Liver regeneration is the basic physiological process after partial hepatectomy (PH), and is important for the functional rehabilitation of the liver after acute hepatic injury. This study was designed to explore the effects of neurolytic celiac plexus block (NCPB) on liver regeneration after PH. We established a model of PH in rats, assessing hepatic blood flow, liver function, and serum CRP, TNF-α, IL-1β and IL-6 concentrations of the residuary liver after PH. Additionally, histopathological studies, immunohistochemistry, and western blotting were also performed. Our results indicated that NCPB treatment after PH improved liver regeneration and survival rates, increased hepatic blood flow, reduced hepatocyte damage, decreased the secretion and release of inflammatory cytokines, increased the expression of B cell lymphoma/leukemia-2 (Bcl-2), and decreased the expression of Bcl-2 associated X protein (Bax). Additionally, Western blotting revealed that the expression of NF-κB p65 and c-Jun were decreased in liver after NCPB. In conclusion, the results of our present study indicate that NCPB treatment has a favorable effect on liver regeneration after PH. We suggest that NCPB can be utilized as an effective therapeutic method to help the functional rehabilitation of the liver after acute hepatic injury or liver cancer surgery.
To assess the image quality and effective radiation dose of prospectively electrocardiogram (ECG)-gated high-pitch spiral acquisition mode (flash mode) of dual-source CT (DSCT) coronary angiography (CTCA) in patients with high heart rates (HRs) as compared with retrospectively ECG-gated spiral acquisition mode.
Materials and Methods
Two hundred and sixty-eight consecutive patients (132 female, mean age: 55 ± 11 years) with mean HR > 65 beats per minute (bpm) were prospectively included in this study. The patients were divided into two groups. Collection was performed in group A CTCA using flash mode setting at 20-30% of the R-R interval, and retrospectively ECG-gated spiral acquisition mode in group B. The image noise, contrast-to-noise ratio (CNR), image quality scores, effective radiation dose and influencing factors on image quality between the two groups were assessed.
There were no significant differences in image quality scores and proportions of non-diagnostic coronary artery segments between two groups (image quality scores: 1.064 ± 0.306 [group A] vs. 1.084 ± 0.327 [group B], p = 0.063; proportion of non-diagnostic coronary artery segments: segment-based analysis 1.52% (group A) vs. 1.74% (group B), p = 0.345; patient-based analysis 7.5% (group A) vs. 6.7% (group B), p = 0.812). The estimated radiation dose was 1.0 ± 0.16 mSv in group A and 7.1 ± 1.05 mSv in group B (p = 0.001).
In conclusion, in patients with HRs > 65 bpm without cardiac arrhythmia, the prospectively high-pitch spiral-acquisition mode with image-acquired timing set at 20-30% of the R-R interval provides a similar image quality and low rate of non-diagnostic coronary segments to the retrospectively ECG-gated low-pitch spiral acquisition mode, with significant reduction of radiation exposure.
High-pitch dual-source CT; Prospectively ECG-gated; Coronary angiography; High heart rates
A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.
Accurate classification of Glioblastoma Multiforme (GBM) is crucial for understanding its biological diversity, and informing diagnosis and treatment. The Cancer Genome Atlas (TCGA) project identified four GBM classes using gene expression data, and separately, identified three classes using methylation data. We sought to integrate multiple data types in GBM classification, understand biological features of the newly defined subtypes, and reconcile with prior studies.
We used allele-specific copy number data to estimate the aneuploid content of each tumor, and incorporated this measure of intratumor heterogeneity in class discovery. We estimated the potential cell of origin of individual subtypes and the euploid and aneuploid fractions using reference datasets of known neuronal cell types.
There exists an unexpected correlation between aneuploid content and the observed among-tumor diversity of expression patterns. Joint use of DNA and mRNA data in ab initio class discovery revealed a distinct group that resembles the Proneural subtype described in a separate study and the G-CIMP+ class based on methylation data. Three additional subtypes, Classical, Proliferative, and Mesenchymal, were also identified, and revised the assignment for many samples. The revision showed stronger differences in patient outcome and clearer cell type-specific signatures. Mesenchymal GBMs had higher euploid content, potentially contributed by microglia/macrophage infiltration.
We clarified the confusion regarding the "Proneural" subtype that was defined differently in different prior studies. The ability to infer within-tumor heterogeneity improved class discovery, leading to new subtypes that are closer to the fundamental biology of GBM.
GBM; classification; aneuploid content; survival time; data integration
Stress response induced by surgery is proposed to play an important role in the pathogenesis of postoperative cognitive dysfunction.
To investigate the association between postoperative serum cortisol level and occurrence of cognitive dysfunction early after coronary artery bypass graft surgery.
Prospective cohort study.
Two teaching hospitals.
One hundred and sixth-six adult patients who were referred to elective coronary artery bypass graft surgery from March 2008 to December 2009.
Main Outcome Measures
Neuropsychological tests were completed one day before and seven days after surgery. Cognitive dysfunction was defined using the same definition as used in the ISPOCD1-study. Blood samples were obtained in the first postoperative morning for measurement of serum cortisol concentration. Multivariate Logistic regression analyses were performed to assess the relationship between serum cortisol level and occurrence of postoperative cognitive dysfunction.
Cognitive dysfunction occurred in 39.8% (66 of 166) of patients seven days after surgery. Multivariate Logistic regression analysis showed that high serum cortisol level was significantly associated with the occurrence of postoperative cognitive dysfunction (odds ratio [OR] 2.603, 95% confidence interval [CI] 1.371-4.944, P = 0.003). Other independent predictors of early postoperative cognitive dysfunction included high preoperative New York Heart Association functional class (OR 0.402, 95% CI 0.207-0.782, P = 0.007), poor preoperative Grooved Pegboard test score of nondominant hand (OR 1.022, 95% CI 1.003-1.040, P = 0.020), use of penehyclidine as premedication (OR 2.565, 95% CI 1.109-5.933, P = 0.028), and occurrence of complications within seven days after surgery (OR 2.677, 95% CI 1.201-5.963, P = 0.016).
High serum cortisol level in the first postoperative morning was associated with increased risk of cognitive dysfunction seven days after coronary artery bypass graft surgery.
Aerobic capacity is a strong predictor of all-cause mortality and can influence many complex traits. To explore the biological basis underlying this connection, we developed via artificial selection two rat lines that diverge for intrinsic (i.e. inborn) aerobic capacity and differ in risk for complex disease traits. Here we conduct the first in-depth pedigree and molecular genetic analysis of these lines, the high capacity runners (HCR) and low capacity runners (LCR). Our results show that both HCR and LCR lines maintain considerable narrow-sense heritability (h2) for the running capacity phenotype over 28 generations (h2 = 0.47 ± 0.02 and 0.43 ± 0.02, respectively). To minimize inbreeding, the lines were maintained by rotational mating. Pedigree records predict that the inbreeding coefficient increases at a rate of <1% per generation, ~37-38% slower than expected for random mating. Genome-wide 10K SNP genotype data for generations 5, 14, and 26 demonstrate substantial genomic evolution: between-line differentiation increased progressively, while within-line diversity deceased. Genome-wide average heterozygosity decreased at a rate of <1% per generation, consistent with pedigree-based predictions and confirming the effectiveness of rotational breeding. Linkage disequilibrium index r2 decreases to 0.3 at ~3 Mb, suggesting that the resolution for mapping quantitative trait loci (QTL) can be as high as 2-3 cM. To establish a test population for QTL mapping, we conducted an HCR-LCR intercross. Running capacity of the F1 population (n=176) was intermediate of the HCR and LCR parentals (28 pairs); and the F2 population (n=645) showed a wider range of phenotypic distribution. Importantly, heritability in the F0-F2 pedigree remained high (h2~0.6). These results suggest that the HCR-LCR lines can serve as a valuable system for studying genomic evolution, and a powerful resource for mapping QTL for a host of characters relevant to human health.
Recently we found that ATP5J was over-expressed in tissue samples from patients with colorectal cancer. However, the clinical significance and function of the over-expression of ATP5J in these patients remains unclear. We investigated these issues in the current study. Our results indicated that expression of ATP5J was significantly higher in colorectal cancer tissue than in adjacent tissue, and it was also significantly higher in metastatic lymph nodes than in primary cancer tissue (P<0.05). A correlation between ATP5J expression and tumor differentiation was detected, but no correlation with gender, age, T stage, lymph node metastasis, or survival status was observed. Down-regulation of ATP5J expression attenuated the ability of cell migration and increased the sensitivity to 5-fluorouracil (5-Fu) in cells of the DLD1 cell line. Inversely, up-regulation of ATP5J expression enhanced cell migration and decreased 5-Fu sensitivity, suggesting that the function of ATP5J in colorectal cancer might involve cell migration and 5-Fu sensitivity.
Migration and invasion of malignant cells are prerequisites for cancer progression and metastasis. The Bcl-2 family of proteins consists of about 25 members and has been extensively studied in the context of apoptosis. Despite the fact that small molecules targeting Bcl-2 proteins have already entered clinical trials, very few studies investigated a role of antiapoptotic Bcl-2 proteins beside cell death in the context of metastasis. The aim of this study was to dissect a potential role of the antiapoptotic Bcl-2 proteins Mcl-1, Bcl-2 and Bcl-xL on migration and invasion of colorectal cancer cells independent of their cell death control function. We used migration and invasion assays as well as three dimensional cell cultures to analyze colorectal cancer cell lines (HT29 and SW480) after siRNA mediated knockdown or overexpression of Mcl-1, Bcl-2 or Bcl-xL. We observed neither spontaneous cell death induction nor impaired proliferation of cells lacking Mcl-1, Bcl-2 or Bcl-xL. In contrast, knockdown of Mcl-1 led to increased proliferation. Strikingly, we demonstrate a profound impairment of both, migration and invasion, of colorectal cancer cells after Mcl-1, Bcl-2 or Bcl-xL knockdown. This phenotype was completely revised in cells overexpressing Mcl-1, Bcl-2 or Bcl-xL. The most pronounced effect among the investigated proteins was observed for Bcl-2. The data presented indicate a pivotal role of Mcl-1, Bcl-2 and Bcl-xL for migration and invasion of colorectal cancer cells independent of their known antiapoptotic effects. Thus, our study illustrates novel antitumoral mechanisms of Bcl-2 protein targeting.
To isolate plant-derived compounds with antimicrobial activity from the leaves of Mikania micrantha, to determine the compounds configuration, and to evaluate their antimicrobial activity against eight plant pathogenic fungi (Exserohilum turcicum, Colletotrichum lagenarium, Pseudoperonispora cubensis, Botrytis cirerea, Rhizoctonia solani, Phytophthora parasitica, Fusarium solani, and Pythium aphanidermatum,) and four plant pathogenic bacteria (gram negative bacteria: Ralstonia dolaanacearum, Xanthomonas oryzae pv. Oryzae, Xanthomonas Campestris pv. Vesicatoria, and Xanthomonas campestris pv. Citri), and four bacteria (gram positive bacteria: Staphyloccocus aureus, Bacillus subtilis, Micrococcus luteus, and Bacillus cereus).
Methods and Results
Antimicrobial constituents of the leaves of M. micrantha were isolated using bioactivity- guided fractionation. The antifungal activity of the isolated compounds was evaluated by the inhibit hypha growth method and inhibit spore germination method. Characterization of antibacterial activity was carried out using the minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs). MIC and MBC were determined by the broth microdilution method. Six compounds – deoxymikanolide, scandenolide, dihydroscandenolide, mikanolide, dihydromikanolide, and m - methoxy benzoic acid – have been isolated from leaves of Mikania micrantha H. B. K. Deoxymikanolide, scandenolide, and dihydroscandenolide were new compounds. The result of bioassay showed that all of isolated compounds were effective against tested strains and deoxymikanolide showed the strongest activity.
Conclusions and Significance
The leaves of M. micrantha may be a promising source in the search for new antimicrobial drugs due to its efficacy and the broadest range. Meanwhile, adverse impact of M. micrantha will be eliminated.
The recently activated RTOG studies on stereotactic body radiation therapy (SBRT) of non-small cell lung cancer (NSCLC) require tissue density heterogeneity correction, where the high and intermediate dose compliance criteria were established based on superposition-algorithm dose calculations. The study was aimed to compare superposition-algorithm dose calculations with Monte Carlo (MC) dose calculations for SBRT NSCLC treatment and to evaluate whether compliance criteria need to be adjusted for MC dose calculations.
Materials and Methods
Fifteen RTOG 0236 study sets were used. The PTV volumes range from 10.7 to 117.1 cm3. SBRT conformal treatment plans were generated using CMS XiO treatment planning software with superposition algorithm to meet the dosimetric high and intermediate compliance criteria recommended by the RTOG 0813 protocol. The plans were recalculated using the MC algorithm of a CMS Monaco treatment planning system. Tissue density heterogeneity correction was applied in both calculations.
Overall, the dosimetric quantities of the MC calculations have larger magnitudes than those of the superposition calculations. On average, R100% (ratio of prescription isodose volume to PTV), R50% (ratio of 50% prescription isodose volume to PTV), D2cm (maximal dose 2 cm from PTV in any direction in percentage of prescription dose), and V20 (percentage of lung receiving dose equal to or larger than 20 Gy) increased by 9%, 12%, 7%, and 18%, respectively. In the superposition plans, 3 cases did not meet the criteria for R50% or D2cm. In the MC recalculated plans, 8 cases did not meet the criteria for R100%, R50%, or D2cm. After re-optimization with MC calculations, 5 cases did not meet the criteria for R50% or D2cm.
The results indicate that the dosimetric criteria, e.g., the criteria for R50%, recommended by RTOG 0813 protocol, may need to be adjusted when MC dose calculation algorithm is employed.
RTOG; stereotactic body radiation therapy; non-small-cell lung cancer; heterogeneity correction; Monte Carlo
Macrophages play a central role in the pathogenesis of rheumatoid arthritis (RA). There is an imbalance of inflammatory and antiinflammatory macrophages in RA synovium. Although the polarization and heterogeneity of macrophages in RA have not been fully uncovered, the identity of macrophages in RA can potentially be defined by their products, including the co-stimulatory molecules, scavenger receptors, different cytokines/chemokines and receptors, and transcription factors. In the last decade, efforts to understand the polarization, apoptosis regulation, and novel signaling pathways in macrophages, as well as how distinct activated macrophages influence disease progression, have led to strategies that target macrophages with varied specificity and selectivity. Major targets that are related to macrophage development and apoptosis include TNF-α, IL-1, IL-6, GM-CSF, M-CSF, death receptor 5 (DR5), Fas, and others, as listed in Table 1. Combined data from clinical, preclinical, and animal studies of inhibitors of these targets have provided valuable insights into their roles in the disease progression and, subsequently, have led to the evolving therapeutic paradigms in RA. In this review, we propose that reestablishment of macrophage equilibrium by inhibiting the development of, and/or eliminating, the proinflammatory macrophages will be an effective therapeutic approach for RA and other autoimmune diseases.
Macrophage; Polarization; Rheumatoid arthritis; Therapy; Management; Reform; Removal; Joint recruitment; Inflammation; Depletion; TRAIL
The evolution of TLR-mediated innate immunity is a fundamental question in immunology. Here, we report the characterization and functional analysis of four TLR members in the lophotrochozoans Crassostreagigas (CgTLRs). All CgTLRs bear a conserved domain organization and have a close relationship with TLRs in ancient non-vertebrate chordates. In HEK293 cells, every CgTLR could constitutively activate NF-κB responsive reporter, but none of the PAMPs tested could stimulate CgTLR-activated NF-κB induction. Subcellular localization showed that CgTLR members have similar and dual distribution on late endosomes and plasma membranes. Moreover, CgTLRs and CgMyD88 mRNA show a consistent response to multiple PAMP challenges in oyster hemocytes. As CgTLR-mediated NF-κB activation is dependent on CgMyD88, we designed a blocking peptide for CgTLR signaling that would inhibit CgTLR-CgMyD88 dependent NF-κB activation. This was used to demonstrate that a Vibrio parahaemolyticus infection-induced enhancement of degranulation and increase of cytokines TNF mRNA in hemocytes, could be inhibited by blocking CgTLR signaling. In summary, our study characterized the primitive TLRs in the lophotrocozoan C. gigas and demonstrated a fundamental role of TLR signaling in infection-induced hemocyte activation. This provides further evidence for an ancient origin of TLR-mediated innate immunity.
We demonstrate the feasibility of a label-free electrochemical method to detect the kinetics of phosphorylation and dephosphorylation of surface-attached peptides catalyzed by kinase and phosphatase, respectively. The peptides with a sequence specific to c-Src tyrosine kinase and protein tyrosine phosphatase 1B (PTP1B) were first validated with ELISA-based protein tyrosine kinase assay and then functionalized on vertically aligned carbon nanofiber (VACNF) nanoelectrode arrays (NEAs). Real-time electrochemical impedance spectroscopy (REIS) measurements showed reversible impedance changes upon the addition of c-Src kinase and PTP1B phosphatase. Only a small and unreliable impedance variation was observed during the peptide phosphorylation, but a large and fast impedance decrease was observed during the peptide dephosphorylation at different PTP1B concentrations. The REIS data of dephosphorylation displayed a well-defined exponential decay following the Michaelis-Menten heterogeneous enzymatic model with a specific constant, kcat/Km, of (2.1 ± 0.1) × 107 M−1 s−1. Consistent values of the specific constant was measured at PTP1B concentration varying from 1.2 to 2.4 nM with the corresponding electrochemical signal decay constant varying from 38.5 to 19.1 s. This electrochemical method can be potentially used as a label-free method for profiling enzyme activities in fast reactions.
real-time electrochemical impedance spectroscopy; phosphorylation and dephosphorylation; carbon nanofiber nanoelectrode array; heterogeneous enzyme kinetics; c-Src kinase; protein tyrosine phosphatase 1B
Devices and materials intended for clinical applications as medical and implant devices should be evaluated to determine their biocompatibility in physiological systems. This article presents results from cytotoxicity assay of L929 mouse fibroblasts culture, tests for skin irritation, intracutaneous reactivity and sensitization, and material implantation tests for the novel copper/low-density polyethylene nanocomposite intrauterine device (nano-Cu/LDPE IUD) with potential for future clinical utilization. Cytotoxicity test in vitro was conducted to evaluate the change in morphology, growth and proliferation of cultured L929 mouse fibroblasts, which in vivo examination for skin irritation (n = 6) and intracutaneous reactivity (n = 6) were carried out to explore the irritant behavior in New Zealand White rabbits. Skin sensitization was implemented to evaluate the potential skin sensitizing in Hartley guinea pigs (n = 35). The materials were implanted into the spinal muscle of rabbits (n = 9). The cytotoxicity grade of the nano-Cu/LDPE IUD was 0–1, suggested that the composite was nontoxic or mildly cytotoxic; no irritation reaction and skin sensitization were identified in any animals of specific extracts prepared from the material under test; similarly to the control sides, the inflammatory reaction was observed in the rabbits living tissue of the implanted material in intramuscular implantation assay. They indicated that the novel composite intrauterine device presented potential for this type of application because they meet the requirements of the standard practices recommended for evaluating the biological reactivity. The nano-Cu/LDPE IUD has good biocompatibility, which is biologically safe for the clinical research as a novel contraceptive device.
Resistance to chemotherapy is a major obstacle in cancer therapy. The main purpose of this study is to evaluate the potential of a folate receptor-targeting nanoparticle to overcome/minimize drug resistance and to explore the underlying mechanisms. This is accomplished with enhanced cellular accumulation and retention of paclitaxel (one of the most effective anticancer drugs in use today and a well-known P-glycoprotein (P-gp) substrate) in a P-gp-overexpressing cancer model. The folate receptor-targeted nanoparticle, HFT-T, consists of a heparin-folate-paclitaxel (HFT) backbone with an additional paclitaxel (T) loaded in its hydrophobic core. In vitro analyses demonstrated that the HFT-T nanoparticle was superior to free paclitaxel or non-targeted nanoparticle (HT-T) in inhibiting proliferation of P-gp-overexpressing cancer cells (KB-8-5), partially due to its enhanced uptake and prolonged intracellular retention. In a subcutaneous KB-8-5 xenograft model, HFT-T administration enhanced the specific delivery of paclitaxel into tumor tissues and remarkably prolonged retention within tumor tissues. Importantly, HFT-T treatment markedly retarded tumor growth in a xenograft model of resistant human squamous cancer. Immunohistochemical analysis further indicated that increased in vivo efficacy of HFT-T nanoparticles was associated with a higher degree of microtubule stabilization, mitotic arrest, antiangiogenic activity, and inhibition of cell proliferation. These findings suggest that when the paclitaxel delivered as an HFT-T nanoparticle, the drug is better retained within the P-gp-overexpressing cells than the free form of paclitaxel. These results indicated that the targeted HFT-T nanoparticle may be promising in minimizing P-gp related drug resistance and enhancing therapeutic efficacy compared with the free form of paclitaxel.
Targeting nanoparticle; paclitaxel; Folate receptor; drug resistance; chemotherapy
Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa, and Goldman-Favre disease. Although physiological ligands have not been identified, it is believed that binding of small molecule agonists, receptor desumoylation, and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 Å resolution. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor’s structural integrity, and allowed us to model a putative active conformation that can accommodate small ligands in its pocket.
Modifications in adhesion molecules profile may change the way tumor cells interact with the surrounding microenvironment. The Cadherin family is a large group of transmembrane proteins that dictate the specificity of the cellular interactions. The Cadherin switch that takes place during epithelial-mesenchymal transition (EMT) contributes to loosening the rigid organization of epithelial tissues and to enhancing motility and invasiveness of tumor cells. Recently, we found Cadherin-6 (CDH6, also known as K-CAD) highly expressed in thyroid tumor cells that display mesenchymal features and aggressive phenotype, following the overexpression of the transcriptional regulator Id1. In this work, we explored the possibility that CDH6 is part of the EMT program in thyroid tumors. We demonstrate that CDH6 is a new transforming growth factor-β (TGF-β) target and that its expression is modulated similarly to other EMT mesenchymal markers, both in vitro and in thyroid tumor patients. We show for the first time that CDH6 is expressed in human thyroid carcinomas and that its expression is enhanced at the invasive front of the tumor. Finally, we show that CDH6 is under the control of the transcription factor RUNX2, which we previously described as a crucial mediator of the Id1 pro-invasive function in thyroid tumor cells. Overall, these observations provide novel information on the mechanism of the EMT program in tumor progression and indicate CDH6 as a potential regulator of invasiveness in thyroid tumors.
The usage of submental flap is a good method for head and neck reconstruction, but it has some risk also, such as anatomical variations and surgical errors. In this article, we present a modified incision design for the submental flap.
We designed a modified submental flap incision method based on the overlap of the incision outline of the submental flap, platysma myocutaneous flap and infrahyoid myocutaneous flap. If we found that the submental flap was unreliable during the neck dissection at the level III, II and Ib areas, the infrahyoid myocutaneous flap or platysma myocutaneous flap was used to replace it. Between 2004 and 2012, we performed 30 cases using this method. As control, 33 radial forearm free flaps were counted. Significant differences were evaluated using the χ2 test and Mann-Whitney U. Survival and recurrence were analyzed using the Kaplan-Meier method.
Of the 30 patients, 27 finally received a submental flap, 1 patient received an infrahyoid myocutaneous flap, and 2 patients received a platysma myocutaneous flap. In patients who received the submental flap, the average operation time was 5.9 hours, 2.4 hours shorter than the radial forearm free flap group; the average age was 61.8, 6.1 years older than the radial forearm free flap group; the survival time and recurrence time did not significantly differ with those of the forearm free flap group; and the success rate was higher than traditional methods.
The wider indications, less required time, the similar low risk of recurrence and death as radial forearm free flap, higher success rate than traditional submental flap harvest methods, and ability to safely harvest a submental flap make the modified incision design a reliable method.
The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone modifying complexes to chromatin. Here, global profiling of CtBP in breast cancer cells reveals that it drives epithelial to mesenchymal transition, stem cell pathways, and genome instability. CtBP expression induces mesenchymal and stem cell-like features while CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively down-regulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumors predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer.
Hybrid materials made from all inorganic components are intriguing in many fields, because they have shown in-depth potential use for electronic and optoelectronic applications including solar cells, gas sensors, photodetectors, and field effect transistors. Hybrid materials made from SnO2 nanoparticles on SnSe nanosheets have been synthesized via a facile, lost-cost and safe solution method, and have been demonstrated as promising multifunctional materials in various prototype devices, including gas sensors, photodetectors, and field effect transistors.
PKCα (protein kinase C alpha, PRKCA) is an important protein involved in several steps of signaling pathways in lung cancer, and microRNAs (miRNAs) have also been shown to participate in lung carcinogenesis. However, it is not clear how PKCα and miRNAs are correlated in the disease. In this report, we aimed to identify novel miRNAs that target PKCα and to study their biological function. Using bioinformatics analysis, we predicted one novel candidate, miR-203, and found differential expression patterns of miR-203 and PKCα in human lung cancer tissues. Moreover, we experimentally validated miR-203 as a direct regulator of PKCα. Finally, we demonstrated that the targeting of PKCα by miR-203 played a critical role in regulating cell proliferation, apoptosis and migration in lung cancer cells. In summary, this study identifies a novel miRNA that targets PKCα and illustrates that the downregulation of PKCα by miR-203 modulates biological processes in lung cancer cells.
Baicalein, a widely used Chinese herbal medicine, has historically been used in anti-inflammatory and anti-cancer therapies. However, the anti-metastatic effect and molecular mechanism(s) of baicalein on hepatocellular carcinoma (HCC) remain poorly understood. Therefore, the purpose of this study was to assess the anti-metastatic effects of baicalein and related mechanism(s) on HCC. Based on assays utilized in both HCC cell lines and in an animal model, we found that baicalein inhibited tumor cell metastasis in vivo and in vitro. Furthermore, after treatment with baicalein for 24 hours, there was a decrease in the levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (u-PA) expression as well as proteinase activity in hepatocellular carcinoma MHCC97H cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 were increased in a dose-dependent fashion. Moreover, baicalein treatment dramatically decreased the levels of the phosphorylated forms of MEK1 and ERK1/2. MEK1 overexpression partially blocked the anti-metastatic effects of baicalein. Combined treatment with an ERK inhibitor (U0126) and baicalein resulted in a synergistic reduction in MMP-2, MMP-9 and u-PA expression and an increase in TIMP-1 and TIMP-2 expression; the invasive capabilities of MHCC97H cells were also inhibited. In conclusion, baicalein inhibits tumor cell invasion and metastasis by reducing cell motility and migration via the suppression of the ERK pathway, suggesting that baicalein is a potential therapeutic agent for HCC.
AL-38022A is a novel synthetic serotonergic (5-HT) ligand that exhibited high affinity for each of the 5-HT2 receptor subtypes (Ki ≤ 2.2 nM), but a significantly lower (>100-fold less) affinity for other 5-HT receptors. In addition, AL-38022A displayed a very low affinity for a broad array of other receptors, neurotransmitter transport sites, ion channels, and second messenger elements, making it a relatively selective agent. AL-38022A potently stimulated functional responses via native and cloned rat (EC50 range: 1.9 – 22.5 nM) and human (EC50 range: 0.5 – 2.2 nM) 5-HT2 receptor subtypes including [Ca2+]i mobilization and tissue contractions with apparently similar potencies and intrinsic activities and was a full agonist at all 5-HT2 receptor subtypes. The CNS activity of AL-38022A was assessed by evaluating its discriminative stimulus effects in both a rat and a monkey drug discrimination paradigm using DOM as the training drug. AL-38022A fully generalized to the DOM stimulus in each of these studies; in monkeys MDL 100907 antagonized both DOM and AL-38022A. The pharmacological profile of AL-38022A suggests that it could be a useful tool in defining 5-HT2 receptor signaling and receptor characterization where 5-HT may function as a neurotransmitter.
Drug discrimination; 5-HT2 receptor; R-DOI; DOM; MDL 100907; rat; monkey