Brain metastasis (BM) is one of the most common failure patterns of pIIIA-N2 non-small cell lung cancer (NSCLC) after complete resection. Prophylactic cranial irradiation (PCI) can improve intracranial control but not overall survival. Thus, it is particularly important to identify the risk factors that are associated with BM and subsequently provide instructions for selecting patients who will optimally benefit from PCI.Between 2011 and 2014, patients with pIIIA-N2 NSCLC who underwent complete resection in our institution were reviewed and enrolled in the study. Clinical characteristics, pathological parameters, treatment mode, BM time, and overall survival were analyzed. A nomogram was built based on the corresponding parameters by Fine and Gray's competing risk analysis to predict the 1-, 3-, and 5-year probabilities of BM. Receiver operating characteristic curves and calibration curves were chosen for validation. A statistically significant difference was set as P <0.05.A total of 517 patients were enrolled in our retrospective study. The median follow-up time for surviving patients was 53.2 months (range, 0.50-123.17 months). The median age was 57 (range, 25-80) years. Of the 517 patients, 122 (23.6%) had squamous cell carcinoma, 391 (75.6%) received adjuvant chemotherapy, and 144 (27.3%) received post-operative radiotherapy. The 1-, 3-, and 5-year survival rates were 94.0, 72.9, and 66.0%, respectively. The 1-, 3-, and 5-year BM rates were 5.4, 15.7, and 22.2%, respectively. According to the univariate analysis, female, non-smokers, patients with non-squamous cell carcinoma, bronchial invasion, perineural invasion, and patients who received adjuvant chemotherapy were more likely to develop BM. In a multivariate analysis, non-squamous cell carcinoma (subdistribution hazard ratios, SHR: 3.968; 95% confidence interval, CI: 1.743-9.040; P = 0.0010), bronchial invasion (SHR: 2.039, 95% CI: 1.325-3.139; P = 0.0012), perineural invasion (SHR: 2.514, 95% CI: 1.058-5.976; P = 0.0370), and adjuvant chemotherapy (SHR: 2.821, 95% CI: 1.424-5.589; P = 0.0030) were independent risk factors for BM. A nomogram model was established based on the final multivariable analysis result. The area under the curve was 0.767 (95% CI, 0.758-0.777).For patients with IIIA-N2 NSCLC after complete resection, a nomogram was established based on clinicopathological factors and treatment patterns for predicting the BM. Based on this nomogram, patients with a high risk of BM who may benefit from PCI can be screened.
OBJECTIVE To investigate the expression of DNMT1 in laryngeal squamous cell carcinoma (LSCC) and its relationship with clinicopathological factors. METHOD Ninety-six cases of LSCC samples were detected by immunohistochemical staining to analyze the expression of DNMT1 protein, while 66 cases of them were detected by real-time PCR. And the relationship between the expression of DNMT1 mRNA and clinicopathologic factors was then analyzed. RESULT The expression of DNMT1 mRNA in LSCC were up-regulated (P < 0.05). The positive rate of DNMT1 protein expression in LSCC and in peri-cancer tissue were 100% (96/96) and 36% (8/22) respectively, which showed a significant difference (P < 0.05). DNMT1 mRNA expression wasn't correlated with patients' age, gender, T stage and lympha node metastasis, but was associated with smoking habit (P < 0.05, respectively). CONCLUSION DNMT1 may initiate the oncogenesis of LSCC by increasing expression, and smoking habit may induce the expression of DNMT1 gene.
Post-translational modifications (PTMs) on the histone H3 tail regulate chromatin structure and impact epigenetics and hence the gene expressions. Current chemical modulation tools, such as unnatural amino acid incorporation, protein splicing, and sortase-based editing, have allowed for the modification of histones with various PTMs in cellular contexts, but most of these methods are not applicable for editing native chromatin. The use of small organic molecules to manipulate histone-modifying enzymes alters endogenous histone PTMs but lacks precise temporal and spatial control. To date, there has been no achievement in modulating biologically significant histone methylation in living cells with spatiotemporal resolution. In this study, we present a new method for temporally editing dimethylation H3K9me2 using a photo-responsive inhibitor that specifically targets the histone methyltransferase G9a upon light irradiation. The photo-caged molecule was stable under physiological conditions and in cellular environments, but rapidly decomposed upon exposure to light, releasing the bioactive component that can immediately inhibit the catalytic ability of the G9a in vitro. Besides, this masked compound could also efficiently promote the inhibition of methyltransferase activity in living cells, subsequently suppress H3K9me2, a mark that regulates various chromatin functions. Therefore, our chemical system will be a valuable tool for manipulating the epigenome for therapeutic purposes and furthering the understanding of epigenetic mechanisms.
1459 Objectives Virtually all Cu-chelating systems to date require heating to achieve high radiochemical yields. We have developed a new series of bis(thiosemicarbazone) based Cu(II)-chelators bearing pendant COOH groups in order to develop a chelating system that labels at ambient temperature and pH for labeling sensitive systems. Methods The new bis(thiosemicarbazone) chelators bearing aliphatic and aromatic linkers were successfully synthesised and radiolabeled with 64-Cu and 99m-Tc. Two chelators were conjugated to stabilised bombesin and postlabeled with 64-Cu. Receptor binding studies, internalisation assays and preliminary biodistribution data was obtained using 64/67Cu-(ATSM)-BBS in nude mice with PC-3 tumour xenografts. Results The radiochemical yields for CuATSM-BBS-1 and CuATSM-BBS-2 at room temperature were 91 % and 85 % respectively, labeling at 75°C resulted in yields of 90-95 %. HPLC analysis after 24h showed that the complexes were stable in solution. EPR characterisation indicates rapid labeling and site specificity are maintained when conjugated to a biologically active molecule. Preliminary in vivo studies indicate good uptake with a tumour/muscle ratio of 9.6:1 at 1 h p.i. Significantly this value was reduced by about 52% during blocking studies. In addition, the same ligands could also be labeled with 99m-Tc in high radiochemical purity. Conclusions Initial in vitro and in vivo evaluations of these first generation bis(thiosemicarbazone) functionalised chelators show that they are in principle suitable for protein targeted PET imaging. 99m-Tc-labeling experiments show that these new ATSM derivatives are also promising for the SPECT labeling of proteins
Abstract Post‐translational modifications on the histone H3 tail regulate chromatin structure, impact epigenetics, and hence the gene expressions. Current chemical modulation tools, such as unnatural amino acid incorporation, protein splicing, and sortase‐based editing, have allowed for the modification of histones with various PTMs in cellular contexts, but are not applicable for editing native chromatin. The use of small organic molecules to manipulate histone‐modifying enzymes alters endogenous histone PTMs but lacks precise temporal and spatial control. To date, there has been no achievement in modulating histone methylation in living cells with spatiotemporal resolution. In this study, a new method is presented for temporally manipulating histone dimethylation H3K9me2 using a photo‐responsive inhibitor that specifically targets the methyltransferase G9a on demand. The photo‐caged molecule is stable under physiological conditions and cellular environments, but rapidly activated upon exposure to light, releasing the bioactive component that can immediately inhibit the catalytic ability of the G9a in vitro. Besides, this masked compound could also efficiently reactivate the inhibition of methyltransferase activity in living cells, subsequently suppress H3K9me2, a mark that regulates various chromatin functions. Therefore, the chemical system will be a valuable tool for manipulating the epigenome for therapeutic purposes and furthering the understanding of epigenetic mechanisms.
Although microfluidic approaches for liposomes preparation have been developed, fabricating microfluidic devices remains expensive and time-consuming. Also, owing to the traditional layout of microchannels, the volumetric throughput of microfluidics has been greatly limited. Herein an ultra-high volumetric throughput nanoliposome preparation method using 3D printed microfluidic chips is presented. A high-resolution projection micro stereolithography (PμSL) 3D printer is applied to produce microfluidic chips with critical dimensions of 400 µm. The microchannels of the microfluidic chip adopt a three-layer layout, achieving the total flow rate (TFR) up to 474 ml min-1, which is remarkably higher than those in the reported literature. The liposome size can be as small as 80 nm. The state of flows in microchannels and the effect of turbulence on liposome formation are explored. The experimental results demonstrate that the 3D printed integrated microfluidic chip enables ultra-high volumetric throughput nanoliposome preparation and can control size efficiently, which has great potential in targeting drug delivery systems.
In vivo imaging of skin is commonly used to investigate dynamic processes in the progression and treatment of psoriasis. Photoacoustic mesoscopy is a new non-invasive imaging modality widely used in bio-imaging, and has recently been applied to imaging skin in vivo. However, photoacoustic imaging has shortcomings. Although high-frequency ultrasonic transducers enable high-resolution photoacoustic imaging, the images may be bandwidth-limited. To overcome this limitation, we designed and fabricated a broadband ultrasonic transducer for photoacoustic mesoscopy. The center frequency of the transducer was 32 MHz (88% bandwidth at -6 dB). The transducer was used to visualize mouse and human skin morphology. Colocalization of high- and low-frequency components revealed information about both the skin surface and dermis. To explore dynamic structural changes in mouse back skin during psoriasis progression, we measured blood oxygen saturation and total hemoglobin in a mouse model using multiwavelength imaging without contrast agents. The results indicate that functional photoacoustic mesoscopy using a broadband high-frequency transducer has great potential for clinical imaging of skin disease.
To investigate the clinical efficacy and influence on thyroid function of ultrasound-guided microwave ablation (UGMWA) in patients with nodular goiter.
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