Drug Sensitivity Screening and Targeted Pathway Analysis Reveal a Multi-Driver Proliferative Mechanism and Suggest a Strategy of Combination Targeted Therapy for Colorectal Cancer Cells

Treatment of colorectal cancer mostly relies on traditional therapeutic approaches, such as surgery and chemotherapy. Limited options of targeted therapy for colorectal cancer narrowly focus on blocking cancer-generic targets VEGFR and EGFR. Identifying the oncogenic drivers, understanding their contribution to proliferation, and finding inhibitors to block such drivers are the keys to developing targeted therapy for colorectal cancer. In this study, ten colorectal cancer cell lines were screened against a panel of protein kinase inhibitors blocking key oncogenic signaling pathways. The results show that four of the 10 cell lines did not respond to any kinase inhibitors significantly, the other six were mildly inhibited by AZD-6244, BMS-754807, and/or dasatinib. Mechanistic analyses demonstrate that these inhibitors independently block the MAP kinase pathway, IR/IGF-1R/AKT pathway, and Src kinases, suggesting a multi-driver nature of proliferative signaling in these cells. Most of these cell lines were potently and synergistically inhibited by pair-wise combinations of these drugs. Furthermore, seven of the 10 cell lines were inhibited by the triple combination of AZD-6244/BMS-754807/dasatinib with IC50’s between 10 and 84 nM. These results suggest that combination targeted therapy may be an effective strategy against colorectal cancer

Same titanium glycolate precursor but different products: Successful synthesis of twinned anatase TiO2 nanocrystals with excellent solar photocatalytic hydrogen evolution capability

Exploiting a synthesis protocol to tailor TiO 2 with a unique morphology and crystal phase has received considerable interest in the energy and environmental fields. We here describe the use of a titanium glycolate precursor in a hydrothermal hydrolysis reaction to engineer TiO 2 nanocrystals with different crystal phases and structures. Anatase TiO 2 nanocrystals with twinned structures were obtained by using a lower amount of NaOH in the hydrolysis system, while brookite TiO 2 nanocrystals were formed when higher amounts of NaOH were employed. The as-synthesized different TiO 2 nanocrystals have a suitable bandgap to harvest photons and a more negative bottom level of the conduction band than the redox potential of H + /H 2 indicating their potential as hydrogen-evolution semiconductor photocatalysts. However, the TiO 2 nanotwins show promoted charge separation efficiency, and thus result in superior photocatalytic H 2 generation activity compared to the anatase and brookite TiO 2 nanocrystals. Our findings provide an effective and versatile solution for the fabrication of TiO 2 -based nanostructures with different phases and morphologies through chemical conversion of powder precursor nanoparticles, which could pave the way to the design of other functional nano-oxides with unique structures

Mining iterative generators and representative rules for software specification discovery

10.1109/TKDE.2010.24IEEE Transactions on Knowledge and Data Engineering232282-296ITKE

The Lesson Learned from the Unique Evolutionary Story of Avirulence Gene AvrPii of Magnaporthe oryzae

Blast, caused by Magnaporthe oryzae, is one of the most destructive diseases affecting rice production. Understanding population dynamics of the pathogen's avirulence genes is pre-required for breeding and then deploying new cultivars carrying promising resistance genes. The divergence and population structure of AvrPii was dissected in the populations of southern (Guangdong, Hunan, and Guizhou) and northern (Jilin, Liaoning, and Heilongjiang) China, via population genetic and evolutionary approaches. The evolutionary divergence between a known haplotype AvrPii-J and a novel one AvrPii-C was demonstrated by haplotype-specific amplicon-based sequencing and genetic transformation. The different avirulent performances of a set of seven haplotype-chimeric mutants suggested that the integrity of the full-length gene structures is crucial to express functionality of individual haplotypes. All the four combinations of phenotypes/genotypes were detected in the three southern populations, and only two in the northern three, suggesting that genic diversity in the southern region was higher than those in the northern one. The population structure of the AvrPii family was shaped by balancing, purifying, and positive selection pressures in the Chinese populations. The AvrPii-J was recognized as the wild type that emerged before rice domestication. Considering higher frequencies of avirulent isolates were detected in Hunan, Guizhou, and Liaoning, the cognate resistance gene Pii could be continuously used as a basic and critical resistance resource in such regions. The unique population structures of the AvrPii family found in China have significant implications for understanding how the AvrPii family has kept an artful balance and purity among its members (haplotypes) those keenly interact with Pii under gene-for-gene relationships. The lesson learned from case studies on the AvrPii family is that much attention should be paid to haplotype divergence of target gene

Construction and validation of a predictive risk model for nosocomial infections with MDRO in NICUs: a multicenter observational study

ObjectivesThis study aimed to construct and validate a predictive risk model (PRM) for nosocomial infections with multi-drug resistant organism (MDRO) in neonatal intensive care units (NICUs), in order to provide a scientific and reliable prediction tool, and to provide reference for clinical prevention and control of MDRO infections in NICUs.MethodsThis multicenter observational study was conducted at NICUs of two tertiary children’s hospitals in Hangzhou, Zhejiang Province. Using cluster sampling, eligible neonates admitted to NICUs of research hospitals from January 2018 to December 2020 (modeling group) or from July 2021 to June 2022 (validation group) were included in this study. Univariate analysis and binary logistic regression analysis were used to construct the PRM. H-L tests, calibration curves, ROC curves and decision curve analysis were used to validate the PRM.ResultsFour hundred and thirty-five and one hundred fourteen neonates were enrolled in the modeling group and validation group, including 89 and 17 neonates infected with MDRO, respectively. Four independent risk factors were obtained and the PRM was constructed, namely: P = 1/ (1+ e−X), X = −4.126 + 1.089× (low birth weight) +1.435× (maternal age ≥ 35 years) +1.498× (use of antibiotics >7 days) + 0.790× (MDRO colonization). A nomogram was drawn to visualize the PRM. Through internal and external validation, the PRM had good fitting degree, calibration, discrimination and certain clinical validity. The prediction accuracy of the PRM was 77.19%.ConclusionPrevention and control strategies for each independent risk factor can be developed in NICUs. Moreover, clinical staff can use the PRM to early identification of neonates at high risk, and do targeted prevention to reduce MDRO infections in NICUs

Trends in cutaneous squamous cell carcinoma on the lip incidence and mortality in the United States, 2000–2019

ObjectiveThis study provided a systematic analysis of the trend in incidence and incidence-based mortality for cutaneous squamous cell carcinoma (cSCC) on the lips in the USA using demographic characteristics from the Surveillance, Epidemiology, and End Results (SEER) database.MethodsPatients diagnosed with cSCC on the lips between 2000 and 2019 from the 17 registries of the USA were identified. Incidence and incidence-based mortality rates were analyzed using SEER*Stat 8.4.0.1 software. This paper calculated incidence rates and incidence-based mortality rates by 100,000 person-years for sex, age, race, SEER registries, median household income ($/year), rural-urban distribution, and primary site. The annual percent changes (APC) in incidence and incidence-based mortality rates were then calculated using joinpoint regression software.ResultsAmong 8,625 patients diagnosed with cSCC on the lips from 2000 to 2019, men (74.67%), white (95.21%), and 60–79 years old were the most common population, and 3,869 deaths from cSCC on the lips occurred. The overall incidence of cSCC on the lips was 0.516 per 100,000 person-years. cSCC on the lip incidence rates were highest among men, white, and patients aged 60–79 years old. cSCC on the lip incidence rates decreased by 3.210%/year over the study period. The incidence of cSCC on the lips has been decreasing in all sexes, ages, high- or low-income households, and urban or rural patients. The overall incidence-based mortality rate of cSCC on the lips during 2000–2019 was 0.235 per 100,000 person-years. cSCC on the lip incidence-based mortality rates were highest among men, whites, and people older than 80 years old. cSCC on the lip incidence-based mortality increased by 4.975%/year over the study period. cSCC on the lip incidence-based mortality rates increased for all sexes, races, ages, primary sites, high- or low-income households, and urban or rural patients during the study period.ConclusionAmong patients in the USA diagnosed with cSCC on the lips from 2000 to 2019, the overall incidence decreased by 3.210% annually, and incidence-based mortality increased by 4.975%/year. These findings update and supplement the epidemiological information of cSCC on the lips in the USA

Novel integrated techniques of drilling-slotting-separation-sealing for enhanced coal bed methane recovery in underground coal mines

Coal bed Methane (CBM), a primary component of natural gas, is a relatively clean source of energy. Nevertheless, the impact of considerable coal mine methane emission on climate change in China has gained an increasing attention as coal production has powered the country's economic development. It is well-known that coal bed methane is a typical greenhouse gas, the greenhouse effect index of which is 30 times larger than that of carbon dioxide. Besides, gas disasters such as gas explosive and outburst, etc. pose a great threat to the safety of miners. Therefore, measures must be taken to capture coal mine methane before mining. This helps to enhance safety during mining and extract an environmentally friendly gas as well. However, as a majority of coal seams in China have low-permeability, it is difficult to achieve efficient methane drainage. Enhancing coal permeability is a good choice for high-efficiency drainage of coal mine methane. In this paper, a modified coal-methane co-exploitation model was established and a combination of drilling–slotting-separation–sealing was proposed to enhance coal permeability and CBM recovery. Firstly, rapid drilling assisted by water-jet and significant permeability enhancement via pressure relief were investigated, guiding the fracture network formation around borehole for high efficient gas flow. Secondly, based on the principle of swirl separation, the coal–water–gas separation instrument was developed to eliminate the risk of gas accumulation during slotting and reduce the gas emission from the ventilation air. Thirdly, to improve the performance of sealing material, we developed a novel cement-based composite sealing material based on the microcapsule technique. Additionally, a novel sealing–isolation combination technique was also proposed. Results of field test indicate that gas concentration in slotted boreholes is 1.05–1.91 times higher than that in conventional boreholes. Thus, the proposed novel integrated techniques achieve the goal of high-efficiency coal bed methane recovery