Gelatinase-stimuli strategy enhances the tumor delivery and therapeutic efficacy of docetaxel-loaded poly(ethylene glycol)-poly(ɛ-caprolactone) nanoparticles

Nanoscale drug carriers have been extensively developed to improve drug therapeutic efficiency. However, delivery of chemotherapeutic agents to tumor tissues and cells has not been favorably managed. In this study, we developed a novel “intelligent” nanoparticle, consisting of a gelatinase-cleavage peptide with poly(ethylene glycol) (PEG) and poly(ɛ-caprolactone) (PCL)-based structure for tumor-targeted docetaxel delivery (DOC-TNPs). The docetaxel-loaded PEG-PCL nanoparticles (DOC-NPs) that did not display gelatinase-stimuli behaviors were used as a control. We found clear evidence that the DOC-TNPs were transformed by gelatinases, allowing drug release and enhancing the cellular uptake of DOC (P < 0.01). In vivo biodistribution study demonstrated that targeted DOC-TNPs could accumulate and remain in the tumor regions, whereas non-targeted DOC-NPs rapidly eliminated from the tumor tissues. DOC-TNPs exhibited higher tumor growth suppression than commercialized Taxotere® (docetaxel; Jiangsu Hengrui Medicine Company, Jiangsu, China) and DOC-NPs on hepatic H22 tumor model via intravenous administration (P < 0.01). Both in vitro and in vivo experiments suggest that the gelatinase-mediated nanoscale delivery system is promising for improvement of antitumor efficacy in various overexpressed gelatinase cancers

Phylogeography of the endangered orchids Cypripedium japonicum and Cypripedium formosanum in East Asia: Deep divergence at infra- and interspecific levels

To date, little is known about the past evolutionary trajectories of rare and endangered orchids native to mainland China, Japan, and Korea (the CJK region). In this study, we focus on two endangered orchids, Cypripedium japonicum (present in the three countries) and C. formosanum (endemic to Taiwan), to understand the divergence/speciation models that would have been operating in this group, including genetic diversity, geographic structure, and colonization pathways across the region. Using a combination of five cpDNA regions, we reconstructed phylogenetic trees and investigated the genetic diversity/structure of 20 populations. Ecological niche modeling was used to gain insight into the paleodistribution and dispersal corridors at the Last Glacial Maximum and to survey climatic niche differences. Populations from mainland China + Korea, Japan, and Taiwan formed three distinct monophyletic lineages and were placed into separate genetic clusters, agreeing with geographic barriers and species boundaries. Populations of C. japonicum in mainland China harbored the highest diversity, suggesting the presence of multiple glacial refugia. The Korean populations would have originated from either western/central or eastern China, probably using a dispersal corridor across the East China Sea shelf. The divergence of C. formosanum is proposed under an allopatric speciation model, also highly influenced by a climate niche shift. In the context of previous studies, a deep divergence in cpDNA sequences between Chinese + Korean and Japanese populations of C. japonicum may be taken as an example of the speciation events of the CJK flora since the late Neogene that have led to its current species richness.This study was supported by the Biodiversity Survey, Observation and Assessment Program of the Ministry of Ecology and Environment of China to HZT and by Basic Science Program through the National Research Foundation of Korea (NRF-2017R1A2B4012215) to MGC, and funded by the Ministry of Science and ICT of the Republic of Korea (NRF-2020R1I1A3074635) to MYC.INTRODUCTION MATERIALS AND METHODS Study species Population sampling DNA extraction cpDNA-PCR optimum primer selection cpDNA sequence alignment and assembly Haplotype distribution, phylogenetic analyses, and genetic diversity Genetic differentiation and structure Mismatch distribution analysis, neutrality detection, and demographic history ENM and population connectivity Niche comparisons in E-space RESULTS Haplotype distribution and phylogeny Genetic diversity Genetic differentiation and structure Mismatch distribution analysis, neutrality detection, and demographic history ENM and population connectivity Niche comparisons in E-space DISCUSSION Deep genetic and climatic divergence of Cypripedium sect. Flabellinervia in the CJK region: taxonomic considerations Haplotype and nucleotide diversity in Cypripedium sect. Flabellinervia: inference of glacial refugia and demographic history Origin of Korean populations of Cypripedium japonicum Origin of Cypripedium formosanum CONCLUSIONS AUTHOR CONTRIBUTIONS ACKNOWLEDGEMENTS Appendix 1: The cpDNA sequence information of Cypripedium sect. Flabellinervia deposited in the GenBank databas

A Global Study for Acute Myeloid Leukemia With RARG Rearrangement

Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (∼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810)

Prevalence and trend of hepatitis C virus infection among blood donors in Chinese mainland: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Blood transfusion is one of the most common transmission pathways of hepatitis C virus (HCV). This paper aims to provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for HCV infection among blood donors in Chinese mainland, so as to help make prevention strategies and guide further research.</p> <p>Methods</p> <p>A systematic review was constructed based on the computerized literature database. Infection rates and 95% confidence intervals (95% CI) were calculated using the approximate normal distribution model. Odds ratios and 95% CI were calculated by fixed or random effects models. Data manipulation and statistical analyses were performed using STATA 10.0 and ArcGIS 9.3 was used for map construction.</p> <p>Results</p> <p>Two hundred and sixty-five studies met our inclusion criteria. The pooled prevalence of HCV infection among blood donors in Chinese mainland was 8.68% (95% CI: 8.01%-9.39%), and the epidemic was severer in North and Central China, especially in Henan and Hebei. While a significant lower rate was found in Yunnan. Notably, before 1998 the pooled prevalence of HCV infection was 12.87% (95%CI: 11.25%-14.56%) among blood donors, but decreased to 1.71% (95%CI: 1.43%-1.99%) after 1998. No significant difference was found in HCV infection rates between male and female blood donors, or among different blood type donors. The prevalence of HCV infection was found to increase with age. During 1994-1995, the prevalence rate reached the highest with a percentage of 15.78% (95%CI: 12.21%-19.75%), and showed a decreasing trend in the following years. A significant difference was found among groups with different blood donation types, Plasma donors had a relatively higher prevalence than whole blood donors of HCV infection (33.95% <it>vs </it>7.9%).</p> <p>Conclusions</p> <p>The prevalence of HCV infection has rapidly decreased since 1998 and kept a low level in recent years, but some provinces showed relatively higher prevalence than the general population. It is urgent to make efficient measures to prevent HCV secondary transmission and control chronic progress, and the key to reduce the HCV incidence among blood donors is to encourage true voluntary blood donors, strictly implement blood donation law, and avoid cross-infection.</p

Nonstandard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants