A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer.

One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.

Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer.

Histone deacetylase (HDAC) inhibitors are an emerging class of targeted therapy against cancers. Thailandepsin A (TDP-A) is a recently discovered class I HDAC inhibitor with broad anti-proliferative activities. In the present study, we aimed to investigate the potential of TDP-A in the treatment of breast cancer. We demonstrated that TDP-A inhibited cell proliferation and induced apoptosis in breast cancer cells at low nanomolar concentrations. TDP-A activated the intrinsic apoptotic pathway through increase of pro-apoptotic protein Bax, decrease of anti-apoptotic Bcl-2, and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). TDP-A also induced cell cycle arrest at the G2/M phase, and promoted the production of reactive oxygen species (ROS). We have successfully encapsulated TDP-A into our recently developed disulfide cross-linked micelles (DCMs), improving its water solubility and targeted delivery. TDP-A loaded DCMs (TDP-A/DCMs) possess the characteristics of high loading capacity (>20%, w/w), optimal and monodisperse particle size (16 ± 4 nm), outstanding stability with redox stimuli-responsive disintegration, sustained drug release, and preferential uptake in breast tumors. In the MDA-MB-231 breast cancer xenograft model, TDP-A/DCMs were more efficacious than the FDA-approved FK228 at well-tolerated doses. Furthermore, TDP-A/DCMs exhibited synergistic anticancer effects when combined with the proteasome inhibitor bortezomib (BTZ) loaded DCMs (BTZ/DCMs). Our results indicate that TDP-A nanoformulation alone or in combination with BTZ nanoformulation are efficacious against breast cancer.

Spatial-temporal variations of Schistosoma japonicum distribution after an integrated national control strategy: a cohort in a marshland area of China.

BACKGROUND: Schistosomiasis transmission is typically focal. Understanding spatial variations of Schistosoma infections and their associated factors is important to help to invent site-specific intervention strategies. METHODS: A five-year longitudinal study was carried out prospectively in 12 natural villages, Guichi district of Anhui province. A GIS-based spatial analysis was conducted to identify geographic distribution patterns of schistosomiasis infections at the household scale. RESULTS: The results of the spatial autocorrelation analysis for 2005 showed that there were significant spatial clusters of human infections at the household level, and these results were in agreement with that of the spatial scan statistic. As prevalence of infections in humans decreased over the course of control, the spatial distribution of these infections became less heterogeneous. CONCLUSIONS: The findings imply that it may be necessary to re-assess risk factors of S. japonicum transmission over the course of control and to adjust accordingly control measures in the communities.

Tumor-targeting multifunctional micelles for imaging and chemotherapy of advanced bladder cancer.

AIM: This work aimed to determine if the treatment outcomes of bladder cancer could be improved by targeting micelles that are decorated with bladder cancer-specific ligands on the surface and loaded with the chemotherapeutic drug paclitaxel. MATERIALS & METHODS: Targeting efficacy and specificity was determined with cell lines. An in vivo targeting and anti-tumor efficacy study was conducted in mice carrying patient-derived xenografts. RESULTS & DISCUSSION: Targeting micelles were more efficient than nontargeting micelles in delivering the drug load into bladder cancer cells both in vitro and in vivo (p < 0.05). The micelle formulation of paclitaxel was less toxic than free paclitaxel in Cremophor(®) (Sigma, MO, USA) and allowed administration of three-times the maximum tolerated dose without increasing the toxicity. Targeting micelles were more effective than the nontargeting micelles in controlling cancer growth (p = 0.0002) and prolonging overall survival (p = 0.002). CONCLUSION: Targeting micelles loaded with paclitaxel offer strong potential for clinical applications in treating bladder cancer.

[Application of saTScan in detection of schistosomiasis clusters in marshland and lake areas].

OBJECTIVE: To detect the schistosomiasis clusters in marshland and lake areas in 2008, so as to provide the reference for schistosomiasis control and the methodology for detection of cluster areas of related diseases. METHODS: SaTScan was used to detect the schistosomiasis clusters based on the spatial database from GIS and related variables, including the number of current patients and population in endemic areas. RESULTS: A total of 5 clusters including 39 counties (districts) were detected by SaTScan, the RRs and the Log-likelihood ratios of 3 clusters among them were over 3 and 1 000 (P < 0.05), respectively. The one with the highest RR and Log-likelihood ratio was located in the boundary of Hubei and Hunan provinces, and the cluster range there was the biggest. From there to the downstream of the Yangtze River, the area and RRs of the 5 clusters became smaller and smaller. CONCLUSION: The 5 provinces in the marshland and lake areas are still the key spatial clusters of schistosomiasis, especially near the boundary of Hubei and Hunan provinces.

[Snail habitats detection in the marshland of Eastern Dongting Lake Area, based on China-Brazil Earth Resources Satellite-02B CCD data].

OBJECTIVE: To detect the snail habitats from the marshland of Eastern Dongting Lake Area, using the Remote Sensing (RS) and Geographic Information System (GIS) technology based on the China-Brazil Earth Resources Satellite-02B (CBERS-02B) CCD images. METHODS: According to the two typical traits of snail habitats in marshland including "water in summer and land in winter" and "no grass, no snails", the "water in summer and land in winter" region and the vegetation coverage region were calculated by RS image processing respectively. The two regions mentioned above were then overlapped to confirm the snail habitats through comparing with the data from field survey under spatial overlapping of Arcgis as the last step. RESULTS: In Eastern Dongting Lake area, the "water in summer and land in winter" region and vegetation coverage region were predicted based on the formula normalized difference water index (NDWI) > 0.01 and normalized difference vegetation index (NDVI) > 0.36, respectively. The snail habitat was determined by theme overlay of the two regions said above. The agreement rate between the prediction and the geospatial data of field survey was 93.55%, which demonstrated the final results were credible and reliable. CONCLUSION: CBERS-02B image could be used to detect the snail habitats and to monitor the changes of them, so as to find out the characteristics of distribution and the trends of diffusion. The snail index (discriminant 1 and 2) seemed to be suitable for the detection of snail habitats in the marshland of Lake area and used for the programs of snail control.

[Spatial characteristic of distribution of Oncomelania hupensis in mountainous regions].

OBJECTIVE: To analyze the spatial characteristic on the distribution of Oncomelania hupensis in mountainous regions. METHODS: Based on the geographic database of snail distribution in Puge county, Sichuan province, spatial autocorrelation analysis and spatial scan statistics were applied to analyze the spatial characteristic of snail distribution. RESULTS: With regard to the rate of frame with snails, the global Moran's I indicator was 0.095 (P < 0.05), which indicated the spatial autocorrelation of snail distribution in Puge county. Data from the local spatial autocorrelation analysis showed that there were 28 snail habitats with statistically significant differences on local indicators of spatial autocorrelation (LISA) value (P < 0.05), among which existed high-high, low-low, low-high and high-low four types of correlation model. The Spatial Scan Statistics had in total identified 24 snail habitat clusters (P < 0.05), including 14 high rate clusters and 10 low rate clusters, and the result was similar to that of LISA analysis. CONCLUSION: There were spatial autocorrelation and spatial aggregation of snail distribution in mountainous regions, meanwhile spatial heterogeneity of snail distribution also existed. This law could be explored for better control of snails.

[Integrated detection and analysis on the clusters of schistosomiasis based on geographic information system].

OBJECTIVE: To detect and analyze the clusters of schistosomiasis on marshland and lake areas based on geographic information system (GIS) in 2008 and to provide suggestions for the development of integrated methodology on the detection of clusters on related diseases. METHODS: Moran's I of global spatial autocorrelation, Getis-Ord Gi of local spatial autocorrelation and SaTScan were used to detect the schistosomiasis clusters based on GIS and comparison of the results for different methods were performed. RESULTS: Results from the global Moran's I tests for all the marshland and lake areas related to the schistosomiasis were statistically significant (P < 0.05) and indicated spatial heterogeneity;the z-score outcomes as calculated by Getis-Ord Gi indicated high cluster that 50 clusters were categorized at the 0.05 significance level and the z-score of these 45 clusters were more than 0. Results of SaTScan statistics appeared the same as local spatial autocorrelation and almost showing the existence of 5 cluster areas. CONCLUSION: The geographical distribution of clusters where schistosomiasis was prevalent showed that it was closely corresponded to the middle and lower Yangtse river and in particular, many clusters were located near the boundary of Hubei and Hunan province.

[Impact of the changing water level on the variance of Oncomelania hupensis populations in Lake Area with general additive model].

OBJECTIVE: To explore the impact and regularity of snail population after changing of water level and to develop effective control and prediction programs. METHODS: A typical snail habitat closed to Changjiang county in Yueyang city, Hunan province was selected as the survey field. Data on water level and the changing trend of snail population during 2001 - 2009 including the average water level, maximum and minimum water levels, snail and infected snail densities, proportion of sampling frames with living and infected snails etc. were collected. The distribution of water level and snail indexes were described and a general additive model (GAM) for the relationships between these indexes were also fitted. RESULTS: Impacts of the average water level and the watered-out days in current year in the surveyed field on the snail density were statistically significant (P<0.01), showing a quadratic curve association. The snail density remained at the lowest level when the average water level was at 25.0 m and the surveyed field watered-out days was 120. The average water level in current year and the field watered-out days in the past year showed statistically significant impacts on the infected snail density (P<0.001), the proportion of sampling frames with infected snails (P<0.05) and living snails (P value neared 0.05), presented a quadratic curve, a cubic curve or even a more complicated piecewise curve association. Both the infected snail density and the proportion of sampling frames with infected snails remained at the lowest level when the average water level was at 25.0 m and the watered-out days in the past year was 110, while the proportion of sampling frames with living snails kept the lowest level when the average water level was at 25.0 m and the watered-out days in the past year was 160. CONCLUSION: The water level and the field watered-out days affected the development of snail population directly. The changing water level had an impact on snail population change, which mainly presented as nonlinear smooth function relation. Impact of the field watered out days on the infected snail density and the proportion of sampling frames with living snails and infected snails showed a hysteresis effect. The snail density was predicted to be retaining a high level when the water level was 24.0 m and the field watered-out days was 3 months. It had obvious advantages to fit the relationship of the changing water level and the snail indexes with a GAM which could get closer to the reality as well as easier to find and explain the potential associations and regulations.

[Metagenesis of intermediate host to Schistosoma japonicum Oncomelania snail in mountainous areas].

OBJECTIVE: To understand the metagenesis of Oncomelania snails in the mountainous regions so as to control the spread of snails and the epidemics of schistosomiasis. METHODS: Observation spot was established at a typical snail habitat close to Puge county, Sichuan province from February 2008 to July 2009. Random sampling was applied to determine the place of each frame during the observation. All the snails in each frame were collected and numbers counted in the laboratory, with the number of mating pairs in each frame also observed. Snails being collected were measured for the body indices and the dissection was carried out to identify gender composition, survival status and the number of live snails in each frame counted. Line graphs of the body indices, mating pairs in each observed months, bar graphs of the snail density, proportions of gender together with the maturity of the snails in each month were drawn. RESULTS: The number of live snail existed the whole year and its density fluctuated. All the three kinds of body indices showed the same time trend and a dynamic circulation. The young snail existed all year around and arose constantly in proportion from May, becoming the dominant snail in October to replace the adult snails. The young and adult snails also showed a dynamic alternative. The gender composition showed no significant difference during each month. The number of the mating pairs was more on April, May and June annually, when were the snail's main multiplying stage. CONCLUSION: In mountain area, the young snails existed through all the year while adult snails appeared to be dominant in each month except for October. Oncomelania snail showed a circular process of metagenesis which started in May and finished in October. The snail population presented a dynamic equilibrium. It was concluded that ecological studies on Oncomelania snail were extremely relevant, either to optimally apply the existing control measures or to develop alternative measures for snail control, ecologically or biologically.

[Influence regarding micro-ecological environment of snail habitats in lake area on the distribution of snails].

OBJECTIVE: To explore the relationships between micro-ecological environmental factors and the density of Snails so as to provide information for the elimination of Snails and control of Schistosomiasis disease, under ecological methods. METHODS: A bottomland close to Junshan Park in Yueyang city, Hunan province was selected as the field for survey during 10, 2007 - 10, 2008, and a systematic sampling method was applied to determine the specific sites of Snail investigation. All the Snails in each frames were collected and the soil surface temperature and vegetation coverage in several frames were measured. 30 g soil sample in each selected frames were also collected simultaneously. The number of live Snails in each frame was counted by dissection, and soil measured pH value and soil moisture were tested in the laboratory. The distribution of Snails and microecological environmental factors, fitted general additive model for the relationship of these factors and the Snail density were described. RESULTS: 104 frames were surveyed, with pH value as between 4.70 - 7.92, vegetation coverage as in 1% to 96%, soil surface temperature as in 14.5 - 32.7°C, the soil moisture as in 0.07 - 2.00. Under General additive model, data showed that there was no significant difference for vegetation coverage. However, other factors were all significantly different (P < 0.001). It was found that a nonlinear relationship was existing between these factors and the Snail density. CONCLUSION: Smoothing function relationship was noticed between the Snail density and micro-ecological environmental factors. It's suggested to fit general additive model to study the relationship between the distribution of Snails and its influencing factors, so as to adopt appropriate measures to change the related ecology to control the diffusion and reproduction of Snails.