of cofilin appears necessary for the regulation of apoptosis.
We report that allyl isothiocyanate (AITC) potently induces mitochondria injury and apoptosis. These events were accompanied by a loss of polymerized filamentous actin (F-actin) and increase in unpolymerized globular actin (G-actin). AITC also induces dephosphorylation of cofilin through activation of PP1 and PP2A. Only dephosphorylated cofilin binds to G-actin and translocates to mitochondria during AITC-mediated apoptosis. Mechanistic study revealed that interruption of ROCK1/PTEN/PI3K signaling pathway plays a critical role in AITC-mediated dephosphorylation and mitochondrial translocation of cofilin and apoptosis. Our in vivo study also showed that AITC-mediated inhibition of tumor growth of mouse leukemia xenograft model is in association with dephosphorylation of cofilin.
These findings support a model in which induction of apoptosis by AITC stems primarily from activation of ROCK1 and PTEN, and inactivation of PI3K, leading in turn to activation of PP1 and PP2A, resulting in dephosphorylation of cofilin, which binds to G-actin and translocates to mitochondria, culminating in the dysfunction of mitochondria, release of cytochrome c and apoptosis.
Allyl isothiocyanate; Apoptosis; Cofilin; ROCK1; PI3K; Leukemia
Several studies suggested that celecoxib interferes with bone healing while others contradict these findings. This study was conducted to investigate the effects of celecoxib on bone healing in rats femur mold with a dose based on body surface area conversion.
Materials and Methods:
72 adult female Sprague Dawley rats were randomly divided into three groups after the internal fixation operation of nondisplaced transverse mid diaphyseal fractures of the right femurs. Each group was treated with 1% methylcellulose, celecoxib (21 mg/kg/d) for 1 week, or celecoxib (21 mg/kg/d) for 4 weeks after surgeries respectively. Bone healing scores and callus formation were evaluated by radiographs at 3, 4, 6 weeks after surgeries. Half of these rats were sacrificed for histological analysis at 4 weeks after surgery. The remaining fractured femurs were evaluated by biomechanical tests at 6 weeks after surgery.
The mean radiographic scores for fracture healing of both short and long term groups were lower than that of the control group and the differences among the three groups were statistically significant (P < 0.05) at 3, 4, 6 weeks after surgery. The mean bone trabecula density of both groups was smaller than that of the control group and the differences were also statistically significant (P < 0.05) at 4 week. The maximum load, total energy and stiffness in both the short term and long term groups were significantly decreased compared with those in the control group (P < 0.05) at 6 week.
Both short term and long term sustained use of celecoxib in rat models has significantly inhibitory effects on rat fracture healing.
Celecoxib; cyclooxygenase-2 inhibitors; fracture healing; prostaglandins
We have recently reported that calreticulin (CRT), a luminal resident protein, can be found in the sera of patients with rheumatoid arthritis and also that recombinant CRT (rCRT) exhibits extraordinarily strong immunological activities. We herein further demonstrate that rCRT fragments 18–412 (rCRT/18-412), rCRT/39-272, rCRT/120-308 and rCRT/120-250 can self-oligomerize in solution and are 50–100 fold more potent than native CRT (nCRT, isolated from mouse livers) in activating macrophages in vitro. We narrowed down the active site of CRT to residues 150–230, the activity of which also depends on dimerization. By contrast, rCRT/18-197 is almost completely inactive. When rCRT/18-412 is fractionated into oligomers and monomers by gel filtration, the oligomers maintain most of their immunological activities in terms of activating macrophages in vitro and inducing specific antibodies in vivo, while the monomers were much less active by comparison. Additionally, rCRT/18-412 oligomers are much better than monomers in binding to, and uptake by, macrophages. Inhibition of macrophage endocytosis partially blocks the stimulatory effect of rCRT/18-412. We conclude that the immunologically active site of CRT maps between residues 198–230 and that soluble CRT could acquire potent immuno-pathological activities in microenvironments favoring its oligomerization.
Soil contamination by chromium (Cr) has become an increasing problem worldwide as a result of extensive industrial activities. Chromium, especially hexavalent Cr, impairs the growth and productivity of plants. Although it has been proposed that plants could modify their metabolism to adapt to Cr stress by reprogramming the expression of genes, especially those related to the antioxidant system, damage response, and electron transport chain, evidence at the protein expression level is lacking. To better understand the precise mechanisms underlying Cr phytoxicity and the plant response to Cr exposure, the time-course of changes in the protein expression profile induced by short-term hexavalent Cr exposure (1, 6 and 24 h) were analyzed in maize leaves. Among the over 1200 protein spots detected reproducibly by two-dimensional electrophoresis (2-DE), 60 were found to be differentially accumulated during Cr stress treatment. Of the Cr-regulated proteins, 58 were identified using tandem mass spectrometry (MS/MS). The Cr-regulated proteins identified were mainly involved in ROS detoxification and defense responses (26%), photosynthesis and chloroplast organization (22%), post-transcriptional processing of mRNA and rRNA (12%), protein synthesis and folding (10%), the DNA damage response (5%), and the cytoskeleton (3%). The possible involvement of these Cr stress-responsive proteins in Cr phytoxicity and the plant response to Cr exposure in maize is discussed, taking into consideration the information available from other plant models. Our results provide preliminary evidence that will facilitate understanding the molecular mechanisms underlying Cr toxicity in maize.
maize; chromium; leaf; proteomics
Marine xylanases are rather less studied compared to terrestrial xylanases. In this study, a new xylanase gene, xynB, was cloned from the marine bacterium, Glaciecola mesophila KMM241, and expressed in Escherichia coli. xynB encodes a multi-domain xylanase XynB of glycoside hydrolase (GH) family 8. The recombinant XynB comprises an N-terminal domain (NTD) with unknown function and a catalytic domain, which is structurally novel among the characterized xylanases of GH family 8. XynB has the highest identity (38%) to rXyn8 among the characterized xylanases. The recombinant XynB showed maximal activity at pH 6–7 and 35 °C. It is thermolabile and salt-tolerant. XynB is an endo-xylanase that demands at least five sugar moieties for effective cleavage and to hydrolyze xylohexaose and xylopentaose into xylotetraose, xylotriose and xylobiose. NTD was expressed in Escherichia coli to analyze its function. The recombinant NTD exhibited a high binding ability to insoluble xylan and avicel and little binding ability to chitosan and chitin. Since the NTD shows no obvious homology to any known carbohydrate-binding module (CBM) sequence in public databases, XynB may contain a new type of CBM.
xylanase; XynB; cold-active; Glaciecola mesophila KMM241; carbohydrate-binding module
AIM: To evaluate potential risk factors in the development of ulcerative colitis (UC) in China.
METHODS: A total of 1308 patients with UC and 1308 age-matched and sex-matched controls were prospectively studied in China. The UC cases were collected from 17 hospitals in China from April 2007 to April 2010. Uniform questionnaires were designed to investigate risk factors including smoking, appendectomy, stress, socio-economic conditions, nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, diet, breastfeeding, infections and family sanitary conditions. Group comparisons by each factor were done using simple logistic regression analysis. Conditional logistic regression was used for multivariate analysis.
RESULTS: By univariate analysis, the variables predictive of UC included feeling stress, light and heavy alcoholic drinking, spicy food, sugar consumption and infectious diarrhea, while heavy tea intake and tap water consumption were protective against UC. On multivariate analysis, the protective factor for UC was tap water consumption [odds ratios (OR) = 0.424, 95%CI: 0.302-0.594, P < 0.001]; while the potential risk factors for UC were heavy sugar consumption (OR = 1.632, 95%CI: 1.156-2.305, P < 0.001), spicy food (light intake: OR = 3.329, 95%CI: 2.282-4.857, P < 0.001; heavy intake: OR = 3.979, 95%CI: 2.700-5.863, P < 0.001), and often feeling stress (OR = 1.981, 95%CI: 1.447-2.711, P < 0.001). Other factors, such as smoking habit, appendectomy, breastfeeding, a history of measles, rural or urban residence, education, oral contraceptives, and NSAID use have not been found to have a significant association with the development of UC in the present study.
CONCLUSION: Our study showed tap water consumption was a protective factor for UC, while spicy food, heavy sugar consumption and often feeling stress were risk factors for UC in this Chinese population.
Ulcerative colitis; Risk factors; Case-control study
Zinc-alpha2-glycoprotein (AZGP1, ZAG) was recently demonstrated to be an important factor in tumor carcinogenesis. However, AZGP1 expression in hepatocellular carcinoma (HCC) and its significance remain largely unknown.
Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to determine mRNA level of AZGP1 in 20 paired fresh HCC tissues. Clinical and pathological data of 246 HCC patients were collected. Tissue-microarray-based immunohistochemistry (IHC) was performed to examine AZGP1 expression in HCC samples. Relationship between AZGP1 expression and clinicopathological features was analyzed by Chi-square test, Kaplan-Meier analysis and Cox proportional hazards regression model.
AZGP1 expression was significantly lower in 80.0% (16/20) of tumorous tissues than that in the corresponding adjacent nontumorous liver tissues (P < 0.001). Consistently, IHC data revealed that decreased expression of AZGP1 was present in 80.1% (197/246) of HCC patient tissues (P < 0.001). Furthermore, AZGP1 expression in HCC significantly associated with several clinicopathological parameters, including serum AFP level (P = 0.013), liver cirrhosis (P = 0.002) and tumor differentiation (P = 0.025). Moreover, HCC patients with high AZGP1 expression survived longer, with better overall survival (P = 0.006) and disease-free survival (P = 0.025). In addition, low AZGP1 expression associated with worse relapse-free survival (P = 0.046) and distant metastatic progression-free survival (P = 0.036).
AZGP1 was downregulated in HCC and could be served as a promising prognostic marker for HCC patients.
AZGP1; Hepatocellular carcinoma; Prognosis; Recurrence; Metastasis
Primary malignant melanoma occurring at an extra cutaneous site is rare. A case of primary malignant melanoma located in the retroperitoneum of an 18-year-old female is presented in this study. Histopathological examination of the tissue biopsies at laparotomy with immunohistochemical stains confirmed a diagnosis of malignant melanoma. Further extensive clinical and radiological investigations proved the retroperitoneum to be the primary site.
malignant melanoma; retroperitoneum; computed tomography; magnetic resonance imaging
To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts.
A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rho-kinase inhibitor fasudil hydrochloride hydrate (10 mg·kg-1·d-1, ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting.
In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved.
The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.
diabetes; myocardial fibrosis; Rho kinase; c-Jun NH2-terminal kinase; transforming growth factor-β
In the title compound, C17H14N2O4S·0.5H2O, the molecule, with the exception of the two methoxyphenyl groups, is nearly planar with an r.m.s. deviation of 0.0305 Å. The two 2-methoxyphenyl rings make dihedral angles of 4.1 (3) and 2.3 (3)° with the thiadiazole ring. In the crystal, intermolecular C—H⋯O and O—H⋯N hydrogen bonds link the molecules.
To investigate whether telmisartan (Telm) pretreatment attenuates isoproterenol (Iso)-induced postinfarction remodeling (PIR) in rats, and whether the effect of Telm is associated with cardiac expression of adiponectin.
PIR was induced in male Wistar rats with two consecutive injections of Iso (80 mg/kg, sc) at an interval of 24 h. Primary culture of ventricular myocytes from neonatal rats was prepared. Iso-induced cardiomyocyte injury was assessed based on cell growth and lactate dehydrogenase (LDH) activity. Cardiac adiponectin expression was measured using qRT-PCR and immunoblot analysis.
In the rats with PIR, Telm (10 mg·kg−1·d−1, po for 65 d) suppressed Iso-induced increases in gravimetric parameters, cardiomyocyte diameter and collagen volume fraction, but had no effect on Iso-induced myocardial hypertrophy and interstitial fibrosis. The protective effect of Telm was associated with enhanced protein expression of cardiac adiponectin. In cultured cardiomyocytes, Telm (5–20 μmol/L) inhibited the cell death and LDH release induced by Iso (10 μmol/L), and reversed Iso-induced reduction in adiponectin protein expression. In cardiomyocytes exposed to Iso (20 μmol/L), GW9662 (30 μmol/L), a selective antagonist of PPAR-γ, blocked the effects of Telm pretreatment on adiponectin protein expression, as well as the protective effects of Telm on Iso-induced cell injury.
Telm attenuates Iso-induced cardiac remodeling and cell injury, which is associated with induction of cardiac adiponectin expression.
telmisartan; angiotensin II receptor blocker; congestive heart failure; cardiac remodeling; cardiac fibrosis; adiponectin; isoproterenol
Objective: To evaluate the predictive values of gene expressions of ribonucleotide reductase M1 (RRM1) and breast cancer susceptibility gene 1 (BRCA1) in peripheral blood from Chinese patients with non-small-cell lung cancer (NSCLC) treated with gemcitabine plus platinum. Methods: Forty Chinese patients with advanced NSCLC were recruited and received gemcitabine 1 200 mg/m2 on Days 1 and 8 plus carboplatin AUC 5 on Day 1. RRM1 and BRCA1 expression levels in peripheral blood were detected by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Kaplan-Meier survival curve and log-rank test were performed to evaluate the correlation between gene expression and overall survival for these subjects. Results: No correlation was observed between gene expression of RRM1 and that of BRCA1 (P>0.05), but there was a strong correlation between the expression of RRM1 and the response to chemotherapy (P=0.003). Subjects with low RRM1 expression levels in peripheral blood had longer survival time than those with high RRM1 expression levels (16.95 vs. 12.76 months, log-rank 3.989, P=0.046). However, no significant association between BRCA1 expression levels and survival time was found (16.80 vs. 13.77 months, log-rank 0.830, P=0.362). Conclusions: Patients with low RRM1 expression levels in peripheral blood have a greater response to chemotherapy and longer survival time. Advanced NSCLC patients with low RRM1 expression levels may benefit from gemcitabine plus platinum therapy. RRM1 mRNA expression in peripheral blood could be used to predict the prognosis of NSCLC treated by gemcitabine and platinum.
Gemcitabine; Ribonucleotide reductase M1 (RRM1); Breast cancer susceptibility gene 1 (BRCA1); Non-small-cell lung cancer (NSCLC); Gene expression
In the crystal structure of the title compound, C10H11NO5, intermolecular O—H⋯O hydrogen bonds link the molecules into chains along the b-axis direction. Weak C—H.·O hydrogen bonds also occur.
The title compound, C11H12N2O2, was synthesized from the reaction of 6-methylpyridin-2-amine and ethyl 3-bromo-2-oxopropionate. In the molecular structure, the six- and five-membered rings are individually almost planar with r.m.s. deviations of 0.003 and 0.002 Å, respectively. The two rings are almost coplanar, the dihedral angle between their planes being 1.4 (3)°. Intermolecular C—H⋯O and C—H⋯N hydrogen bonds are present in the crystal structure.