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Effective and accurate delivery of drugs to tissue with spinal cord injury (SCI) is the key to rehabilitating neurological deficits. Sustained-release microspheres (MS) have excellent degradability and can aid in the long-term release of drugs. However, the burst release phenomenon can cause unexpected side effects. Herein, we developed and optimized an injectable poly(lactic-co-glycolic acid) (PLGA) MS loaded with melatonin(Mel), which were mixed further with Laponite hydrogels (Lap/MS@Mel, a micro-gel compound) in order to reduce the burst release of MS. Thus, these MS were able to achieve stable and prolonged Mel release, as well as synergistic Lap hydrogel in order to repair neural function in SCI by in situ injection. In clinical practice, patients with SCI have complicated conditions and significant inter-individual differences, which means that a single route of administration does not meet actual clinical needs. Thus, the nanospheres are synthesized and subsequently coated with platelet membrane (PM) in order to form PM/MS@Mel (nano-PM compound) for sustained and precision-targeted delivery of Mel intravenously in the SCI. Notably, optimized microsphere delivery systems have improved Mel regulation polarization of spinal microglial/macrophages, which can reduce loss of biomaterials due to macrophage-induced immune response during implantation of spinal cord tissue. These two new delivery systems that are based on MS provide references for the clinical treatment of SCI, according to different requirements., Graphical Abstract Schematic representation of repair of neurological deficits using Lap/MS@Mel and PM/MS@Mel nanoparticles in a rat model of spinal cord injury.

Confucian Image Politics: Masculine Morality in Seventeenth-Century China. By Ying Zhang. Seattle: University of Washington Press, 2016. Pp. xvi + 306. $50.

Modern machine learning models towards various tasks with omic data analysis give rise to threats of privacy leakage of patients involved in those datasets. Despite the advances in different privacy technologies, existing methods tend to introduce too much computational cost (e.g. cryptographic methods) or noise (e.g. differential privacy), which hampers either model usefulness or accuracy in protecting privacy in biological data. Here, we proposed a secure and privacy-preserving machine learning method (PPML-Omics) by designing a decentralized version of the differential private federated learning algorithm. We applied PPML-Omics to analyze data from three sequencing technologies, and addressed the privacy concern in three major tasks of omic data, namely cancer classification with bulk RNA-seq, clustering with single-cell RNA-seq, and the integration of spatial gene expression and tumour morphology with spatial transcriptomics, under three representative deep learning models. We also examined privacy breaches in depth through privacy attack experiments and demonstrated that PPML-Omics could protect patients’ privacy. In each of these applications, PPML-Omics was able to outperform methods of comparison under the same level of privacy guarantee, demonstrating the versatility of the method in simultaneously balancing the privacy-preserving capability and utility in practical omic data analysis. Furthermore, we gave the theoretical proof of the privacy-preserving capability of PPML-Omics, suggesting the first mathematically guaranteed method with robust and generalizable empirical performance in protecting patients’ privacy in omic data.

Oleic acid (OA) emulsion is widely used in nanomaterial synthesis and applications. The emulsion droplets can serve as template scaffolds for nanoparticle self-organization, while adding nanopartic...

Multidrug resistance (MDR) restricts chemotherapy efficacy due to P-glycoprotein (P-gp) mediated drug efflux, whereas current approaches to suppressing P-gp expression suffer from intrinsic challenges, such as low transfection, high toxicity and poor specificity. Here, hollow ferric-tannic acid complex nanocapsules (HFe-TA), which can be effectively degraded by the reaction with adenosine triphosphate (ATP), are synthesized for the delivery of glucose oxidase (GOx) and doxorubicin (DOX) for tumor treatment. The findings indicate that the intracellular ATP is significantly decreased due to the combined effect of HFe-TA degradation and GOx-mediated glucose consumption. Along with this ATP down-regulation, P-gp expression of tumor cells is suppressed remarkably, which in turn promotes the intracellular accumulation and anticancer efficacy of DOX. In addition, the production of •OH by Fe ions released from HFe-TA is promoted by the by-products of the oxidation of glucose process by GOx. In consequence, HFe-TA nanocapsules loaded with DOX and GOx enable significant inhibition effect to tumors both in vitro and in vivo due to the synergistic effect of cascade reactions. This study has therefore provided an alternative therapeutic platform for effective tumor inhibition with the potential in overcoming intrinsic MDR.

Although islet transplantation plays an effective and powerful role in the treatment of diabetes, a large amount of islet grafts are lost at an early stage due to instant blood-mediated inflammatory reactions, immune rejection, and β-cell toxicity resulting from immunosuppressive agents. Timely intervention based on the viability and function of the transplanted islets at an early stage is crucial. Various islet transplantation imaging techniques are available for monitoring the conditions of post-transplanted islets. Due to the development of various imaging modalities and the continuous study of contrast agents, non-invasive islet transplantation imaging in vivo has made great progress. The tracing and functional evaluation of transplanted islets in vivo have thus become possible. However, most studies on contrast agent and imaging modalities are limited to animal experiments, and long-term toxicity and stability need further evaluation. Accordingly, the clinical application of the current achievements still requires a large amount of effort. In this review, we discuss the contrast agents for MRI, SPECT/PET, BLI/FI, US, MPI, PAI, and multimodal imaging. We further summarize the advantages and limitations of various molecular imaging methods.

Background Pancreatic cancer is a highly malignant tumor of the digestive system. Early pancreatic cancer is often difficult to diagnosis due to its atypical clinical symptoms. Patients with pancreatic cancer have a very poor prognosis because they have lost the opportunity for radical surgical tumor resection and they are less sensitive to the clinically used radiotherapy and chemotherapy. Methods In this study, a peptide targeting pancreatic cancer cells was screened by phage display technology, and its targeting property was evaluated in vitro using PANC1 cells by fluorescence imaging and flow cytometry. Furthermore, the targeting peptide was conjugated to the pro-apoptotic KLAKLAKKLAKLAK (KLA), the fusion peptide and its targeting ability that allowing KLA to specifically enter pancreatic tumor cells in vitro and in vivo was confirmed by fluorescence imaging and in vivo imaging system (IVIS). Its mechanism was determined using flow cytometry, mitochondrial membrane potential evaluation and Western blot. The inhibitory effect on pancreatic tumor growth and toxic effects were evaluated by animal experiment. Results Due to the internalization facilitated by the targeting mechanism of the targeting peptide, KLA specifically entered pancreatic cancer cells, destroyed mitochondria and induced apoptosis. The fusion peptide and its targeting ability that allowing KLA to specifically enter pancreatic tumor cells and exert a significant inhibitory effect on pancreatic tumor growth with reduced toxic effects. Conclusion This approach possesses potential advantages in the clinical diagnosis and treatment of pancreatic cancer.

Background High‐quality randomized controlled trials have demonstrated the benefit of radiotherapy (RT) in patients with radical resected gastric cancer (GC), however, utilization rates of postoperative RT remain remarkably low. Patterns, incidences, and time of recurrence provide biological bases for clinical monitoring of GC patients and guiding potential complementary therapies. Thus, the aim of this study is to understand the location of locoregional recurrence which may allow individualized RT strategies and minimize radiation‐related toxic effects. Methods A relatively large sample of GC patients in a single institution who had undergone curative D2 resection was retrospectively reviewed and the relevant recurrence patterns were illustrated. Independent recurrence‐related risk factors were analyzed by logistic regression analysis. New logistic regression models were further developed to predict the probability of recurrence. Results Overall, among 776 GC patients who had continuous and complete follow‐up data, 300 cases relapsed after curative resection. Lymphovascular invasion, lymph node metastases, and tumor stage were indicators for early recurrence. Peritoneal, regional, local, and distant recurrence initially occurred in 51 (6.6%), 151 (19.4%), 56 (7.2%), and 164 (21.1%) patients, respectively. Among patients with regional recurrence, the most common sites were lymph node stations 16a2, 8, 12, 16b1, and 9. Remnant stomach recurrence was not so prominent that it seemed reasonable to be excluded from an irradiation field for patients with negative surgical/pathologic margins. Conclusions For GC patients who underwent radical D2 resection, distant and regional recurrences were still common. Besides, optimizing regional control of lymph nodes outside the D2 dissected area was crucial for rational design of the RT field. Furthermore, the new logistic regression models might act as useful tools to evaluate recurrence risk and determine which patients should receive postoperative chemoradiotherapy., Recurrence patterns of a relatively large sample of gastric cancer patients were retrospectively illustrated. All detailed information was critical for selecting appropriate therapeutic modalities and delineating individualized radiotherapy target coverage.

The dense fibrotic stroma in pancreatic ductal adenocarcinoma (PDA) resists drug diffusion into the tumor and leads to an unsatisfactory prognosis. To address this problem, we demonstrate a dendrimer-camptothecin (CPT) conjugate that actively penetrates deep into PDA tumors through γ-glutamyl transpeptidase (GGT)-triggered cell endocytosis and transcytosis. The dendrimer-drug conjugate was synthesized by covalent attachment of CPT to polyamidoamine (PAMAM) dendrimers through a reactive oxygen species (ROS)-sensitive linker followed with surface modification with glutathione. Once the conjugate was delivered to the PDA tumor periphery, the overexpressed GGT on the vascular endothelial cell or tumor cell triggers the γ-glutamyl transfer reactions of glutathione to produce primary amines. The positively charged conjugate was rapidly internalized via caveolae-mediated endocytosis and followed by vesicle-mediated transcytosis, augmenting its deep penetration within the tumor parenchyma and releasing active CPT throughout the tumor after cleavage by intracellular ROS. The dendrimer-drug conjugate exhibited high antitumor activity in multiple mice tumor models, including patient-derived PDA xenograft and orthotopic PDA cell xenograft, compared to the standard first-line chemotherapeutic drug (gemcitabine) for advanced pancreatic cancer. This study demonstrates the high efficiency of an active tumor-penetrating dendrimer-drug conjugate via transcytotic transport with ROS-responsive drug release for PDA therapy.

Introduction As heterologous islets or islet-like stem cells become optional sources for islet transplantation, the subcutaneous site appears to be an acceptable replacement of the intrahepatic site due to its graft retrievability. The device-less (DL) procedure improves the feasibility; however, some limitations such as fibrotic overgrowth or immunodeficiency still exist. Nanofibers could mimic the extracellular matrix to improve the vitality of transplanted islets. Therefore, we designed a vascular endothelial growth factor (VEGF)-modified polyvinyl alcohol (PVA)/silicone nanofiber (SiO2-VEGF) to optimize the DL procedure. Methods SiO2-VEGF nanofibers were designed by nano-spinning and characterized the physical-chemical properties before subcutaneous islet transplantation. Cell viability, vessel formation, and glucose-stimulated insulin secretion were tested in vitro to ensure biocompatibility; and blood glucose level (BGL), transplanted islet function, and epithelial-mesenchymal transition (EMT)-related biomarker expression were analyzed in vivo. Results The intensity of inflammatory reaction induced by SiO2 nanofibers was between nylon and silicone, which did not bring out excessive fibrosis. The vascularization could be enhanced by VEGF functionalization both in vitro and in vivo. The BGL control was better in the DL combined with SiO2-VEGF group. The percentage of recipients that achieved normoglycemia was higher and earlier (71% at day 57), and the intraperitoneal glucose tolerance test (IPGTT) also confirmed better islet function. The expressions of vimentin, α-SMA, and twist-1 were upregulated, which indicated that SiO2-VEGF nanofibers might promote islet function by regulating the EMT pathway. Discussion In summary, our new SiO2-VEGF combined with DL procedure might improve the feasibility of subcutaneous islet transplantation for clinical application.

Nanoparticles presenting promoted catalytic activity, oxygen induction and loading capability are in high demand for effective synergistic tumor therapy. Herein, ferric-tannic acid complex nanocapsules with fine hollow microstructure (HFe-TA) are synthesized and loaded with a photosensitizer (indocyanine green, ICG) for synergistic tumor therapy. In acidic environment, ICG@HFe-TA decomposes and releases Fe3+ ions, TA and ICG molecules. Fe3+, with low catalytic activity, is effectively converted into highly catalytic Fe2+ by the reductant TA, enabling promoted efficacy of ˙OH induction. More importantly, the ROS (1O2) induction by ICG is significantly enhanced under 808 nm laser irradiation due to the O2 byproduct of Fe3+/Fe2+ conversion. In consequence, the ICG@HFe-TA nanoparticles exhibit considerable in vitro and in vivo tumor inhibition owing to the combined effect of ˙OH and 1O2 induced intracellularly. This study has therefore demonstrated a potential platform enabling combined photodynamic and chemodynamic therapy with high efficacy.

Amino acids are the fundamental building blocks of proteins in tumor cells. The consumption of amino acid can be an effective approach for destroying the tumor cytoskeleton and malfunctioning of the intracellular metabolic balance. Following this concept, herein, amino acid oxidase (AAO) is delivered by hollow Fe3+/tannic acid nanocapsules (HFe-TA) and incorporated within the cancer cell membrane (M) for the first time for synergistic tumor therapy. In this system (M@AAO@HFe-TA), the intracellularly delivered AAO molecules catalyze the oxidative deamination effectively and consume amino acids significantly. The upregulation of intracellular acid and H2O2 concentration facilitates the HFe-TA mediated Fenton reaction and enhances the induction of cytotoxic ˙OH. With the combined effects, considerable in vitro and in vivo tumor inhibition was achieved by M@AAO@Fe-TA due to the activated Bcl-2/Bax/Cyt C/caspase 3 mitochondrial apoptotic pathway. This study offers an alternative therapeutic platform, functioning as a biomimetic cascade nanozyme, to enable synergistic starvation and chemodynamic tumor therapy with high efficacy.

Drug resistance to chemotherapy and molecularly targeted therapies is a current challenge in cancer treatments. The underlying mechanisms of resistance to cytotoxic chemotherapeutics and to drugs that target a specific molecule are not understood completely. In recent years, emerging evidence has frequently suggested that the dysregulation of deubiquitinating enzymes (DUBs) plays important roles in the development of drug resistance. We focus on the molecular mechanisms through which DUBs enable cancer cells to escape cell death and survive when exposed to a variety of anti-cancer drugs. Furthermore, this review summarizes the potential application of DUB inhibitors in combination therapies to overcome drug resistance.

Islet transplantation is a potential treatment option for certain patients with type 1 diabetes; however, it still faces barriers to widespread use, including the lack of tools to monitor islet grafts post-transplantation. This study investigates whether labeling neonatal porcine islets (NPI) with polyvinylpyrrolidone-coated superparamagnetic iron oxide nanoparticles (PVP-SPIO) affects their function, and whether this nanoparticle can be utilized to monitor NPI xenografts with magnetic resonance imaging (MRI) in a mouse model. In vitro, PVP-SPIO-labeled NPI in an agarose gel was visualized clearly by MRI. PVP-SPIO-labeled islets were then transplanted under the kidney capsules of immunodeficient nondiabetic and diabetic mice. All diabetic mice that received transplantation of PVP-SPIO-labeled islets reached normoglycemia. Grafts appeared as hypo-intense areas on MRI and were distinguishable from the surrounding tissues. Following injection of spleen cells from immunocompetent mice, normoglycemic recipient mice became diabetic and islet grafts showed an increase in volume, accompanied by a mixed signal on MRI. Overall, this study demonstrates that PVP-SPIO did not affect the function of NPI that PVP-SPIO-labeled islets were easily seen on MRI, and changes in MRI signals following rejection suggest a potential use of PVP-SPIO-labeled islets to monitor graft viability.

Islet transplantation is being considered as an alternative treatment for type 1 diabetes. Despite recent progress, transplant recipients continue to experience progressive loss of insulin independence. Cyanidin-3-O-Glucoside (C3G) has shown to be protective against damage that may lead to post-transplant islet loss. In this study, human islets cultured with or without C3G were treated with human amylin, Aβ1-42, H2O2, or rapamycin to mimic stresses encountered in the post-transplant environment. Samples of these islets were collected and assayed to determine C3G’s effect on cell viability and function, reactive oxygen species (ROS), oxidative stress, amyloid formation, and the presence of inflammatory as well as autophagic markers. C3G treatment of human islets exposed to either amylin or Aβ1-42 increased cell viability (pin vitro islet function were also observed in C3G-treated islets exposed to amylin or Aβ1-42, although not significantly. Additionally, treatment with C3G resulted in a significant reduction in the protein expression of inflammatory markers IL-1β and NLRP3 (p1-42, rapamycin, or H2O2. Thus, C3G appears to have a multi-faceted protective effect on human islets in vitro, possibly through its anti-oxidant property and alteration of inflammatory as well as autophagic pathways.

Although the toxicity of acrylamide (ACR) has been extensively investigated in different experimental models, its perturbations to multiple nodes of the cellular signaling network have not been systematically associated. In this study, changes at different omics layers in ACR exposed Saccharomyces cerevisiae cells were monitored using a multi-omics strategy. The results of the analysis highlighted the impairment of oxidative-reductive balance, energy metabolism, lipid metabolism, nucleotide metabolism, and ribosome function in yeast cells. Response to acute ACR damage, glutathione synthesis was upregulated, the process of protein degradation was accelerated, and the autophagy flux was initiated. Meanwhile, yeast upregulates gene expression levels of enzymes in carbohydrate metabolism and speeds up the oxidation process of fatty acids to compensate for energy depletion. Importantly, the multi-omics strategy captures features that have rarely been addressed in previous studies on the toxicology of ACR, including blocked de novo nucleotide synthesis, decreased levels of metabolic enzyme cofactors thiamine and D-biotin, increased intracellular concentrations of neurotoxic N-methyl d-aspartic acid and l-glutamic acid, and release of death mediators ceramide. The ACR perturbation network constructed in this work and the discovery of new damage features provide a theoretical basis for subsequent point-to-point toxicological studies.

The optimization of nanoparticle size for passing through glomerular filtration membrane, inefficient renal cellular uptake and rapid urinary excretion of nanoparticles are the major obstacles for renal disease treatment via a nanoparticle delivery system. Herein, we propose a concept of a two-step nanoparticular cascade of size control and enhancement of renal cellular uptake to overcome the renal delivery obstacles. Methods: We prepared kidney-targeted rhein (RH)-loaded liponanoparticles (KLPPR) with a yolk-shell structure composed by polycaprolactone-polyethyleneimine (PCL-PEI)-based cores and kidney targeting peptide (KTP)-modified lipid layers. The KLPPR size within the range of 30 ~ 80 nm allowed KLPPR distribute into kidney by passing through the glomerular filtration membrane and the KTP (sequence: CSAVPLC) decoration promoted the renal cellular uptake and endocytosis via a non-lysosomal pathway. Results: The KLPPR had an average size of 59.5±6.2 nm and exhibited high RH loading, sustained release, good stability and biocompatibility, rapid cellular uptake in HK-2 cells. In addition, intravenous administration of KLPPR resulted in excellent kidney-targeted distribution and low urinary excretion in mice with streptozocin-induced diabetic nephropathy (DN), lowered the parameters of urea nitrogen, serum creatinine and kidney index, as well as facilitated the recovery of renal physiological function in improving the levels of urinary creatinine and the creatinine clearance rate by suppressing secretion and accumulation of fibronectin and TGF-β1. Conclusion: Definitely, KLPPR were able to target the diseased kidney and improve the therapeutic effect of RH on DN by exploiting the two-step nanoparticular cascade of size control and enhancement of cellular uptake. This study offers a promising strategy for renal diseases treatment using liponanoparticle delivery system.

Detection of divalent mercury attracts great significance in most biological and environmental systems. In this study, a Thymine-divalent mercuric ions-Thymine (T-Hg2+-T) structure based colorimetr...

Cancer-associated fibroblasts (CAFs), which are an important component of the tumor microenvironment, have been identified in the blood circulation of patients with cancer metastasis, and metastatic cancer cells can recruit circulating CAFs. However, primary carcinoma sites usually regulate the behavior of metastatic cancer cells through exosomes. Here, we hypothesized that cancer-derived exosomes could enhance CAF recruitment. Exosomes secreted by pancreatic cancer cells (PANC-1 and MIA PaCa-2) were isolated and characterized. The ability of pancreatic cancer to recruit pancreatic stellate cells (PSCs) was assessed with Transwell assays in vitro and bioluminescent imaging in a mouse model in vivo, and the underlying molecular mechanism was also investigated. The results showed that pancreatic cancer cell-derived exosomes (Exo-Pan and Exo-Mia) promoted the pancreatic cancer recruitment of PSCs. This effect was mediated partially by the transfer of the exosomal protein Lin28B to the recipient cells to activate the Lin28B/let-7/HMGA2/PDGFB signaling pathway. These results suggested that exosomes derived from local cancer could promote the formation of distant metastases through transferring the exosomal protein Lin28B to the metastatic cancer cells.

Field-measured forest productivity and its time-series are critical for understanding the impact of climate change on forest carbon cycling, and also for validating process-based models. Tree-rings are widely used to reconstruct stand productivity history. However, it remains ambiguous how to ensure a good sample design to estimate forest productivity precisely, and meanwhile minimize the sampling effort. Here we addressed the following questions: (1) how many minimum tree-ring samples are needed to estimate forest productivity history accurately? (2) Can we predict optimum sampling design from climate conditions and forest structure? (3) Are commonly used sampling methods accurate enough? We set up 48 forest plots across four succession stages at four study sites along a latitude gradient in Northeast China. Tree-rings were sampled from all trees in each plot, and stand and individual productivity history over the past 20 years was reconstructed. We simulated different sampling designs by randomly extracting trees in each plot to select an optimal design that could estimate stand productivity history accurately but with the least sampling size, and to evaluate the accuracy of commonly used tree-ring sampling methods. We analyzed the influence of climatic gradient, forest type, distribution of productivity and biomass across DBH classes, and further developed models to predict sampling design. It was found that ca. 100%, 42%, 18% and 10% of individuals should be sampled from the 1/4 largest to the 1/4 smallest trees, respectively, to ensure an accurate estimation of stand productivity history. The optimum sampling design was highly related with the distribution of productivity and biomass across diameter classes of the plots, and changed significantly along climate gradient but showed no clear trend across successional stages. Sampling designs inferred from models based on climate indices and the biomass ratio in each diameter class by each plot could estimate stand productivity history satisfactorily from other validation plots. It was also showed that previous sampling methods to estimate forest productivity may incur large uncertainties. As such, these data should be viewed with caution. We proposed a new tree-ring sampling strategy based on the fact that forest productivity and its temporal variation were largely determined by large trees. We further showed that the optimal sampling design was predictable from forest structure and climate conditions. More studies are needed in other regions to develop models to optimize sampling designs for different forest types under different climate conditions, for a more accurate estimation of forest productivity dynamics under global climate change.

Tree radial growth is widely found to respond differently to climate change across altitudinal gradients, but the relative roles of biotic factors (e.g. forest type, height and density) vs. climate gradient remain unclear. We sampled tree rings from 15 plots along a large altitudinal gradient in northeast China, and examined how climate gradient, forest type, height, tree size and density affect: (1) temporal growth variability [mean sensitivity (MS) and standard deviation (SD) of the chronologies], and (2) the relationship of ring width indices (RWI) with historical climate. We used BIC based model selection and variable importance to explore the major drivers of their altitudinal patterns. The results showed that: both growth variability and RWI-climate relationships changed significantly with altitude. Forest height was the most important predictor for altitudinal changes of MS and SD. For RWI-climate relationships, forest type was more important than climate gradient, while height and stem density were weak but necessary predictors. We showed that the altitudinal difference in growth response to climate change cannot be explained by climate gradient alone, and highlight the necessity to examine the influence of biotic factors (which covary with climate across geographic gradient) to better understand forest response to climate change.

BackgroundIndoor daylight levels can directly affect people’s physical and psychological state. However, the effect of indoor daylight levels on patient’s clinical recovery process remains controversial. To evaluate the effect of indoor daylight levels on hospital costs and average length of stay (LOS) of a large patient population in general surgery wards.MethodsData were collected retrospectively and analysed of patients in the Second Affiliated Hospital of Zhejiang University, School of Medicine between January 2015 and August 2020. We measured light levels in the patient rooms of general surgery and assessed their association with patients’ total hospital costs and LOS.ResultsA total of 2,998 patients were included in this study with 1,478 each assigned to two light level groups after matching. Overall comparison of hospital total costs and LOS among patients according to light levels did not show a significant difference. Subgroup analysis showed when exposed to higher intensity of indoor daylight, illiterate patients had lower total hospital costs and shorter LOS as compared to those exposed to lower intensity.ConclusionsIndoor daylight levels were not associated with the hospital costs and LOS of patients in the wards of general surgery, except for those who were illiterate. It might be essential to design guidelines for medical staff and healthcare facilities to enhance indoor environmental benefits of daylight for some specific population.

Background: The high recurrence rate after radical resection of pancreatic ductal adenocarcinoma (PDAC) leads to its poor prognosis. We aimed to develop a model to preoperatively predict the risk of recurrence based on computed tomography (CT) radiomics and multiple clinical parameters. Methods: Datasets were collected and analysed of 220 PDAC patients who underwent contrast-enhanced computed tomography (CE-CT) and received radical resection at 3 institutions between 2013 and 2017, with 153 from one institution as a training set, the remaining 67 as a validation set. For each patient, CT radiomics features were extracted from intratumoral and peritumoral regions to establish intratumoral, peritumoral and combined radiomics models using artificial neural network (ANN) algorithm. By incorporating clinical factors, radiomics-clinical nomograms were finally built by multivariable logistic regression analysis to predict 1- and 2-year recurrence risk. Findings: The developed radiomics model integrating intratumoral and peritumoral radiomics features was superior to the conventionally constructed model merely using intratumoral radiomics features. Further, radiomics-clinical nomograms outperformed other models in predicting 1-year recurrence with an area under the receiver operating characteristic curve (AUROC) of 0.920 in the training set and 0.744 in the validation set, and 2-year recurrence with an AUROC of 0.902 in the training set and 0.780 in the validation set. Interpretation: This study has developed and externally validated a radiomics-clinical nomogram integrating intra- and peritumoral CT radiomics signature as well as clinical factors to predict the recurrence risk of PDAC after radical resection, which will facilitate optimized and individualized treatment strategies. Funding: This work was supported by the General Program of National Natural Science Foundation of China [grant number: 81772562, 2017] (Yulian Wu), the Fundamental Research Funds for the Central Universities [grant number: 2021FZZX005-08] (Xiawei Li), the National Key R&D Program of China [grant number: 2018YFE0114800](Tianye Niu), the General Program of Natural Science Foundation of China [grant number: 81871351, 2018](Tianye Niu) and Zhejiang Provincial Key Projects of Technology Research [grant number: WKJZJ- 2033] (Tianye Niu). Declaration of Interest: The authors declare no potential conflicts of interest. Ethical Approval: This retrospective analysis was approved by the institutional ethical review boards of three centers including the Second Affiliated Hospital (Institution I), the Forth Affiliated Hospital (Institution II), Zhejiang University school of Medicine and the Zhejiang Cancer Hospital (Institution III).

Making the Palace Machine Work: Mobilizing People, Objects, and Nature in the Qing Empire brings the studies of institutions, labour, and material cultures to bear on the history of science and technology by tracing the workings of the Imperial Household Department (Neiwufu) in the Qing court and empire. An enormous apparatus that employed 22,000 men and women at its heyday, the Department operated a "machine" with myriad moving parts. The first part of the book portrays the people who kept it running, from technical experts to menial servants, and scrutinises the paper trails they left behind. Part II uncovers the working principles of the machine by following the production chains of some of its most splendid products: gilded statues, jade, porcelain, and textiles. Part III examines the complex task of managing living organisms and natural environments, including lotus plants grown in imperial ponds in Beijing, fresh medicines sourced from disparate regions, and tribute elephants from Southeast Asia.

Simian virus 40 (SV40) causes multiple diseases due to its low immunogenicity and strong infectivity. Here, the development of a label-free fluorescent sensor designed to detect double-stranded DNA (dsDNA) via a functionalized molecular beacon (MB) produced using triplex DNA and guanine (G)-quadruplexes is described. A SV40-specific dsDNA sequence was used as the target dsDNA (T-dsDNA). The MB was designed to comprise a G-quadruplex sequence, a complementary homopyrimidine sequence for T-dsDNA, and a partially complementary sequence for G-quadruplex sequence. Addition of T-dsDNA forces the MB to unfold, forming triplex DNA, and releasing the G-quadruplex sequence that binds to N-methyl mesoporphyrin IX (NMM), producing a signal. The G-quadruplex/NMM complex augments the signal at 610 nm and allows qualitative SV40 detection. Under optimal conditions, this strategy demonstrates a low limit of detection (0.4 nM). Compared to traditional biosensors, this sensor is enzyme-free, rapid, selective, sensitive, and was used to determine T-dsDNA in serum, suggesting that this strategy has applications in clinical analysis and for other viruses.

Background To evaluate the clinical characteristics and indications for surgery for bezoar-induced small bowel obstruction (BI-SBO). Methods Forty patients with BI-SBO were treated at our hospital from January 2017 to December 2019, and these patients’ clinical and computed tomography (CT) data were analyzed. Results Twenty-seven and 13 BI-SBO patients constituted the non-ST group and ST group, respectively. The clinical manifestations of BI-SBO in both groups were abdominal pain, nausea, vomiting, and lack of defecation. Comparing the non-ST vs ST groups, respectively: mean age (years): 63.15 ± 16.15 vs 60.38 ± 12.47; duration of symptoms (hours): 55.11 ± 44.08 vs 59.33 ± 72.90; mean bezoar length (cm): 5.31 ± 0.74 vs 3.72 ± 0.53; mean bezoar width (cm): 3.74 ± 0.48 vs 2.9 ± 0.64; bezoar CT maximum Hounsfield units (HU): 97.23 ± 12.36 vs 21.11 ± 7.27; total hospital stay (days): 5.56 ± 4.23 vs 7.12 ± 6.12 (mean: 8.62 ± 2.81); and total hospitalization costs (RMB): 6378.02 ± 3015.68 vs 8213.71 ± 5564.29. Mean operation time was 85.00 ± 8.90 minutes, and mean operation blood loss was 32.31 ± 19.64 mL. Bezoars were located 60 to 160 cm from the ileocecal junction. Univariate analysis demonstrated that bezoar length and width and maximum CT value were significant risk factors for surgery. Conclusion Large bezoar size and high CT values may be indications for surgery. Surgery is necessary and effective when nonsurgical treatment is ineffective.

Objective: To evaluate the comparative therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection (HR) for breast cancer liver metastases (BCLMs). Methods: Studies that had examined the outcomes for both RFA and HR for BCLM were identified by searching the electronic databases PubMed, EMBASE, and the Cochrane Library. Pooled analyzes of the overall survival (OS), disease-free survival (DFS), and short-term outcomes of BCLM were performed. Results: Patients with BCLM gained many more survival benefits from HR than from RFA with regard to the 3-year OS rate (combined odds ratio (OR) 0.41, 95% confidence interval (CI) 0.29–0.59, P

BackgroundIndoor daylight levels can directly affect people’s physical and psychological state. However, the effect of indoor daylight levels on patient’s clinical recovery process remains controversial.AimTo evaluate the effect of indoor daylight levels on hospital costs and average length of stay (LOS) of a large patient population in general surgery wards.MethodsData were collected retrospectively and analysed of patients in the Second Affiliated Hospital of Zhejiang University, School of Medicine between January 2015 and August 2020. We measured light levels in the patient rooms of general surgery and assessed their association with patients’ total hospital costs and LOS.ResultsA total of 2,998 patients were included in this study with 1,478 each assigned to two light level groups after matching. Overall comparison of hospital total costs and LOS among patients according to light levels did not show a significant difference. Subgroup analysis showed when exposed to higher intensity of indoor daylight, illiterate patients had lower total hospital costs and shorter LOS as compared to those exposed to lower intensity.ConclusionsIndoor daylight levels were not associated with the hospital costs and LOS of patients in the wards of general surgery, except for those who were illiterate. It might be essential to design guidelines for healthcare facilities to enhance indoor environmental benefits of daylight for some specific population.

Regulated necrosis is an emerging type of cell death independent of caspase. Recently, with increasing findings of regulated necrosis in the field of biochemistry and genetics, the underlying molecular mechanisms and signaling pathways of regulated necrosis are gradually understood. Nowadays, there are several modes of regulated necrosis that are tightly related to cancer initiation and development, including necroptosis, ferroptosis, parthanatos, pyroptosis, and so on. What’s more, accumulating evidence shows that various compounds can exhibit the anti-cancer effect via inducing regulated necrosis in cancer cells, which indicates that caspase-independent regulated necrosis pathways are potential targets in cancer management. In this review, we expand the molecular mechanisms as well as signaling pathways of multiple modes of regulated necrosis. We also elaborate on the roles they play in tumorigenesis and discuss how each of the regulated necrosis pathways could be therapeutically targeted.

Amino acids are the fundamental building blocks of proteins in tumor cells. The consumption of amino acid can be an effective approach for destroying the tumor cytoskeleton and malfunctioning of the intracellular metabolic balance. Following this concept, herein, amino acid oxidase (AAO) is delivered by hollow Fe3+/tannic acid nanocapsules (HFe-TA) and incorporated within the cancer cell membrane (M) for the first time for synergistic tumor therapy. In this system (M@AAO@HFe-TA), the intracellularly delivered AAO molecules catalyze the oxidative deamination effectively and consume amino acids significantly. The upregulation of intracellular acid and H2O2 concentration facilitates the HFe-TA mediated Fenton reaction and enhances the induction of cytotoxic ˙OH. With the combined effects, considerable in vitro and in vivo tumor inhibition was achieved by M@AAO@Fe-TA due to the activated Bcl-2/Bax/Cyt C/caspase 3 mitochondrial apoptotic pathway. This study offers an alternative therapeutic platform, functioning as a biomimetic cascade nanozyme, to enable synergistic starvation and chemodynamic tumor therapy with high efficacy.

Nanoparticles presenting promoted catalytic activity, oxygen induction and loading capability are in high demand for effective synergistic tumor therapy. Herein, ferric-tannic acid complex nanocapsules with fine hollow microstructure (HFe-TA) are synthesized and loaded with a photosensitizer (indocyanine green, ICG) for synergistic tumor therapy. In acidic environment, ICG@HFe-TA decomposes and releases Fe

To evaluate the comparative therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection (HR) for breast cancer liver metastases (BCLMs). Studies that had examined the outcomes for both RFA and HR for BCLM were identified by searching the electronic databases PubMed, EMBASE, and the Cochrane Library. Pooled analyzes of the overall survival (OS), disease-free survival (DFS), and short-term outcomes of BCLM were performed. Patients with BCLM gained many more survival benefits from HR than from RFA with regard to the 3-year OS rate (combined odds ratio (OR) 0.41, 95% confidence interval (CI) 0.29–0.59, P

The prognosis for patients with liver metastases from gastric cancer is very poor. Nevertheless, standard therapeutic strategies have not been established yet. The impact of hepatic surgical treatment on survival of patients with metachronous liver metastases from gastric cancer still remains controversial. We conducted a retrospective analysis on records of 436 patients who received radical gastrectomy (with D2 lymphadenectomy, regardless of hepatic surgical treatment) for gastric cancer with metachronous (≥ 3 months after gastrectomy) liver metastases in our center between 2001 and 2016. All patients were followed until 2017/10/31 or withdrawn from the follow-up because of death. The median interval for non-hepatic metastases of the 436 patients who underwent radical gastrectomy is 14 months. T (P = 0.041), N (P = 0.023) and lymphovascular invasion (P

Background: The purpose of this study was to find the factors that may be helpful for differentiating pancreatic cancer-associated diabetes mellitus (PC + DM) from common type 2 diabetes for the early diagnosis of pancreatic cancer. Methods: From January 2008 to August 2013, 171 patients with pancreatic cancer and new-onset diabetes were recruited for the study; 242 age- and gender-matched patients with common type 2 diabetes were also identified as control during the same period. The patient’s characteristics and laboratory parameters were compared between the 2 groups. Results: By multivariate logistic regression analysis, we found that body mass index (BMI), the age of onset of diabetes, hepatitis B virus (HBV) infection, total bilirubin (TBIL), alanine aminotransferase (ALT), creatinine (Cr), apolipoprotein-A1 (APO-A1), and white blood cell (WBC) were independent predictive factors for differentiating PC + DM from common type 2 diabetes; the areas under receiver operating characteristic curves were up to 0.815 for the combination of these 8 markers. Conclusions: These results suggest that BMI, the age of onset of diabetes, HBV infection, TBIL, ALT, Cr, APO-A1, and WBC are factors that could differentiate PC + DM from common type 2 ­diabetes and may be used for early diagnosis of pancreatic cancer.

With the speedy progress in electrical engineering field globally, power electronics course has aroused attention from academic community. English immersion teaching methods applied to power electronics course aim to introduce advanced counterpart academic knowledge from abroad to China and equip students and teaching staffs with international views as well as English-oriented logical and critical thinking in power electronics, and thus to promote power electronics development in China in the long term. By utilizing English immersion teaching methods for power electronics course, which involves problem-based learning, English-project-based assessment method and English-based laboratory operation, the challenges that the innovative teaching methods confront could be solved during each process of power electronics course. For further illustration, English immersion teaching methods for energy storage will be analysed as a study case. Consequently, the new English immersion teaching methods for power electronics course in China can be spread and applied in other non-native English-speaking countries to upgrade and reform power electronics course and related discipline.

Oxidative stress is a major cause of islet injury and dysfunction during isolation and transplantation procedures. Cyanidin-3-O-glucoside (C3G), which is present in various fruits and vegetables especially in Chinese bayberry, shows a potent antioxidant property. In this study, we determined whether C3G could protect neonatal porcine islets (NPI) from reactive oxygen species (H2O2)-induced injury in vitro and promote the function of NPI in diabetic mice. We found that C3G had no deleterious effect on NPI and that C3G protected NPI from damage induced by H2O2. Significantly higher hemeoxygenase-1 (HO1) gene expression was detected in C3G-treated NPI compared to untreated islets before and after transplantation (P P

In somatic cell reprogramming, cells must escape the somatic cell-specific gene expression program to adopt other cell fates. Here, in vitro chemical induction with RepSox generated chemically induced mammary epithelial cells (CiMECs) with milk secreting functions from goat ear fibroblasts (GEFs). Transplanted CiMECs regenerated the normal mammary gland structure with milk-secreting functions in nude mice. Single-cell RNA sequencing revealed that during the reprogramming process, GEFs may sequentially undergo embryonic ectoderm (EE)-like and different MEC developmental states and finally achieve milk secreting functions, bypassing the pluripotent state. Mechanistically, Smad3 upregulation induced by transforming growth factor β (TGFβ) receptor 1 (TGFβR1) downregulation led to GEF reprogramming into CiMECs without other reprogramming factors. The TGFβR1-Smad3 regulatory effects will provide new insight into the TGFβ signaling pathway regulation of somatic cell reprogramming. These findings suggest an innovative strategy for autogenous cell therapy for mammary gland defects and the production of transgenic mammary gland bioreactors.

Objective: The aim of this study was to evaluate the safety and efficiency of enucleation (EU) for proximal pancreatic non-invasive neoplasms. Methods: Patients with solitary non-invasive neoplasms in the proximal pancreas from January 1998 to April 2014 at the Second Affiliated Hospital of Zhejiang University, Hangzhou, China were included. Different operations and outcomes were analyzed. Results: A total of 123 patients were enrolled. Forty patients (32.5%) underwent EU including 18 patients who had tumors close to the main pancreatic duct (MPD). Sixty-one patients (49.6%) had pancreaticoduodenectomy (PD) performed and 22 (17.9%) underwent central pancreatectomy (CP). Pathological outcomes included neuroendocrine tumors, cystic lesions, and solid pseudopapillary tumors. Operation time, intra-operative blood loss, and duration of hospital stay were significantly reduced in the EU group. PD was associated with the greatest complication rate (55.7%), followed by EU (50%) and CP (40.9%), though the pancreatic fistula rate after EU was the highest (50%), especially in patients with tumors larger than 3 cm and tumors close to the MPD. EU had advantages in the preservation of pancreatic parenchyma and endocrine and exocrine function. Conclusions: EU can be carried out safely and effectively for tumors in the proximal pancreas with improved outcomes compared with standard resections, even if the tumor is larger than 3 cm and close to the MPD.

Dual enzymatic reactions were introduced to fabricate programmed gemcitabine (GEM) nanovectors for targeted pancreatic cancer therapy. Dual-enzyme-sensitive GEM nanovectors were prepared by conjugation of matrix metalloproteinase-9 (MMP-9) detachable poly(ethylene glycol) (PEG), cathepsin B-cleavable GEM, and targeting ligand CycloRGD to CdSe/ZnS quantum dots (QDs). The GEM nanovectors decorated with a PEG corona could avoid nonspecific interactions and exhibit prolonged blood circulation time. After GEM nanovectors were accumulated in tumor tissue by the enhanced permeability and retention (EPR) effect, the PEG corona can be removed by overexpressed MMP-9 in tumor tissue and RGD would be exposed, which was capable of facilitating cellular internalization. Once internalized into pancreatic cancer cells, the elevated lysosomal cathepsin B could further promote the release of GEM. By employing dual enzymatic reactions, the GEM nanovectors could achieve prolonged circulation time while maintaining enhanced cellular internalization and effective drug release. The proposed mechanism of the dual enzymatic reaction-assisted GEM delivery system was fully investigated both in vitro and in vivo. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2',2'-difluorodeoxyuridine (dFdU) could be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.

Dementia is a serious public health problem. The more extensive dementia knowledge is, the more conducive it is to early prevention and treatment of dementia. However, no assessment of the general population&rsquo, s dementia awareness has been conducted so far in China. Thus, this study assessed the national public knowledge of dementia based on mobile internet in China. We assessed 10,562 national respondents recruited based on the most popular social networking service in China, WeChat and analyzed the data using quantitative methods. The overall correct rate of total dementia knowledge was 63.14%. Only half of the participants (50.84%) could identify risk factors accurately. The level of dementia knowledge was positively associated with high education, city residency, and experience of exposure to information on dementia. The sandwich generation (aged 20&ndash, 60 years) had the highest level of dementia knowledge. Chinese people were found to have a low level of knowledge about dementia, especially those aged over 60 years, with low education and living in rural areas. Further educational programs and campaigns are needed to improve dementia knowledge, with greater focus on the older population as the target audience, emphasis on dementia risk factors as educational content, correcting misconceptions about dementia, and providing more experience of exposure to dementia.

Pancreatic ductal adenocarcinoma (PDAC) is intractable due to its strong invasiveness and metastatic ability. Epithelial-mesenchymal transition (EMT) is the pivotal driver of tumor invasion and metastasis. The four-and-a-half LIM domain (FHL) family is involved in regulating transforming growth factor (TGF)-β and Ras signaling, which might control the EMT process. In this study, we found that higher expression of four-and-a-half LIM domains 3 (FHL3) predicted poor prognosis in PDAC. The decreasing of FHL3 changed the EMT phenotype by blocking the TGFβ/Atk/GSK3β/ubiquitin pathways. Interestingly, the GSK3β inhibitor could abrogate the role of FHL3 in the regulation of snail1 and twist1 expression, which implied that GSK3β plays a pivotal role in the FHL3-mediated EMT process. Furthermore, we found that FHL3 can directly bind to GSK3β, which weakened the interaction between GSK3β and snail1/twist1. We also found that the LIM-3 domain of FHL3 was required for the binding of FHL3 to GSK3β. Collectively, our study implied that FHL3, as a binding partner of GSK3β, promoted tumor metastasis in PDAC through inhibiting the ubiquitin-degradation of snail1 and twist1.

Pancreatic cancer (PC) is a highly lethal malignancy with few effective therapies. Deguelin, a natural compound of the flavonoid family of products, has been reported to have an inhibitory effect on various cancers. In the present study, we investigated whether deguelin had antitumor efficacy in PC. Deguelin treatment was observed to inhibit growth and induce apoptosis in two PC cell lines (Bxpc-3 and Panc-1). In addition, it inhibited migration and invasion in these two cell lines. The activation of the hedgehog (Hh) signaling pathway, as well as matrix metalloproteinases (MMP)-2 and MMP-9, was suppressed by deguelin. These results suggest that deguelin may be a potential chemotherapeutic agent for PC, possibly through the suppression of the Hh signaling pathway.