Silica nanoparticle design for colorectal cancer treatment: Recent progress and clinical potential.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer death. Nanotherapies are able to selectively target the delivery of cancer therapeutics, thus improving overall antitumor efficiency and reducing conventional chemotherapy side effects. Mesoporous silica nanoparticles (MSNs) have attracted the attention of many researchers due to their remarkable advantages and biosafety. We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.

Cytoplasmic Escape of Mitochondrial DNA Mediated by Mfn2 Downregulation Promotes Microglial Activation via cGas-Sting Axis in Spinal Cord Injury.

Neuroinflammation is associated with poor outcomes in patients with spinal cord injury (SCI). Recent studies have demonstrated that stimulator of interferon genes (Sting) plays a key role in inflammatory diseases. However, the role of Sting in SCI remains unclear. In the present study, it is found that increased Sting expression is mainly derived from activated microglia after SCI. Interestingly, knockout of Sting in microglia can improve the recovery of neurological function after SCI. Microglial Sting knockout restrains the polarization of microglia toward the M1 phenotype and alleviates neuronal death. Furthermore, it is found that the downregulation of mitofusin 2 (Mfn2) expression in microglial cells leads to an imbalance in mitochondrial fusion and division, inducing the release of mitochondrial DNA (mtDNA), which mediates the activation of the cGas-Sting signaling pathway and aggravates inflammatory response damage after SCI. A biomimetic microglial nanoparticle strategy to deliver MASM7 (named MSNs-MASM7@MI) is established. In vitro, MSNs-MASM7@MI showed no biological toxicity and effectively delivered MASM7. In vivo, MSNs-MASM7@MI improves nerve function after SCI. The study provides evidence that cGas-Sting signaling senses Mfn2-dependent mtDNA release and that its activation may play a key role in SCI. These findings provide new perspectives and potential therapeutic targets for SCI treatment.

The c-di-GMP Phosphodiesterase PipA (PA0285) Regulates Autoaggregation and Pf4 Bacteriophage Production in Pseudomonas aeruginosa PAO1.

In Pseudomonas aeruginosa PAO1, 41 genes encode proteins predicted to be involved in the production or degradation of c-di-GMP, a ubiquitous secondary messenger that regulates a variety of physiological behaviors closely related to biofilm and aggregate formation. Despite extensive effort, the entire picture of this important signaling network is still unclear, with one-third of these proteins remaining uncharacterized. Here, we show that the deletion of pipA, which produces a protein containing two PAS domains upstream of a GGDEF-EAL tandem, significantly increased the intracellular c-di-GMP level and promoted the formation of aggregates both on surfaces and in planktonic cultures. However, this regulatory effect was not contributed by either of the two classic pathways modulating biofilm formation, exopolysaccharide (EPS) overproduction or motility inhibition. Transcriptome sequencing (RNA-Seq) data revealed that the expression levels of 361 genes were significantly altered in a ΔpipA mutant strain compared to the wild type (WT), indicating the critical role of PipA in PAO1. The most remarkably downregulated genes were located on the Pf4 bacteriophage gene cluster, which corresponded to a 2-log reduction in the Pf4 phage production in the ΔpipA mutant. The sizes of aggregates in ΔpipA cultures were affected by exogenously added Pf4 phage in a concentration-dependent manner, suggesting the quantity of phage plays a part in regulating the formation of aggregates. Further analysis demonstrated that PipA is highly conserved across 83 P. aeruginosa strains. Our work therefore for the first time showed that a c-di-GMP phosphodiesterase can regulate bacteriophage production and provided new insights into the relationship between bacteriophage and bacterial aggregation. IMPORTANCE The c-di-GMP signaling pathways in P. aeruginosa are highly organized and well coordinated, with different diguanylate cyclases and phosphodiesterases playing distinct roles in a complex network. Understanding the function of each enzyme and the underlying regulatory mechanisms not only is crucial for revealing how bacteria decide the transition between motile and sessile lifestyles, but also greatly facilitates the development of new antibiofilm strategies. This work identified bacteriophage production as a novel phenotypic output controlled transcriptionally by a phosphodiesterase, PipA. Further analysis suggested that the quantity of phage may be important in regulating autoaggregation, as either a lack of phage or overproduction was associated with higher levels of aggregation. Our study therefore extended the scope of c-di-GMP-controlled phenotypes and discovered a potential signaling circuit that can be target for biofilm treatment.

A pan-kidney cancer study identifies subtype specific perturbations on pathways with potential drivers in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a complex disease and is comprised of several histological subtypes, the most frequent of which are clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PRCC) and chromophobe renal cell carcinoma (ChRCC). While lots of studies have been performed to investigate the molecular characterizations of different subtypes of RCC, our knowledge regarding the underlying mechanisms are still incomplete. As molecular alterations are eventually reflected on the pathway level to execute certain biological functions, characterizing the pathway perturbations is crucial for understanding tumorigenesis and development of RCC. METHODS: In this study, we investigated the pathway perturbations of various RCC subtype against normal tissue based on differential expressed genes within a certain pathway. We explored the potential upstream regulators of subtype-specific pathways with Ingenuity Pathway Analysis (IPA). We also evaluated the relationships between subtype-specific pathways and clinical outcome with survival analysis. RESULTS: In this study, we carried out a pathway-based analysis to explore the mechanisms of various RCC subtypes with TCGA RNA-seq data. Both commonly altered pathways and subtype-specific pathways were detected. To identify the distinctive characteristics of each subtype, we focused on subtype-specific perturbed pathways. Specifically, we observed that some of the altered pathways were regulated by several recurrent upstream regulators which presenting different expression patterns among distinct RCC subtypes. We also noticed that a large number of perturbed pathways were controlled by the subtype-specific upstream regulators. Moreover, we also evaluated the relationships between perturbed pathways and clinical outcome. Prognostic pathways were identified and their roles in tumor development and progression were inferred. CONCLUSIONS: In summary, we evaluated the relationships among pathway perturbations, upstream regulators and clinical outcome for differential subtypes in RCC. We hypothesized that the alterations of common upstream regulators as well as subtype-specific upstream regulators work together to affect the downstream pathway perturbations and drive cancer initialization and prognosis. Our findings not only increase our understanding of the mechanisms of various RCC subtypes, but also provide targets for personalized therapeutic intervention.

Correlation Analysis of Histopathology and Proteogenomics Data for Breast Cancer.

Tumors are heterogeneous tissues with different types of cells such as cancer cells, fibroblasts, and lymphocytes. Although the morphological features of tumors are critical for cancer diagnosis and prognosis, the underlying molecular events and genes for tumor morphology are far from being clear. With the advancement in computational pathology and accumulation of large amount of cancer samples with matched molecular and histopathology data, researchers can carry out integrative analysis to investigate this issue. In this study, we systematically examine the relationships between morphological features and various molecular data in breast cancers. Specifically, we identified 73 breast cancer patients from the TCGA and CPTAC projects matched whole slide images, RNA-seq, and proteomic data. By calculating 100 different morphological features and correlating them with the transcriptomic and proteomic data, we inferred four major biological processes associated with various interpretable morphological features. These processes include metabolism, cell cycle, immune response, and extracellular matrix development, which are all hallmarks of cancers and the associated morphological features are related to area, density, and shapes of epithelial cells, fibroblasts, and lymphocytes. In addition, protein specific biological processes were inferred solely from proteomic data, suggesting the importance of proteomic data in obtaining a holistic understanding of the molecular basis for tumor tissue morphology. Furthermore, survival analysis yielded specific morphological features related to patient prognosis, which have a strong association with important molecular events based on our analysis. Overall, our study demonstrated the power for integrating multiple types of biological data for cancer samples in generating new hypothesis as well as identifying potential biomarkers predicting patient outcome. Future work includes causal analysis to identify key regulators for cancer tissue development and validating the findings using more independent data sets.

Expression of WNT1 in ameloblastoma and its significance.

The present study aimed to measure the expression of WNT1 in ameloblastoma (AB). Immunohistochemistry was used to observe changes in WNT1 expression in 80 AB samples, 10 keratocystic odontogenic tumor (KCOT) samples and 10 normal oral mucosa (NOM) samples. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to measure WNT1 protein and mRNA expression, respectively, in 30 AB samples, 5 KCOT samples, 5 NOM samples and 3 tooth germ samples. Ectopic cytoplasmic expression of WNT1 was detected in AB; 88.8% (71/80) of the samples were WNT1-positive. The western blotting results demonstrated that compared with NOM (0.57±0.05), WNT1 expression was significantly higher in AB tissue (1.74±0.36, P<0.05), whereas it was not significantly different between AB and KCOT samples (0.80±0.06, P>0.05). RT-qPCR revealed that the level of WNT1 gene expression in AB was increased 2.43-fold compared with normal mucosa, and 1.77-fold compared with tooth germ tissue. In conclusion, WNT1 protein and mRNA expression were increased in AB, and there was ectopic cytoplasmic expression. This indicates that WNT1 may serve an important role in AB occurrence and development.

Analyzing and modeling rheological behavior of liver fibrosis in rats using shear viscoelastic moduli.

The process of liver fibrosis changes the rheological properties of liver tissue. This study characterizes and compares liver fibrosis stages from F0 to F4 in rats in terms of shear viscoelastic moduli. Here two viscoelastic models, the Zener model and Voigt model, were applied to experimental data of rheometer tests and then values of elasticity and viscosity were estimated for each fibrosis stage. The results demonstrate that moderate fibrosis (≤F2) has a good correlation with liver viscoelasticity. The mean Zener elasticity E1 increases from (0.452±0.094) kPa (F0) to (1.311±0.717) kPa (F2), while the mean Voigt elasticity E increases from (0.618±0.089) kPa (F0) to (1.701±0.844) kPa (F2). The mean Zener viscosity increases from (3.499±0.186) Pa·s (F0) to (4.947±1.811) Pa·s (F2) and the mean Voigt viscosity increases from (3.379±0.316) Pa·s (F0) to (4.625±1.296) Pa·s (F2). Compared with viscosity, the elasticity shows smaller variations at stages F1 and F2 no matter what viscoelastic model is used. Therefore, the estimated elasticity is more effective than viscosity for differentiating the fibrosis stages from F0 to F2.

Quantitative imaging of young's modulus of soft tissues from ultrasound water jet indentation: a finite element study.

Indentation testing is a widely used approach to evaluate mechanical characteristics of soft tissues quantitatively. Young's modulus of soft tissue can be calculated from the force-deformation data with known tissue thickness and Poisson's ratio using Hayes' equation. Our group previously developed a noncontact indentation system using a water jet as a soft indenter as well as the coupling medium for the propagation of high-frequency ultrasound. The novel system has shown its ability to detect the early degeneration of articular cartilage. However, there is still lack of a quantitative method to extract the intrinsic mechanical properties of soft tissue from water jet indentation. The purpose of this study is to investigate the relationship between the loading-unloading curves and the mechanical properties of soft tissues to provide an imaging technique of tissue mechanical properties. A 3D finite element model of water jet indentation was developed with consideration of finite deformation effect. An improved Hayes' equation has been derived by introducing a new scaling factor which is dependent on Poisson's ratios v, aspect ratio a/h (the radius of the indenter/the thickness of the test tissue), and deformation ratio d/h. With this model, the Young's modulus of soft tissue can be quantitatively evaluated and imaged with the error no more than 2%.

Highly sensitive computer aided diagnosis system for breast tumor based on color Doppler flow images.

A computer-aided diagnosis (CAD) system for breast tumor based on color Doppler flow images is proposed. Our system consists of automatic segmentation, feature extraction, and classification of breast tumors. First, the B-mode grayscale image containing anatomical information was separated from a color Doppler flow image (CDFI). Second, the boundary of the breast tumor was automatically defined in the B-mode image and then morphologic and gray features were extracted. Third, an optimal feature vector was created using K-means cluster algorithm. Then a back-propagation (BP) artificial neural network (ANN) was used to classify breast tumors as benign, malignant or uncertain. Finally, the blood flow feature was extracted selectively from the CDFI, and was used to classify the uncertain tumor as benign or malignant. Experiments on 500 cases show that the proposed system yields an accuracy of 100% for the malignant and 80.8% for the benign classification. Comparing with other systems, the advantage of our system is that it has a much lower percentage of malignant tumor misdiagnosis.

[The application of circular stapler in extraperitoneal colostomy].

OBJECTIVE: To evaluate the clinical and application value of circular stapler in extraperitoneal colostomy. METHODS: Retrospective analysis was made to 22 cases that experienced extraperitoneal colostomy with circular stapler from Match 2008 to March 2009 in the department of colon and anal surgery of the first hospital of Jilin University. RESULTS: The length of surgery was (15 +/- 5) min when circular stapler- assisted extraperitoneal colostomy was used, and all of the colostomies were successfully completed during the first procedure. No complications occurred after surgery, such as stoma bleeding, necrosis, infection, retraction, stenosis, intestinal obstruction and hernia beside the stoma etc. Colostomy size of the uniform, beautiful shape formation. Although there were three cases requiring hemostasis due to anastomotic bleeding that occurred during the operation. About 3 months later, staples of the stoma fell off by themselves. All patients were followed up for 6 to 24 months after operation, form and function of colostomy are well. CONCLUSION: The popularization of the application of circular stapler in extraperitoneal colostomy is important and worthwhile for its obvious advantages such as simple operation, good stoma appearance and reduced complications.

Detection of Acute and Established HIV Infections in Sexually Transmitted Disease Clinics in Guangxi, China: Implications for Screening and Prevention of HIV Infection.

BACKGROUND: Human immunodeficiency virus (HIV) has spread throughout China and to some degree has penetrated the general heterosexual population in some regions. METHODS: A cross-sectional survey of 11,461 sexually transmitted disease (STD) clinic attendees in 8 cities in Guangxi, China, was conducted for syphilis and for acute and established HIV infections. RESULTS: The prevalence of acute and established HIV infections was 1.2% among the participants. Five acute (preseroconversion) HIV infections were detected. Multivariate analysis showed that HIV infection was independently related to unmarried status (odds ratio [OR], 1.73 [95% confidence interval {CI}, 1.00-2.99), less education (OR for less than primary school, 4.21 [90% CI, 1.21-14.58]), residence in city A (OR, 11.48 [95% CI, 2.05-64.31]) or city B (OR, 7.93 [95% CI, 1.75-35.91]), working in the entertainment industry (OR, 3.98 [95% CI, 1.14-13.88]), injection drug use (OR, 25.09 [95% CI, 10.43-60.39]), no condom use during most recent sexual intercourse (OR, 4.97 [95% CI, 1.38-17.88]), and syphilitic infection (OR, 1.91 [95% CI, 1.03-3.56]). CONCLUSIONS: HIV prevalence in STD clinics is significantly greater than that in the general population, and subjects were identified who would be missed by conventional surveillance. China's nationwide system of public STD clinics, which reach down to the township level, should be used for HIV control programs.

Automatic segmentation of echocardiography based on a morphological reconstruction algorithm.

OBJECTIVE: To improve the precision of the traditional segmentation of echocardiogram, by suppressing the influence from inherent speckle noises in medical ultrasonic images. METHOD: An automatic segmentation method based on reconstructed morphology was proposed in this paper. First, the opening and closing operations by reconstruction were imposed to the ultrasonic image. Second, the top-hat operation was used to extract the bright and/or dark features and to find out the boundaries corresponding to these features, whereby implemented the automatic segmentation. RESULT: The segmented echocardiogram had less artificial boundaries resulted from speckle noise, and could accurately be extracted the artery and ventricle. CONCLUSION: The presented method can detect both dark and bright objects accurately, and the boundary has a fine continuity. In addition, the algorithm is also applicable to the extraction of sole bright/dark features, accordingly to reduce the complexity and time needed and to improve the accuracy.

[A medical ultrasonic image filtering method based on anisotropic diffusion].

OBJECTIVE: To remove the speckle noise in ultrasonic images by using anisotropic diffusion method. METHOD: Based on anisotropic diffusion, a partial differential equation, of which the initial data was the input images, was transformed into differential forms and solved with iterations. The speckle scale function of the equation was modified to make better use in filtering medical ultrasonic images. RESULT: By comparing the results with other three filters, the anisotropic diffusion method could smooth the speckles very well and the edge of the image was also clear. CONCLUSION: Anisotropic diffusion can remove the speckle noise effectively and has great potential in filtering medical ultrasonic images.

[Research of myocardial velocity characteristics of paced canine heart based on ultrasonic Doppler tissue imaging].

OBJECTIVE: To quantitatively analyze the characteristics of regional myocardial velocities of paced heart over His bundle, and explore the myocardial velocity pattern. METHOD: 5 dogs were paced at 120 times/min over His bundle. We defined the His bundle adjacent region and the top region of interventricular septum (IVS) as our regions of interest (ROI). Images of Doppler tissue velocity in ROI and corresponding electrocardiograms were observed and recorded by a 2-D Color Doppler tissue imaging (DTI) system. Quantitative velocities of myocardial DTI images were mapped by a neural network from the image sequences. Finally the velocity characteristics of the myocardium around His bundle and IVS were analyzed. RESULT: We obtained myocardial time-velocity curves in the ROI, and some results based on those curves: In the His bundle adjacent region intervals of myocardial systole and diastole were (209.75 +/- 19.41) ms and (294.50 +/- 17.87) ms, respectively. Myocardial systole velocity (S), early diastole velocity (E) and late diastole velocity (A) were (5.43 +/- 1.53) cm/s, (3.95 +/- 1.18) cm/s and (1.72 +/- 0.77) cm/s, respectively, E/A was 2.06 +/- 0.95; In IVS region intervals of myocardial systole and diastole were (191.33 +/- 17.23) ms and (294.70 +/- 17.91) ms, respectively. S, E and A were (3.17 +/- 1.34) cm/s, (2.17 +/- 0.64) cm/s and (1.48 +/- 0.52) cm/s, respectively. E/A was 1.305 +/- 0.287. CONCLUSION: The primary characteristics of myocardial velocities paced over His bundle were: 1) Myocardial velocities in His bundle adjacent region were higher than those in IVS. 2) E/A was greater than one.

Quantitative analysis of sinoatrial node using Doppler tissue images.

A method has been developed to quantitatively analyze sinoatrial nodes (SAN) using Doppler tissue images (DTI). Doppler tissue images of SAN are acquired using an intracardiac catheter via the superior vena cava in an in vivo experiment. A sequence of DTI images of a SAN is obtained, and a complete cycle of the SAN excitation is observed. The tissue acceleration of the SAN is extracted and quantitatively analyzed. The estimated time-acceleration curve of the SAN exhibits remarkable similarity to the electrocardiogram curve. This is the first report on such finding. The experimental results show that the tissue movement of the SAN correlates with electrical cardiac activities and closely associates with the different phases of the cardiac cycle. This method has great potential in characterizing the local cardiac activities through the study of the conduct pathway.

[A design of ultrasonic tele-diagnosis and quality control system].

Objective. To study the method for constructing an ultrasonic tele-diagnosis and quality control system. Method. The standard of Intemet/Intranet technology was used for the system. The compression and up-loading component based on wavelet and the software platform of ultrasound image processing were developed to suit the ultrasound image characteristics. The information exchange and storage (DICOM) was studied for the compatibility between the system and the Hospital Information System (HIS). Both of them were combined to form an integrated system. Result. WWW server, relevant case history managing and image processing software were constructed in the system. Conclusion. It is feasible to establish a low cost and maintainable system for ultrasound tele-diagnosis and quality control system based on Internet/Intranet technology.

[Dynamic 3D reconstruction of Doppler flow ultrasound medical images].

OBJECTIVE: To implement dynamic 3D reconstruction of ultrasonic flow images by the technique of 3D reconstruction of ultrasonic medical images combined with Doppler flow imaging method. METHOD: Through analyzing the color-coded mode of Doppler flow images and utilizing the Color Bar in DFI provided by ultrasound system, the information of anatomical structure and blood flow velocity were separated from original DFI images. Then 3D reconstruction of blood velocity and its fusion display with 3D anatomical structure was implemented. RESULT: Clinical experiments showed that in vivo blood flow in heart cavity could be shown in 3D space simultaneously with anatomical structure of the heart, and the relationship between them was consistent with cardiology. The images rendered in such a way could show more medical information than that in traditional methods. CONCLUSION: The combination of 3D reconstruction of ultrasonic medical images and Doppler imaging technique could realize functional 3D reconstruction of ultrasonic medical images so as to give more medical information. It would have great potential application and present a new future for ultrasonic medical imaging.