Radiomics models to predict bone marrow metastasis of neuroblastoma using CT.

Background: Bone marrow is the leading site for metastasis from neuroblastoma and affects the prognosis of patients with neuroblastoma. However, the accurate diagnosis of bone marrow metastasis is limited by the high spatial and temporal heterogeneity of neuroblastoma. Radiomics analysis has been applied in various cancers to build accurate diagnostic models but has not yet been applied to bone marrow metastasis of neuroblastoma. Methods: We retrospectively collected information from 187 patients pathologically diagnosed with neuroblastoma and divided them into training and validation sets in a ratio of 7:3. A total of 2632 radiomics features were retrieved from venous and arterial phases of contrast-enhanced computed tomography (CT), and nine machine learning approaches were used to build radiomics models, including multilayer perceptron (MLP), extreme gradient boosting, and random forest. We also constructed radiomics-clinical models that combined radiomics features with clinical predictors such as age, gender, ascites, and lymph gland metastasis. The performance of the models was evaluated with receiver operating characteristics (ROC) curves, calibration curves, and risk decile plots. Results: The MLP radiomics model yielded an area under the ROC curve (AUC) of 0.97 (95% confidence interval [CI]: 0.95-0.99) on the training set and 0.90 (95% CI: 0.82-0.95) on the validation set. The radiomics-clinical model using an MLP yielded an AUC of 0.93 (95% CI: 0.89-0.96) on the training set and 0.91 (95% CI: 0.85-0.97) on the validation set. Conclusions: MLP-based radiomics and radiomics-clinical models can precisely predict bone marrow metastasis in patients with neuroblastoma.

Circulating white blood cell traits and prolonged night shifts: a cross-sectional study based on nurses in Guangxi.

This study aimed to elucidate the effects of long day and night shifts on immune cells in a population of nurses. This cross-sectional study in December 2019 was based on a group of nurses. 1568 physically healthy caregivers were included, including 1540 women and 28 men. 1093 nurses had long-term shift work (working in a rotating system for > 1 year). The receiver operating characteristic curve, Ensemble Learning, and Logistic regression analyses were used to evaluate factors related to long-term shift work. The night shift group nurses had significantly higher MPV, PLCR, and WBC and significantly lower BASO%, ELR, MCHC, PLR, RDW-CV, and RDW-SD (P < 0.01). ROC curves showed that WBC, PLR, ELR, RDW_CV, and BASO% were more related to the night shift. Ensemble Learning, combined with the LASSO model, finally filtered out three indicators of night shifts related to ELR, WBC, and RDW_SD. Finally, logistic regression analysis showed that the nurses' night shift situation greatly influenced two peripheral blood ELR and WBC indicators (ELR: log (OR) = - 3.9, 95% CI: - 5.8- - 2.0; WBC: log (OR) = 0.25, 95% CI: 0.18-0.32). Finally, we showed that, unlike WBC, the relative riskiness of ELR showed opposite results among junior nurses and middle-senior nurses (log (OR) 6.5 (95% CI: 1.2, 13) and - 7.1 (95% CI: - 10, - 3.8), respectively). Our study found that prolonged night shifts were associated with abnormal WBC and ELR, but after strict age matching, WBC remained significantly different. These findings help to confirm that COVID-19 and tumorigenesis (e.g., breast cancer) are significantly associated with circadian rhythm disruption. However, more detailed studies are needed to confirm this.

Real-world advantage and challenge of post-autologous stem cell transplantation MRD negativity in high-risk patients with double-hit multiple myeloma.

BACKGROUND: Autologous stem-cell transplantation (ASCT) remains a beneficial approach for patients with newly diagnosed multiple myeloma (NDMM) in the age of novel therapeutic agents. Nevertheless, limited real-world data is available to establish criteria for identifying high-risk ASCT patients. METHODS: We analyzed outcomes for 168 NDMM patients who underwent ASCT at our center from December 2015 to December 2022. We investigated the impact of the number of high-risk cytogenetics (HRCA), defined as t(4;14), t(14;16), 1q21 gain/amplification, and del(17p), as well as the post-ASCT minimal residual disease (MRD) status as prognostic indicators. We assessed progression-free survival (PFS) and overall survival (OS), and focused on identifying risk factors. RESULTS: The cohort included 42% of patients (n = 71) with 0 HRCA, 42% (n = 71) with 1 HRCA, and 16% (n = 26) with ≥ 2 HRCA. After a median follow-up of 31 months, the median PFS was 53 months (95% CI, 37-69), and OS was not reached for the entire cohort. Despite similar rates of MRD-negativity post-ASCT, patients with ≥ 2 HRCA, termed "double hit" (DH), had a significantly higher risk of progression/mortality than those with 0 or 1 HRCA. Multivariate analysis highlighted DH (HR 4.103, 95% CI, 2.046-8.231) and MRD positivity post-ASCT (HR 6.557, 95% CI, 3.217-13.366) as adverse prognostic factors for PFS, with DH also linked to inferior OS. As anticipated, DH patients with post-ASCT MRD positivity displayed the poorest prognosis, with a median PFS of 7 months post-ASCT. Meanwhile, DH patients with MRD negativity post-ASCT showed improved prognosis, akin to MRD-negative non-DH patients. It is noteworthy to exercise caution, as DH patients who initially achieved MRD negativity experienced a 41% cumulative loss of that status within one year. CONCLUSIONS: This study strongly advocates integrating DH genetic assessments for eligible ASCT patients and emphasizes the importance of ongoing MRD monitoring, as well as considering MRD-based treatment adaptation for those patients in real-world settings.

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion.

BACKGROUND: Despite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach. METHODS: In this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KD BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients. RESULTS: Compared with parental BCMA CAR-T cells, PD-1KD BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KD BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity. CONCLUSIONS: Our study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.

ETV6::ACSL6 translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression.

ETV6::ACSL6 represents a rare genetic aberration in hematopoietic neoplasms and is often associated with severe eosinophilia, which confers an unfavorable prognosis requiring additional anti-inflammatory treatment. However, since the translocation is unlikely to produce a fusion protein, the mechanism of ETV6::ACSL6 action remains unclear. Here, we performed multi-omics analyses of primary leukemia cells and patient-derived xenografts from an acute lymphoblastic leukemia (ALL) patient with ETV6::ACSL6 translocation. We identified a super-enhancer located within the ETV6 gene locus, and revealed translocation and activation of the super-enhancer associated with the ETV6::ACSL6 fusion. The translocated super-enhancer exhibited intense interactions with genomic regions adjacent to and distal from the breakpoint at chromosomes 5 and 12, including genes coding inflammatory factors such as IL-3. This led to modulations in DNA methylation, histone modifications, and chromatin structures, triggering transcription of inflammatory factors leading to eosinophilia. Furthermore, the bromodomain and extraterminal domain (BET) inhibitor synergized with standard-of-care drugs for ALL, effectively reducing IL-3 expression and inhibiting ETV6::ACSL6 ALL growth in vitro and in vivo. Overall, our study revealed for the first time a cis-regulatory mechanism of super-enhancer translocation in ETV6::ACSL6ALL, leading to an ALL-accompanying clinical syndrome. These findings may stimulate novel treatment approaches for this challenging ALL subtype.

Machine-learning radiomics to predict bone marrow metastasis of neuroblastoma using magnetic resonance imaging.

Background: Neuroblastoma is one common pediatric malignancy notorious for high temporal and spatial heterogeneities. More than half of its patients develop distant metastases involving vascularized organs, especially the bone marrow. It is thus necessary to have an economical, noninvasive method without much radiation for follow-ups. Radiomics has been used in many cancers to assist accurate diagnosis but not yet in bone marrow metastasis in neuroblastoma. Methods: A total of 182 patients with neuroblastoma were retrospectively collected and randomly divided into the training and validation sets. Five-hundred and seventy-two radiomics features were extracted from magnetic resonance imaging, among which 41 significant ones were selected via T-test for model development. We attempted 13 machine-learning algorithms and eventually chose three best-performed models. The integrative performance evaluations are based on the area under the curves (AUCs), calibration curves, risk deciles plots, and other indexes. Results: Extreme gradient boosting, random forest (RF), and adaptive boosting were the top three to predict bone marrow metastases in neuroblastoma while RF was the most accurate one. Its AUC was 0.90 (0.86-0.93), F1 score was 0.82, sensitivity was 0.76, and negative predictive value was 0.79 in the training set. The values were 0.82 (0.71-0.93), 0.80, 0.75, and 0.92 in the validation set, respectively. Conclusions: Radiomics models are likely to contribute more to metastatic diagnoses and the formulation of personalized healthcare strategies in clinics. It has great potential of being a revolutionary method to replace traditional interventions in the future.

Bioinspired synthesis and biological evaluation of ent-protulactones A and B.

The bioinspired and stereoselective synthesis of the furo[3,2-b] furan lactone (-)-protulactone A and the dioxabicyclo[3.3.1]nonane lactone (+)-protulactone B has been achieved based on the chiron approach. The synthesis features the utilization of a number of one-pot, sequential transformations, including a cascade reaction of reductive elimination and nucleophilic addition in a one-pot process and a one-pot sequence via cross-metathesis/acetonide deprotection/O-Michael addition/lactonization to streamline the synthesis route and avoid the tedious work of product purification. Synthetic protulactones and their analogues were evaluated for their in vitro antiproliferative activity against selected tumor cell lines (MCF-7 and Capan 2) and showed minor cytotoxicity.

A novel long-tailed myovirus represents a new T4-like cyanophage cluster.

Cyanophages affect the abundance, diversity, metabolism, and evolution of picocyanobacteria in marine ecosystems. Here we report an estuarine Synechococcus phage, S-CREM2, which represents a novel viral genus and leads to the establishment of a new T4-like cyanophage clade named cluster C. S-CREM2 possesses the longest tail (~418 nm) among isolated cyanomyoviruses and encodes six tail-related proteins that are exclusively homologous to those predicted in the cluster C cyanophages. Furthermore, S-CREM2 may carry three regulatory proteins in the virion, which may play a crucial role in optimizing the host intracellular environment for viral replication at the initial stage of infection. The cluster C cyanophages lack auxiliary metabolic genes (AMGs) that are commonly found in cyanophages of the T4-like clusters A and B and encode unique AMGs like an S-type phycobilin lyase gene. A variation in the composition of tRNA and cis-regulatory RNA genes was observed between the marine and freshwater phage strains in cluster C, reflecting their different modes of coping with hosts and habitats. The cluster C cyanophages are widespread in estuarine and coastal regions and exhibit equivalent or even higher relative abundance compared to those of clusters A and B cyanophages in certain estuarine regions. The isolation of cyanophage S-CREM2 provides new insights into the phage-host interactions mediated by both newly discovered AMGs and virion-associated proteins and emphasizes the ecological significance of cluster C cyanophages in estuarine environments.

Peripheral blood lipid and liver and kidney function test results in long-term night shift nurses: a cross-sectional study in South China.

Purpose: This study aimed to elucidate the effects of long-term day and night shifts on liver function and lipid metabolism in a group of nurses. Methods: This cross-sectional study in December 2019 was based on a group of nurses. A total of 1,253 physically healthy caregivers were included, including 1231 women and 22 men. A total of 886 nurses had long-term shift work (working in a rotating system for >1 year). The receiver operating characteristic (ROC) curve and logistic regression analyses were used to evaluate factors related to long-term shift work. Results: We observed differences in liver and kidney indicators between the non-night and night shift groups. The ROC curve revealed that CHO (AUC: 62.4%), LDLC (AUC: 62%), and GLUO (AUC: 61.5%) were more related to the night shift. Logistic regression analysis showed that night shift work was associated significantly with CREA (log (OR) = -0.02, 95% CI: -0.04 to -0.01), CHO (log (OR) = -0.38, 95% CI: -0.67 to -0.09), and GLUO (log (OR) = -0.35, 95% CI: -0.56 to -0.17). This correlation was observed only for CHO and LDHC (CHO: log (OR) = -0.55, 95% CI: -0.98 to -0.12; LDLC: log (OR) = 0.83, 95% CI: 0.32, 1.4) after age standardization. After using propensity score matching, we did not find evidence to support that the indicators differed between night and non-night shift groups. Conclusion: Our study observed an association of long-term night work with abnormal liver and kidney function and dyslipidemia, but the difference was not significant after strict age matching. Although these findings may support interventions for long-term night shift nurses, more detailed studies are needed to confirm.

Cholesterol modulates the physiological response to nanoparticles by changing the composition of protein corona.

Nanoparticles (NPs) in biological fluids form a layer of biomolecules known as the protein corona. The protein corona has been shown to determine the biological identity and in vivo fate of NPs, but whether and how metabolites, especially disease-related small molecules, regulate the protein corona and subsequently impact NP fate in vivo is relatively poorly understood. Here we report on the effects of cholesterol on the generation of protein corona and subsequent effects. We find that high levels of cholesterol, as in hypercholesterolemia, result in a protein corona with enriched apolipoproteins and reduced complement proteins by altering the binding affinity of the proteins to the NPs. The cholesterol-mediated protein corona can induce stronger inflammatory responses to NPs in macrophages and promote the cellular uptake of NPs in hepatocytes by enhancing the recognition of lipoprotein receptors when compared with normal protein corona. The result of in vivo biodistribution assays shows that, compared with healthy mice, NPs in hypercholesterolemic mice were more likely to be delivered to the liver, spleen and brain, and less likely to be delivered to the lungs. Our findings reveal that the metabolome profile is an unexploited factor impacting the target efficacy and safety of nanomedicines, providing a way to develop personalized nanomedicines by harnessing disease-related metabolites.

Modification of Soft Wheat Protein for Improving Cake Quality by Superheated Steam Treatment of Wheat Grain.

Many varieties of soft wheat in China cannot fully satisfy the requirements of making high-quality cakes due to their undesirable protein properties, which leads to shortages of high-quality soft wheat flour. Therefore, a modification of soft wheat protein is essential for improving the quality of soft wheat and thus improving cake quality. In order to modify the protein properties of soft wheat used for cake production, superheated steam (SS) was used to treat soft wheat grains at 165 °C and 190 °C for 1, 2, 3, 4, and 5 min, respectively, followed by the milling of wheat grains to obtain refined wheat flour. The properties of proteins and cakes were analyzed using refined wheat flour as materials. First, changes in the structures of wheat proteins were analyzed by determining the solubility, molecular weight distribution and secondary structure of proteins in wheat flour. Secondly, changes in the functional properties of proteins were analyzed by determining the foaming properties and emulsifying properties of proteins in wheat flour. Finally, the specific volume and texture of cakes with wheat flour milled from SS-treated wheat were analyzed. At the initial stage of SS treatment, some of the gliadin and glutenin aggregated, and the gluten macro-polymer (GMP) contents increased. This allowed a more stable gluten network to form during dough kneading, leading to an improvement in dough elasticity. In addition, a short time period (1-3 min) of SS treatment improved the emulsifying properties and foaming ability of wheat protein, which helped to improve the specific volume and texture of cakes. Increasing the SS temperature from 165 °C to 190 °C reduced the optimal treatment time needed to improve cake quality from 3 min to 1 min. SS treatment for longer time (>3 min) periods led to severe protein aggregation and a decrease in the foaming ability and emulsifying properties of protein, which led to a deterioration in the cake quality. Thus, SS treatment at 165 °C for 1-3 min and 190 °C for 1 min could be a suitable method of improving the physicochemical properties of soft wheat used to make cakes with high specific volumes and good texture.

Scientific research ability of specialist nurses in Guangxi Zhuang Autonomous Region, China: A cross-sectional study.

AIM: This study investigated the scientific research ability of Chinese specialist nurses (SNs) in the Guangxi Zhuang Autonomous Region and its influencing factors. DESIGN: A cross-sectional design. METHODS: A total of 652 SNs in the Guangxi Zhuang Autonomous Region were investigated from March to October 2021. The nursing scientific research ability level was measured using the Nursing Research Competence of Nurses Self-evaluation Scale. Descriptive statistics, univariate analysis and ordinal logistic regression analysis were used to evaluate factors affecting the scientific research ability of SNs. RESULTS: The median score of scientific research ability of SNs was 31 (interquartile range: 19-41). Approximately 74.8% of clinical speciality nurses had low scientific research ability. Educational background, working hospital level, being the first author of a published paper and successful application for scientific research projects were identified as factors influencing scientific research ability score.

An Estuarine Cyanophage S-CREM1 Encodes Three Distinct Antitoxin Genes and a Large Number of Non-Coding RNA Genes.

Cyanophages play important roles in regulating the population dynamics, community structure, metabolism, and evolution of cyanobacteria in aquatic ecosystems. Here, we report the genomic analysis of an estuarine cyanophage, S-CREM1, which represents a new genus of T4-like cyanomyovirus and exhibits new genetic characteristics. S-CREM1 is a lytic phage which infects estuarine Synechococcus sp. CB0101. In contrast to many cyanomyoviruses that usually have a broad host range, S-CREM1 only infected the original host strain. In addition to cyanophage-featured auxiliary metabolic genes (AMGs), S-CREM1 also contains unique AMGs, including three antitoxin genes, a MoxR family ATPase gene, and a pyrimidine dimer DNA glycosylase gene. The finding of three antitoxin genes in S-CREM1 implies a possible phage control of host cells during infection. One small RNA (sRNA) gene and three cis-regulatory RNA genes in the S-CREM1 genome suggest potential molecular regulations of host metabolism by the phage. In addition, S-CREM1 contains a large number of tRNA genes which may reflect a genomic adaption to the nutrient-rich environment. Our study suggests that we are still far from understanding the viral diversity in nature, and the complicated virus-host interactions remain to be discovered. The isolation and characterization of S-CREM1 further our understanding of the gene diversity of cyanophages and phage-host interactions in the estuarine environment.

Reduction of Aflatoxin B1 and Zearalenone Contents in Corn Using Power Ultrasound and Its Effects on Corn Quality.

The degradation of aflatoxin B1 (AFB1) and zearalenone (ZEA) is investigated using power ultrasound to identify suitable methods to reduce the mycotoxin content of corn. AFB1 and ZEA in corn are simultaneously degraded via power ultrasound; thus, this method has a significant effect on corn quality. The power intensity, solid-liquid ratio, and ultrasonic treatment modes significantly affect the degradation rates of AFB1 and ZEA. The dissolution of AFB1 and ZEA in water also facilitates their degradation. At the initial stage of ultrasonic treatment, power ultrasound promotes the dissolution of mycotoxins in water, whereupon they are partially oxidized by free radicals. With a treatment time of 10 min, the reduction rates decreased owing to the dissolution of combined-state mycotoxins. After ultrasonic treatment, the contents of the essential amino acids, the total number of amino acids, and the fatty acids in corn decreased; however, ΔH values decreased during starch gelatinization. In contrast, the amylose content and viscosity of corn significantly increased during gelatinization. Therefore, this method is potentially suitable for the reduction of AFB1 and ZEA contents in corn.

PEGylation of Goldbody: PEG-aided conformational engineering of peptides on gold nanoparticles.

It is still a great challenge to engineer flexible non-functional molecules into special conformations to carry out novel functions. Previously, we successfully restored the native conformations and functions of the flexible complementary-determining regions (CDRs) of antibodies on the surface of gold nanoparticles (AuNPs), and created a class of AuNP-based artificial antibodies, denoted as Goldbodies. Yet, in these Goldbodies, there are dozens of CDRs on one Goldbody. Herein, we show that the number of CDRs per Goldbody could be reduced by more than one order of magnitude, by replacing the majority of the CDRs with polyethylene glycol (PEG) with a molecular weight around 600 Da, while the native conformations and functions of the CDRs could still be restored on AuNPs. Also, we find that the PEG with two terminal -SH groups is much better than the PEG with a single -SH group for aiding the restoration of the native conformation of the CDRs on AuNPs. To demonstrate the potential generic applicability of the PEGylation in aiding conformational engineering of peptides, two PEGylated Goldbodies have been created, which can specifically recognize lysozyme and epidermal growth factor receptor, respectively. The PEGylated Goldbodies further prove the mechanism of conformational engineering and the "Confined Lowest Energy Fragments" (CLEFs) hypothesis, and pave the way for future applications of Goldbodies.

A Unique Set of Auxiliary Metabolic Genes Found in an Isolated Cyanophage Sheds New Light on Marine Phage-Host Interactions.

Cyanophages, viruses that infect cyanobacteria, are abundant and widely distributed in aquatic ecosystems, playing important roles in regulating the abundance, activity, diversity, and evolution of cyanobacteria. A T4-like cyanophage, S-SCSM1, infecting Synechococcus and Prochlorococcus strains of different ecotypes, was isolated from the South China Sea in this study. For the first time, a mannose-6-phosphate isomerase (MPI) gene was identified in the cultured cyanophage. At least 11 phylogenetic clusters of cyanophage MPIs were retrieved and identified from the marine metagenomic data sets, indicating that cyanophage MPIs in the marine environment are extremely diverse. The existence of 24 genes encoding 2-oxoglutarate (2OG)-Fe(II) oxygenase superfamily proteins in the S-SCSM1 genome emphasizes their potential importance and diverse functions in reprogramming host metabolism during phage infection. Novel cell wall synthesis and modification genes found in the S-SCSM1 genome indicate that diverse phenotypic modifications imposed by phages on cyanobacterial hosts remain to be discovered. Two noncoding RNAs of cis-regulatory elements in the S-SCSM1 genome were predicted to be associated with host exopolysaccharide metabolism and photosynthesis. The isolation and genomic characterization of cyanophage S-SCSM1 provide more information on the genetic diversity of cyanophages and phage-host interactions in the marine environment. IMPORTANCE Cyanophages play important ecological roles in aquatic ecosystems. Genomic and proteomic characterizations of the T4-like cyanophage S-SCSM1 indicate that novel and diverse viral genes and phage-host interactions in the marine environment remain unexplored. The first identified mannose-6-phosphate isomerase (MPI) gene from a cultured cyanophage was found in the S-SCSM1 genome, although MPIs were previously found in viral metagenomes at high frequencies similar to those of the cyanophage photosynthetic gene psbA. The presence of 24 genes encoding 2-oxoglutarate (2OG)-Fe(II) oxygenase superfamily proteins, novel cell wall synthesis and modification genes, a nonbleaching protein A gene, and 2 noncoding RNAs of cis-regulatory elements in the S-SCSM1 genome as well as the presence of a virion-associated regulatory protein indicate the diverse functions that cyanophages have in reprogramming the metabolism and modifying the phenotypes of hosts during infection.

On the Cellular Uptake and Exocytosis of Carbon Dots─Significant Cell Type Dependence and Effects of Cell Division.

Understanding the cellular uptake and exocytosis processes of nanoparticles (NPs) is essential for developing the nanomedicines and assessing the health risk of nanomaterials. Considerable efforts have been made to reveal how physicochemical properties of NPs influence these processes. However, little attention has been paid to how cell type impacts these processes, especially exocytosis. Herein, the uptake and exocytosis of the carbon dots (CDs) obtained from the carbonization of citric acid with polyethylenimine (PEI) oligomers (CDs-PEI) in five human cell lines (HeLa, A549, BEAS-2B, A431, and MDA-MB-468) are analyzed to understand how cell type influences the fate of CDs in cells. The cell division is taken into account by the correction of cell number for accurate quantification of the uptake and exocytosis of CDs-PEI. The results indicate that the cell type significantly affects the cellular uptake, trafficking, and exocytosis of CDs-PEI. Among the cell types investigated, MDA-MB-468 cells have the greatest capacity for both uptake and exocytosis, and HeLa cells have the least capacity. The kinetics of the exocytosis largely follows a single exponential decay function, with the remaining CDs-PEI in cells reaching plateaus within 24 h. The kinetic parameters are cell-dependent but insensitive to the initial intracellular CDs-PEI content. Generally, the Golgi apparatus pathways are more important in exocytosis than the lysosomal pathway, and the locations of CDs-PEI in the beginning of exocytosis are not correlated with their exocytosis pathways. The findings on the cell type-dependent cellular uptake and exocytosis reported here may be valuable to the future design of high-performance and safe CDs and related nanomaterials in general.

Folding of Flexible Protein Fragments and Design of Nanoparticle-Based Artificial Antibody Targeting Lysozyme.

It is generally believed that a protein's sequence solely determines its native structure, but how the long- and short-range interactions jointly determine the native structure/conformation of the protein or every local fragment of the protein is still not fully understood. Since most protein fragments are unstructured on their own, direct observation of the folding of flexible protein fragments is very difficult. Interestingly, we show that it is possible to graft the complementary-determining regions (CDRs) of antibodies onto the surface of a gold nanoparticle (AuNP) to create AuNP-based artificial antibodies (denoted as Goldbodies), such as an antilysozyme Goldbody. Goldbodies can specifically recognize the corresponding antigens like the original natural antibodies do, but direct structural evidence for the refolding or restoration of native conformation of the grafted CDRs on AuNPs is still missing and in high demand. Herein we design a new Goldbody that targets an epitope on the lysozyme different from that of the previous antilysozyme Goldbody, and the one circle of helix in the CDR makes it possible to distinguish the unfolded conformation of the free CDR and its folded conformation on AuNPs by circular dichroism (CD) spectroscopy. The refolding of flexible protein fragments on NPs provides unique evidence and inspiration for understanding the fundamental principles of protein folding.

Ectopic expression of a combination of 5 genes detects high risk forms of T-cell acute lymphoblastic leukemia.

BACKGROUND: T cell acute lymphoblastic leukemia (T-ALL) defines a group of hematological malignancies with heterogeneous aggressiveness and highly variable outcome, making therapeutic decisions a challenging task. We tried to discover new predictive model for T-ALL before treatment by using a specific pipeline designed to discover aberrantly active gene. RESULTS: The expression of 18 genes was significantly associated with shorter survival, including ACTRT2, GOT1L1, SPATA45, TOPAZ1 and ZPBP (5-GEC), which were used as a basis to design a prognostic classifier for T-ALL patients. The molecular characterization of the 5-GEC positive T-ALL unveiled specific characteristics inherent to the most aggressive T leukemic cells, including a drastic shut-down of genes located on the mitochondrial genome and an upregulation of histone genes, the latter characterizing high risk forms in adult patients. These cases fail to respond to the induction treatment, since 5-GEC either predicted positive minimal residual disease (MRD) or a short-term relapse in MRD negative patients. CONCLUSION: Overall, our investigations led to the discovery of a homogenous group of leukemic cells with profound alterations of their biology. It also resulted in an accurate predictive tool that could significantly improve the management of T-ALL patients.