Hepatocellular carcinoma (HCC) is a common and highly malignant tumor that is prone to recurrence and metastasis and has no effective treatment. Unsurprisingly, its prognosis is quite poor; early detection methods and effective low-toxicity treatments are urgently needed. To achieve these goals, we designed a multifunctional, U.S. Food and Drug Administration-approved Prussian blue (PB) nanoparticle (NP) with a porous metal organic frame loaded with sorafenib (SF), conjugated with HCC-specific targeting peptide SP94 and the near-infrared dye cyanine (Cy)5.5. These NPs are amenable to multimodal imaging for dynamic monitoring of their biodistribution and tumor-targeting effects. The SP94-PB-SF-Cy5.5 NPs achieved targeted delivery and controlled SF release and exhibited good photothermal effects. In this strategy, photothermal therapy and SF treatment complement each other, reducing the side effects of SF and achieving a therapeutic effect without local tumor recurrence. In addition, the catalase-like ability of the NPs alleviates tumor hypoxia, and their photothermal effects induce immunogenic cell death, leading to the release of tumor-associated antigens. These effects combine to trigger an antitumor immune response; the NPs also displayed promising inhibitory effects on tumor metastasis and recurrence and produced an abscopal effect and long-term immunological memory when combined with antiprogrammed death-ligand 1 (PD-L1) immunotherapy. These safe, multifunctional NPs represent a valuable treatment option for HCC. In addition, this next-generation treatment model may provide some ideas for the management of HCC and other cancers.

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The spinach CSP41 protein has been shown to bind and cleave chloroplast RNA in vitro. Arabidopsis thaliana, like other photosynthetic eukaryotes, encodes two copies of this protein. Several functions have been described for CSP41 proteins in Arabidopsis, including roles in chloroplast rRNA metabolism and transcription. CSP41a and CSP41b interact physically, but it is not clear whether they have distinct functions. It is shown here that CSP41b, but not CSP41a, is an essential and major component of a specific subset of RNA-binding complexes that form in the dark and disassemble in the light. RNA immunoprecipitation and hybridization to gene chips (RIP-chip) experiments indicated that CSP41 complexes can contain chloroplast mRNAs coding for photosynthetic proteins and rRNAs (16S and 23S), but no tRNAs or mRNAs for ribosomal proteins. Leaves of plants lacking CSP41b showed decreased steady-state levels of CSP41 target RNAs, as well as decreased plastid transcription and translation rates. Representative target RNAs were less stable when incubated with broken chloroplasts devoid of CSP41 complexes, indicating that CSP41 proteins can stabilize target RNAs. Therefore, it is proposed that (i) CSP41 complexes may serve to stabilize non-translated target mRNAs and precursor rRNAs during the night when the translational machinery is less active in a manner responsive to the redox state of the chloroplast, and (ii) that the defects in translation and transcription in CSP41 protein-less mutants are secondary effects of the decreased transcript stability.

Multifunctional nanotheranostic agents have been highly commended due to the application to image-guided cancer therapy. Herein, based on the chemically disordered face centered cubic (fcc) FePt nanoparticles (NPs) and graphene oxide (GO), we develop a pH-responsive FePt-based multifunctional theranostic agent for potential in vivo and in vitro dual modal MRI/CT imaging and in situ cancer inhibition. The fcc-FePt will release highly active Fe ions due to the low pH in tumor cells, which would catalyze HO decomposition into reactive oxygen species (ROS) within the cells and further induce cancer cell apoptosis. Conjugated with folic acid (FA), the iron platinum-dimercaptosuccinnic acid/PEGylated graphene oxide-folic acid (FePt-DMSA/GO-PEG-FA) composite nanoassemblies (FePt/GO CNs) could effectively target and show significant toxicity to FA receptor-positive tumor cells, but no obvious toxicity to FA receptor-negative normal cells, which was evaluated by WST-1 assay. The FePt-based multifunctional nanoparticles allow real-time monitoring of Fe release by T-weighted MRI, and the selective contrast enhancement in CT could be estimated in vivo after injection. The results showed that FePt-based NPs displayed excellent biocompatibility and favorable MRI/CT imaging ability in vivo and in vitro. Meanwhile, the decomposition of FePt will dramatically decrease the T-weighted MRI signal and increase the ROS signal, which enables real-time and in situ visualized monitoring of Fe release in tumor cells. In addition, the self-sacrificial decomposition of fcc-FePt will be propitious to the self-clearance of the as-prepared FePt-based nanocomposite in vivo. Therefore, the FePt/GO CNs could serve as a potential multifunctional theranostic nanoplatform of MRI/CT imaging guided cancer diagnosis and therapy in the clinic.

Chloroplast development requires the coordinated expressions of nuclear and chloroplast genomes, and both anterograde and retrograde signals exist and work together to facilitate this coordination. We have utilized the Arabidopsis yellow variegated (var2) mutant as a tool to dissect the genetic regulatory network of chloroplast development. Here, we report the isolation of a new (to our knowledge) var2 genetic suppressor locus, SUPPRESSOR OF VARIEGATION9 (SVR9). SVR9 encodes a chloroplast-localized prokaryotic type translation initiation factor 3 (IF3). svr9-1 mutant can be fully rescued by the Escherichia coli IF3 infC, suggesting that SVR9 functions as a bona fide IF3 in the chloroplast. Genetic and molecular evidence indicate that SVR9 and its close homolog SVR9-LIKE1 (SVR9L1) are functionally interchangeable and their combined activities are essential for chloroplast development and plant survival. Interestingly, we found that SVR9 and SVR9L1 are also involved in normal leaf development. Abnormalities in leaf anatomy, cotyledon venation patterns, and leaf margin development were identified in svr9-1 and mutants that are homozygous for svr9-1 and heterozygous for svr9l1-1 (svr9-1 svr9l1-1/+). Meanwhile, as indicated by the auxin response reporter DR5:GUS, auxin homeostasis was disturbed in svr9-1, svr9-1 svr9l1-1/+, and plants treated with inhibitors of chloroplast translation. Genetic analysis established that SVR9/SVR9L1-mediated leaf margin development is dependent on CUP-SHAPED COTYLEDON2 activities and is independent of their roles in chloroplast development. Together, our findings provide direct evidence that chloroplast IF3s are essential for chloroplast development and can also regulate leaf development.

BackgroundWhether men with a prostate‐specific antigen (PSA) level of 4–10 ng/mL should be recommended for a biopsy is clinically challenging.PurposeTo develop and validate a radiomics model based on multiparametric MRI (mp‐MRI) in patients with PSA levels of 4–10 ng/mL to predict prostate cancer (PCa) preoperatively and reduce unnecessary biopsies.Study TypeRetrospective.SubjectsIn all, 199 patients with PSA levels of 4–10 ng/mL.Field Strength/Sequence3T, T2‐weighted, diffusion‐weighted, and dynamic contrast‐enhanced MRI.AssessmentLesion regions of interest (ROIs) from T2‐weighted, diffusion‐weighted, and dynamic contrast‐enhanced MRI were annotated by two radiologists. A total of 2104 radiomic features were extracted from the ROI of each patient. A random forest classifier was used to build the radiomics model for PCa in the primary cohort. A combined model was constructed using multivariate logistic regression by incorporating the radiomics signature and clinical‐radiological risk factors.Statistical TestsFor continuous variables, variance equality was assessed by Levene's test and Student's t‐test, and Welch's t‐test was used to assess between‐group differences. For categorical variables, Pearson's chi‐square test, Fisher's exact test, or the approximate chi‐square test was used to assess between‐group differences. P < 0.05 was considered statistically significant.ResultsThe combined model incorporating the multi‐imaging fusion model, age, PSA density (PSAD), and the PI‐RADS v2 score yielded area under the curve (AUC) values of 0.956 and 0.933 on the primary (n = 133) and validation (n = 66) cohorts, respectively. Compared with the clinical‐radiological model, the combined model performed better on both the primary and validation cohorts (P < 0.05). Furthermore, the use of the combined model to predict PCa could identify more negative PCa patients than the use of the clinical‐radiological model by 18.4%.Data ConclusionThe combined model was developed and validated to provide potential preoperative prediction of PCa in men with PSA levels of 4–10 ng/mL and might aid in treatment decision‐making and reduce unnecessary biopsies.Level of Evidence: 3Technical Efficacy Stage: 3J. Magn. Reson. Imaging 2020;51:1890–1899.

The development of functional chloroplasts relies on the fine coordination of expressions of both nuclear and chloroplast genomes. We have been using the Arabidopsis () () leaf variegation mutant as a tool to dissect the regulation of chloroplast development. In this work, we screened for genetic enhancer modifiers termed () mutants and report the characterization of the first locus, We showed that encodes the cytosolic 80S ribosome 40S small subunit protein RPS21B and the loss of causes the enhancement of leaf variegation. We further demonstrated that combined S21 activities from EVR1 and its close homolog, EVR1L1, are essential for Arabidopsis, and they act redundantly in regulating leaf development and leaf variegation. Moreover, using additional cytosolic ribosomal protein mutants, we showed that although mutations in cytosolic ribosomal proteins all enhance leaf variegation to varying degrees, the 40S subunit appears to have a more profound role over the 60S subunit in regulating VAR2-mediated chloroplast development. Comprehensive genetic analyses with suppressors that are defective in chloroplast translation established that the enhancement of leaf variegation by cytosolic ribosomal protein mutants is dependent on chloroplast translation. Based on our data, we propose a model that incorporates the suppression and enhancement of leaf variegation, and hypothesize that VAR2/AtFtsH2 may be intimately involved in the balancing of cytosolic and chloroplast translation programs during chloroplast biogenesis.

BackgroundEndoscopic full-thickness resection (EFTR) is a mini-invasive technique for gastric subepithelial tumors originating from the muscularis propria, which enables a full-thickness resection of tumors and can provide a complete basis for pathological diagnosis. Gastric fistula closure after EFTR is a challenge for endoscopists. In this study, we introduced EFTR with fistula closure using the over-the-scope clip (OTSC) system for gastric subepithelial tumors originating from the muscularis propria.ObjectivesTo evaluate the feasibility and safety of fistula closure with OTSC by a retrospective analysis on the cases of EFTR with defect closure using OTSC for gastric subepithelial tumors originating from the muscularis propria in our hospital.MethodsThe patients were selected who underwent EFTR for gastric subepithelial tumors originating from the muscularis propria (tumor diameter ≤2 cm) in our hospital from October 2013 to March 2014. After a full-thickness resection of tumors, the bilateral gastric mucous membranes of defect were clamped using twin graspers and then drawn into the transparent cap of OTSC, and the OTSC was released to close the defect after full suctioning. The success rate of defect closure with OTSC was observed, and the endoscopic follow-up was performed at 1 week, 1 and 6 months after operation to check OTSC closure.ResultsTotally 23 patients were included into the study. The full-thickness resection rate of gastric tumors in the muscularis propria was 100 % (23/23), the success rate of defect closure was 100 %, and the average time of defect closure was 4.9 min (range 2–12 min). All patients experienced no postoperative complications such as bleeding and perforation. The postoperative follow-up time was 1–6 months (mean 3 months), and no OTSC detachment was found.ConclusionsOTSC can be used to perform EFTR with defect closure for gastric tumors in the muscularis propria (tumor diameter ≤2 cm). It is simple, convenient, safe and effective.Electronic supplementary materialThe online version of this article (doi:10.1007/s00464-015-4076-2) contains supplementary material, which is available to authorized users.