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Liver metastasis (LM) significantly shortens the survival time of colorectal neuroendocrine neoplasms (NENs) patients. This research aimed to explore risk and prognostic factors in colorectal NENs patients with LM and develop nomograms for predicting the risk of LM and survival probability quantitatively. A total of 9926 colorectal NENs patients registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017 were included. Risk factors for LM in colorectal NENs patients were identified by multivariate logistic regression analysis. Potential prognostic factors for colorectal NENs patients with LM were identified by multivariable Cox regression analysis. Nomograms were constructed for quantifying the probability of LM occurrence and survival. At diagnosis, 8.7% of colorectal NENs patients suffered LM, with 1-, 3-, and 5-year cancer-specific survival (CSS) rates of 44.3%, 26.5%, and 18.0%, respectively. Factors associated with LM occurrence included gender, age at diagnosis, primary tumor location, carcinoembryonic antigen (CEA), histological differentiation, T stage, and N stage. Age at diagnosis, race, histological differentiation, N stage, tumor size, primary tumor location, primary site surgery, and extraliver metastasis were prognostic factors of cancer-specific mortality. The area under the receiver operating characteristics (ROC) curve of the nomogram for predicting LM was 0.888 (95% CI: 0.877–0.898), and the C-index of the nomogram for estimating CSS probability was 0.705 (95% CI: 0.682–0.729). This research identified the risk and prognostic factors in colorectal NENs patients with LM. The nomograms constructed by this study can be convenient tools for facilitating clinical decision-making.

Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer. However, systemic chemotherapy is limited by poor therapeutic efficiency and severe toxic side effects, due to the extremely low delivery efficacy and non-specificity of anticancer drugs. Herein, we report a sericin microparticles enveloped with metal-organic networks as a pulmonary delivery system for treating lung metastasis of breast cancer in an animal model. The sericin microparticles (SMPs) were prepared using water in oil (w/o) emulsification method. After doxorubicin (DOX) loading, tannic acid (TA)/ferric irons (Fe3+) based metal organic networks (MON) were coated on the particles to obtain DOX-loaded microparticles (DOX@SMPs-MON). The SMPs-MON with good biocompatibility could effectively encapsulate DOX and sustainably unload cargos in a pH-dependent manner. The DOX-loaded microparticles could be uptaken by 4T1 cells, and effectively kill the cancer cells. In vivo, DOX@SMPs-MON was deposited in the lungs and remained for over 5 days after pulmonary administration. In contrast to conventional DOX treatment that did not show significantly inhibitory effects on lung metastatic tumor, DOX@SMPs-MON markedly decreased the number and size of metastatic nodules in lungs, and the lung weight and appearance were similar to those of healthy mice. In summary, the sericin microparticles with MON wrapping might be a promising pulmonary delivery system for treating lung metastatic cancer., Graphical abstract Image 1, Highlights • Biocompatible and biodegradable materials (sericin, tannic acid, ferric iron) based microparticles (SMPs-MON) were developed. • SMPs-MON enhances the doxorubicin accumulation and retention in the lungs as a pulmonary drug release system. • DOX-loaded SMPs-MON could significantly decrease the number and size of metastasis nodules in lungs.

Cancer chemotherapy is challenged by multidrug resistance (MDR) mainly attributed to overexpressed transmembrane efflux pump P-glycoprotein (P-gp) in cancer cells. Improving drug delivery efficacy while co-delivering P-gp inhibitors to suppress drug efflux is an often-used nanostrategy for combating MDR, which is however challenged by cascaded bio-barriers en route to cancer cells and P-gp inhibitors' adverse effects. To effectively breach the cascaded bio-barriers while avoiding P-gp inhibitors' adverse effects, a stealthy, sequentially responsive doxorubicin (DOX) delivery nanosystem (RCMSNs) is fabricated, composed of an extracellular-tumor-acidity-responsive polymer shell (PEG-b-PLLDA), pH/redox dual-responsive mesoporous silica nanoparticle-based carriers (MSNs-SS-Py), and cationic β-cyclodextrin-PEI (CD-PEI) gatekeepers. The PEG-b-PLLDA corona makes RCMSNs stealthy with prolonged blood circulation time. Once tumors are reached, extracellular acidity degrades PEG-b-PLLDA, reversing nanosystem's surface charges to be positive, which drastically improves RCMSNs' tumor accumulation, penetration, and cellular internalization. Within cancer cells, CD-PEI gatekeepers detach to allow DOX unloading in response to intracellular acidity and glutathione and functionally act as a P-gp inhibitor, dampening P-gp's efflux activity by impairing ATP production. Thus, the resultant high-efficacy drug delivery along with reduced P-gp function cooperatively reverses MDR in vitro. Importantly, in preclinical tumor models, DOX@RCMSNs potently suppress MDR tumor growth without eliciting systemic toxicity, demonstrating their potential of clinical translation.

Chemodrug resistance is a major reason accounting for tumor recurrence. Given the mechanistic complexity of chemodrug resistance, molecular inhibitors and targeting drugs often fail to eliminate drug-resistant cancer cells, and sometimes even promote chemoresistance by activating alternative pathways. Here, by exploiting biochemical fragility of high-level but dynamically balanced cellular redox homeostasis in drug-resistant cancer cells, we design a nanosized copper/catechol-based metal-organic framework (CuHPT) that effectively disturbs this homeostasis tilting the balance toward oxidative stress. Within drug-resistant cells, CuHPT starts disassembly that is triggered by persistent consumption of cellular glutathione (GSH). CuHPT disassembly simultaneously releases two structural elements: catechol ligands and reductive copper ions (Cu

Distant metastases and chemotherapy repellency are the key causes of colorectal cancer (CRC)-related mortality. Regorafenib, an oral multi-kinase inhibitor approved for treating advanced CRC with distant metastases and/or chemo-resistance, however only improves median overall survival by 1.4 months. Such limited therapeutic effect is likely due to the low bioavailability of orally administered hydrophobic regorafenib. A regorafenib nanodrug is fabricated by one-step self-assembly with a clinically often-used fluorescent agent (indocyanine green) for overcoming regorafenib’s limitations, towards improving regorafenib’s therapeutic efficacy in advanced CRC. This nanodrug (nanoRF) was characterized, and its antitumor effects were assessed in three preclinical CRC models. NanoRF converts regorafenib’s delivery approach from oral to intravenous with a significantly high encapsulation efficacy of regorafenib (96%) and a long-time colloidal stability. Nanodrug (nanoRF) markedly prolongs regorafenib’s blood circulation by halving clearance rate, and enhances regorafenib’s tumor accumulation. Across three preclinical CRC models (xenografted tumor, chemodrug-resistant xenografted tumor, and liver metastasis), nanoRF drastically enhances regorafenib’s tumor inhibiting efficacy by 0.5–4 folds and effectively extends survival by 0.5–5 folds. This regorafenib nanodrug is a simple, safe, and efficient therapeutic nanodrug for treating advanced CRC with a ready-to-be-clinically-translated potential.

ObjectiveReciprocal cellular crosstalk within the tumour microenvironment (TME) actively participates in tumour progression. The anterior gradient-2 (AGR2) can be secreted to extracellular compartments and contribute to colorectal cancer (CRC) metastasis. We investigated the cellular source for secreted AGR2 in the TME and underlying mechanisms mediating secreted AGR2’s effects.DesignTissue microarray, tumour tissues, blood samples and tumour-associated neutrophils (TANs) from patients with CRC were isolated for phenotypical and functional analyses. The role of TAN-secreted AGR2 was determined in neutrophil-specific Agr2 knockout (Agr2f/f;Mrp-Cre) mice. The biological roles and mechanisms of secreted AGR2 in CRC metastasis were determined in vitro and in vivo.ResultsTANs were a predominant cell type for secreting AGR2 in the TME of CRC. TANs-secreted AGR2 promoted CRC cells’ migration. Neutrophils-specific ablation of Agr2 in mice ameliorated CRC liver metastases. The heavy chain of CD98 (CD98hc) served as the functional receptor for secreted AGR2. Mechanistically, secreted AGR2 increased xCT activity in a CD98hc-dependent manner, subsequently activating Ras homologue family member A/Rho-associated protein kinase 2 cascade. CRC cells actively recruited TANs through the C-X-C motif chemokine 2. Moreover, CRC-derived transforming growth factor beta 1 (TGF-β1) educated peripheral blood neutrophils to become AGR2+TANs that secrete AGR2. Abundant infiltration of AGR2+TANs and high expression of TGF-β1 and CD98hc–xCT were correlated with poor prognosis of patients with CRC.ConclusionsOur study unveils a novel crosstalk between TANs and CRC cells involving the secreted AGR2–CD98hc–xCT axis that promotes metastasis and impacts the outcomes of patients with CRC.

Summary Background The outbreak of coronavirus-disease-2019 (COVID-19) has rapidly spread to many places outside Wuhan. Previous studies on COVID-19 mostly included older hospitalized-adults. Little information on infectivity among and characteristics of youngsters with COVID-19 is available. Methods A cluster of 22 close-contacts of a 22-year-old male (Patient-Index) including youngsters with laboratory-confirmed COVID-19 and hospitalized close-contacts testing negative for severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) in Anhui Province, China was prospectively-traced. Results Since January 23, 2020, we enrolled a cluster of eight youngsters with COVID-19 (median age [range], 22 [16–23] years; six males) originating from Patient-Index returning from Wuhan to Hefei on January 19. Patient-Index visited his 16-year-old female cousin in the evening on his return, and met 15 previous classmates in a get-together on January 21. He reported being totally asymptomatic and were described by all his contacts as healthy on January 19-21. His very first symptoms were itchy eyes and fever developed at noon and in the afternoon on January 22, respectively. Seven youngsters (his cousin and six classmates) became infected with COVID-19 after a-few-hour-contact with Patient-Index. None of the patients and contacts had visited Wuhan (except Patient-Index), or had any exposure to wet-markets, wild-animals, or medical-institutes within three months. For affected youngsters, the median incubation-period was 2 days (range, 1–4). The median serial-interval was 1 day (range, 0–4). Half or more of the eight COVID-19-infected youngsters had fever, cough, sputum production, nasal congestion, and fatigue on admission. All patients had mild conditions. Six patients developed pneumonia (all mild; one bilateral) on admission. As of February 20, four patients were discharged. Conclusions SARS-CoV-2-infection presented strong infectivity during the incubation-period with rapid transmission in this cluster of youngsters outside Wuhan. COVID-19 developed in these youngsters had fast onset and various nonspecific atypical manifestations, and were much milder than in older patients as previously reported.

Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB phosphorylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharmacotherapeutic strategy for FXS.

China Daily is the most influential English newspaper in China. With the deepening of China’s opening up, China Daily has become the authoritative medium for foreigners to know more about China and its policies. The corpus material of this study is the news from China Daily related to the NPC, the CPPCC, the 18th National Congress of the CPC and some international news in 2012. The purpose of this study is to give a detailed description of the political news in China Daily. This study analyzes its political nature and stylistic features, such as vocabulary with Chinese characteristics, grammar and syntax. Keywords-component; stylistic features ; China Daily ; political news