"Targeted plus controlled" - Composite nano delivery system opens the tumor vascular and microenvironment normalization window for anti-tumor therapy.

The bottleneck of traditional anti-tumor therapy is mainly limited by the abnormal microenvironment of tumors. Leaky vessels are difficult for drugs or immune cells to penetrate deep into tumors, but tumor cells can easily escape through which and metastasize to other organs. Reprogramming the tumor microenvironment is one of the main directions for anti-cancer research, among which, tumor vascular normalization has received increasing attention. However, how to control the dose and time of anti-angiogenic drugs for stable vascular normalizing effect limits it for further research. We developed a composite nano delivery system, P-V@MG, with double delivery function of pH-responsibility and sustained drug release. The PHMEMA shell improves amphiphilicity of nano delivery system and prolongs in vivo retention, and releases V@MG in the weakly acidic tumor microenvironment, which slowly release anti-angiogenic drugs, Vandetanib. We found that P-V@MG not only prolonged the normalization window of tumor vascular but also reprogram tumor microenvironment with increased perfusion, immune cells infiltration and relieved hypoxia, which further opened the pathway for other anti-cancer therapeutics. This synergy was proved by the improving anti-tumor efficiency by combination of P-V@MG with the doxorubicin hydrochloride in 4 T1 breast cancer model suggesting the desirable value of pro-vascular normalization nano delivery systems in the field of anti-tumor combination therapy.

Subgenome dominance and its evolutionary implications in crop domestication and breeding.

Polyploidization or whole-genome duplication (WGD) is a well-known speciation and adaptation mechanism in angiosperms, while subgenome dominance is a crucial phenomenon in allopolyploids, established following polyploidization. The dominant subgenomes contribute more to genome evolution and homoeolog expression bias, both of which confer advantages for short-term phenotypic adaptation and long-term domestication. In this review, we firstly summarize the probable mechanistic basis for subgenome dominance, including the effects of genetic [transposon, genetic incompatibility, and homoeologous exchange (HE)], epigenetic (DNA methylation and histone modification), and developmental and environmental factors on this evolutionary process. We then move to Brassica rapa, a typical allopolyploid with subgenome dominance. Polyploidization provides the B. rapa genome not only with the genomic plasticity for adapting to changeable environments, but also an abundant genetic basis for morphological variation, making it a representative species for subgenome dominance studies. According to the 'two-step theory', B. rapa experienced genome fractionation twice during WGD, in which most of the genes responding to the environmental cues and phytohormones were over-retained, enhancing subgenome dominance and consequent adaption. More than this, the pangenome of 18 B. rapa accessions with different morphotypes recently constructed provides further evidence to reveal the impacts of polyploidization and subgenome dominance on intraspecific diversification in B. rapa. Above and beyond the fundamental understanding of WGD and subgenome dominance in B. rapa and other plants, however, it remains elusive why subgenome dominance has tissue- and spatiotemporal-specific features and could shuffle between homoeologous regions of different subgenomes by environments in allopolyploids. We lastly propose acceleration of the combined application of resynthesized allopolyploids, omics technology, and genome editing tools to deepen mechanistic investigations of subgenome dominance, both genetic and epigenetic, in a variety of species and environments. We believe that the implications of genomic and genetic basis of a variety of ecologically, evolutionarily, and agriculturally interesting traits coupled with subgenome dominance will be uncovered and aid in making new discoveries and crop breeding.

Meta-analysis of Long-Term Relapse Rate of Type 2 Diabetes Following Initial Remission After Roux-en-Y Gastric Bypass.

This study aims to determine the long-term relapse rate of type 2 diabetes (T2DM) following initial remission after Roux-en-Y gastric bypass (RYGB) surgery. We searched studies in PubMed, Embase, and the Cochrane Library. A total of 17 eligible studies were included for analysis. Meta-analysis suggested a pooled long-term relapse rate of 0.30 (95% confidence interval [CI], 0.26-0.34) and a remission rate of 0.63 (95% CI, 0.55-0.72) after RYGB and a hazard ratio of 0.73 (95% CI, 0.66-0.81) for comparison of RYGB and sleeve gastrectomy (SG). Subgroup analyses established pooled results. This study suggested RYGB may be a preferred regime for obese patients with T2DM because it is associated with lower long-term relapse and relatively higher initial remission and was also superior to SG due to lower risk of recurrence.

DDR1 enhances invasion and metastasis of gastric cancer via epithelial-mesenchymal transition.

In this study, we investigated the effects of DDR1 on the invasion and metastasis in gastric cancer (GC) via epithelial-mesenchymal transition (EMT). Immunohistochemistry analysis was used to detect DDR1, E-cadherin, and Vimentin expression in GC tissues as well as DDR1 expression in GC cell lines and normal gastric epithelial cells. The relationship between DDR1 expression and EMT in GC cell lines was explored by down and upregulating DDR1 and examining corresponding changes in the expression of EMT-related proteins and in biological characteristics. Furthermore, a nude mice model with a transplantation tumor generating from stably transfected GC cells with DDR1 overexpression was established and performed to further reveal the effects of DDR1 expression on cellular morphology and growth of GC. Our results showed that DDR1 was highly expressed in GC tissues and cell lines compared with adjacent tissues and normal cell line, and its expression was significantly higher in GC having poor differentiation (p < 0.01), advanced depth of wall invasion (p = 0.020), lymph node metastasis (p = 0.0001), liver metastasis (p < 0.01), and high TNM stage (p < 0.01). Western blot analyses revealed that DDR1 overexpression resulted in a significant decrease in the expression of E-cadherin (p < 0.01) and an increase in the expression of Vimentin and Snail (p < 0.01), while knockdown of DDR1 led to opposite outcomes. We further demonstrated that DDR1 overexpression promoted GC cell proliferation (p < 0.05), migration (p < 0.01), and invasion (p < 0.01), and accelerated the growth (p < 0.05) as well as the microvessel formation (p < 0.01) of transplantation tumor in nude mice. Our study establishes that DDR1 enhances invasion and metastasis of gastric cancer via EMT.

Hinokitiol induces DNA damage and autophagy followed by cell cycle arrest and senescence in gefitinib-resistant lung adenocarcinoma cells.

Despite good initial responses, drug resistance and disease recurrence remain major issues for lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations taking EGFR-tyrosine kinase inhibitors (TKI). To discover new strategies to overcome this issue, we investigated 40 essential oils from plants indigenous to Taiwan as alternative treatments for a wide range of illnesses. Here, we found that hinokitiol, a natural monoterpenoid from the heartwood of Calocedrus formosana, exhibited potent anticancer effects. In this study, we demonstrated that hinokitiol inhibited the proliferation and colony formation ability of lung adenocarcinoma cells as well as the EGFR-TKI-resistant lines PC9-IR and H1975. Transcriptomic analysis and pathway prediction algorithms indicated that the main implicated pathways included DNA damage, autophagy, and cell cycle. Further investigations confirmed that in lung cancer cells, hinokitiol inhibited cell proliferation by inducing the p53-independent DNA damage response, autophagy (not apoptosis), S-phase cell cycle arrest, and senescence. Furthermore, hinokitiol inhibited the growth of xenograft tumors in association with DNA damage and autophagy but exhibited fewer effects on lung stromal fibroblasts. In summary, we demonstrated novel mechanisms by which hinokitiol, an essential oil extract, acted as a promising anticancer agent to overcome EGFR-TKI resistance in lung cancer cells via inducing DNA damage, autophagy, cell cycle arrest, and senescence in vitro and in vivo.