Effect of Jianpi Bushen formula for colon cancer patients who underwent adjuvant chemotherapy:Statistical analysis plan for a multicenter trial

Background:Patients with colon cancer who receive chemotherapy usually experience various gastrointestinal adverse reactions,including nausea,vomiting,and diarrhea,which make it challenging for them to adhere to treatment.As an effective traditional Chinese medicine,the Jianpi Bushen formula has been widely used to alleviate the side effects of chemotherapy.Objective:To evaluate the efficacy and safety of Jianpi Bushen formulae for patients who undergo chemotherapy.This statistical analysis plan(SAP)is intended to enhance the transparency and research quality of our randomized controlled trial.Methods:Our study is a multicenter,double-blind,randomized controlled clinical trial.This trial aimed to compare the completion rate of chemotherapy in colon cancer patients who are using and not using Jianpi Bushen formula.To attenuate possible selection bias in the final report,we declared the overall trial design,outcome measures,subgroup analyses,and safety measures.Also,we described the data management and statistical analysis methods in detail.Conclusion:The SAP provides more detailed information than the trial protocol for data management and statistical analysis methods.Further post-hoc analyses can be performed by referring to the SAP,and possible selection bias can be attenuated.

Ultrasonographic evaluation of enthesitis in patients with ankylosing spondylitis

The aim of this study was to assess sensitivity and responsiveness of power Doppler ultrasound （PDUS） in detecting enthesitis for ankylosing spondylitis （AS） patients compared to clinical examinations. Twenty AS patients initiating etanerceptunderwent clinical and PDUS examinations of six bilateral entheseal sites at baseline and after 1, 2 and 3 months of treatment. Clinical and PDUS examinations identified at least one entheseal lesion in nine （45%） and 19 （95%） patients, respectively. Furthermore, of 240 entheseal sites examined in these 20 patients, PDUS detected 123 entheseal lesions （51.3% of sites）, compared with only 47 entheseal lesions （19.6%） detected by clinical examination （P〈0.05）. The entheseal lesions found on PDUS were most commonly identified by calcification （33.3%）, tendon edema （29.2%）, abnormal blood flow （25.8%）, a thickened tendon （22.1%）, cortical irregularity （12.9%）, bony erosions （9.6%） and bursitis at the tendon insertion to the bone cortex （7.1%）. Improvements in clinical symptoms and laboratory parameters, and significant decreases in PDUS scores were observed following treatment with etanereept. Improvements in PDUS scores continued during follow-up in patients who entered remission following treatment. In conclusion, PDUS improves detection of structural and inflammatory abnormalities of the enthesis in AS compared to physical examination. In addition, PDUS may be useful inascertaining medications.

Microfluidic Generation of Multicomponent Soft Biomaterials

Soft biomaterials hold great potential for a plethora of biomedical applications because of their deforma-bility,biodegradability,biocompatibility,high bioactivity,and low antigenicity.Multicomponent soft bio-materials are particularly attractive as a way of accommodating components made of different materials and generating combinative functions.Microfluidic technology has emerged as an outstanding tool in generating multicomponent materials with elaborate structures and constituents,in that it can manipu-late multiphasic flows precisely on the micron scale.In recent decades,much progress has been achieved in the microfluidic fabrication of multicomponent soft biomaterials with finely defined physicochemical properties capable of controllable therapeutics delivery,three-dimensional(3D)cell culture,flexible devices and wearable electronics,and biosensing for molecules.In the paper,we summarize current pro-gress in multicomponent soft biomaterials derived from microfluidics and emphasize their applications in biomedical fields.We also provide an outlook of the remaining challenges and future trends in this field.

Microfluidics for Medical Additive Manufacturing

Additive manufacturing plays a vital role in the food,mechanical,pharmaceutical,and medical fields.Within these fields,medical additive manufacturing has led to especially obvious improvements in medical instruments,prostheses,implants,and so forth,based on the advantages of cost-effectiveness,customizability,and quick manufacturing.With the features of precise structural control,high throughput,and good component manipulation,microfluidic techniques present distinctive benefits in medical additive manufacturing and have been applied in the areas of drug discovery,tissue engineering,and organs on chips.Thus,a comprehensive review of microfluidic techniques for medical additive manufacturing is useful for scientists with various backgrounds.Herein,we review recent progress in the development of microfluidic techniques for medical additive manufacturing.We evaluate the distinctive benefits associated with microfluidic technologies for medical additive manufacturing with respect to the fabrication of droplet/fiber templates with different structures.Extensive applications of microfluidic techniques for medical additive manufacturing are emphasized,such as cell guidance,three-dimensional(3D)cell culture,tissue assembly,and cell-based therapy.Finally,we present challenges in and future perspectives on the development of microfluidics for medical additive manufacturing.

Expression of c-kit receptor in peripheral blood mononuclear cells in patients with systemic lupus erythematosus

Objective： To determine the expression of c-kit receptor in peripheral blood mononuclear cells （PBMCs） in patients with systemic lupus erythematosus （SLE）, and analyze the relationship between the c-kit expression level of PBMCs and clinical parameters. Methods： Peripheral blood mononuclear cells in 47 patients with SLE and 21 healthy volunteers were collected. Expression of c-kit mRNA in PBMCs were determined with reverse transcription-polymerase chain reaction （RT-PCR）. The protein of c-kit receptor （CDllT） in PBMCs was measured by flow cytometry. Results： Expression of c-kit receptor protein and mRNA in patients with active or inactive SLE （ n = 47） were significantly higher than those in controls. The c-kit receptor of PBMCs in SLE patients were significantly higher than those in healthy controls （ n = 21 ）, the c-kit receptor of PBMCs in active patients （ n = 27） were significantly higher than those in inactive patients （ n = 20） and there was no significant difference was found between patients with inactive SLE and healthy controls（ P 〉 0.05）. The c-kit receptor of PBMCs in SLE have significant association with activity index. Conclusion： Production of c-kit receptor is aberrantly increased in PBMCs in patients with SLE. C-kit receptor might be more closely related to the clinical parameters in SLE patients, which might reflect the clinical status of SLE patients.

Deep3DSketch-im:rapid high-fidelity AI 3D model generation by single freehand sketches

The rise of artificial intelligence generated content(AIGC)has been remarkable in the language and image fields,but artificial intelligence(AI)generated three-dimensional(3D)models are still under-explored due to their complex nature and lack of training data.The conventional approach of creating 3D content through computer-aided design(CAD)is labor-intensive and requires expertise,making it challenging for novice users.To address this issue,we propose a sketch-based 3D modeling approach,Deep3DSketch-im,which uses a single freehand sketch for modeling.This is a challenging task due to the sparsity and ambiguity.Deep3DSketch-im uses a novel data representation called the signed distance field(SDF)to improve the sketch-to-3D model process by incorporating an implicit continuous field instead of voxel or points,and a specially designed neural network that can capture point and local features.Extensive experiments are conducted to demonstrate the effectiveness of the approach,achieving state-of-the-art(SOTA)performance on both synthetic and real datasets.Additionally,users show more satisfaction with results generated by Deep3DSketch-im,as reported in a user study.We believe that Deep3DSketch-im has the potential to revolutionize the process of 3D modeling by providing an intuitive and easy-to-use solution for novice users.

MCP-1 and IL-4 encapsulated hydrogel particles with macrophages enrichment and polarization capabilities for systemic lupus erythematosus treatment

Macrophages play a pivotal role in systemic lupus erythematosus(SLE)therapy.Efforts have been made to develop multifunctional drug delivery systems capable of directing macrophage polarization.Here,we present a novel hyaluronic acid methacrylate(HAMA)hydrogel microparticle encapsulating multiple cytokines for SLE remission though enhancing macrophage functions.The HAMA microparticles loaded with monocyte chemotactic protein-1(MCP-1)and interleukin-4(IL-4)were fabricated by using a microfluidic technology.The released MCP-1 facilitates the aggregation of inflammatory macrophages,after which IL-4 induces the macrophage phenotype shift from inflammatory M1 to immune-protective M2,thus restoring immune balance.We have demonstrated in MRL/lpr mice that the hydrogel microparticles could improve their efficacy of intraperitoneal drug delivery,modulate immune function,and attenuate the disease symptoms.These results suggest that our proposed microparticles delivery platform has potential clinical value for treating autoimmune diseases.

Recent advances in artificial intelligence generated content

Artificial intelligence generated content(AIGC)has been a research hotspot in the field of artificial intelligence in recent years.It is expected to replace humans in performing some of the work of content generation at a low cost and a high volume,such as music,painting,multimodal content generation,news articles,summary reports,stock commentary summaries,and even content and digital people generated in the meta-universe.AIGC provides a new technical path for the development and implementation of AI in the future.

A Pilot Study of the Therapeutic Efficacy and Mechanism of Artesunate in the MRL/lpr Murine Model of Systemic Lupus Erythematosus

Recent evidence indicates that artesunate has immunomodulatory properties that might be useful for treating autoimmune disease.In this study,we conducted a pilot study and explored the effect and mechanism of artesunate on the treatment of systemic lupus erythematosus using an MRL/lpr murine model.MRL/lpr mice were divided into control,cyclophosphamide(CTX)and artesunate treatment groups.Blood was collected to measure serum levels of creatinine,antinuclear antibody(ANA)and anti-double-stranded DNA(anti-dsDNA)antibody.Twenty-four-hour urine was collected to measure levels of proteinuria.The concentration of monocyte chemotactic protein-1(MCP-1)in serum and urine was measured.The expression of MCP-1 in kidney was detected by Western blot and immunohistochemistry assay,respectively.The expression of B cell activating factor(BAFF)in spleen was determined by real time-PCR and immunoblotting.We found that artesunate significantly increased the survival rate,body weight and blood leukocyte counts,and reduced the serum levels of ANA and anti-dsDNA antibody titer,24 h urinary protein,and serum creatinine.Our results indicated that artesunate could decrease MCP-1,major pro-inflammation cytokine,in serum,urine and kidney.We also found that the level of BAFF,the major B cell activation factor,was decreased in artesunate treated MRL/lpr mice.Its efficacy was comparable with that of CTX in this study.Taken together,we have demonstrated that artesunate can inhibit the progression of disease and reverse the pathologic lesion of lupus nephritis.

Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling

Mesenchymal stem cells(MSCs)influence T cells in health,disease and therapy through messengers of intercellular communication including extracellular vesicles(EVs).Apoptosis is a mode of cell death that tends to promote immune tolerance,and a large number of apoptotic vesicles(apoVs)are generated from MSCs during apoptosis.In an effort to characterize these apoVs and explore their immunomodulatory potential,here we show that after replenishing them systemically,the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued,leading to the amelioration of inflammation and lupus activity.ApoVs directly interacted with CD4^(+)T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner.A broad range of Th1/2/17 subsets and cytokines including IFNγ,IL17A and IL-10 were suppressed while Foxp3^(+)cells were maintained.Mechanistically,exposed phosphatidylserine(PtdSer/PS)on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction.Remarkably,administration of apoVs prevented Th17 differentiation and memory formation,and ameliorated inflammation and joint erosion in murine arthritis.Collectively,our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4^(+)T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases.

UI layers merger: merging UI layers via visual learning and boundary prior

With the fast-growing graphical user interface(GUI)development workload in the Internet industry,some work attempted to generate maintainable front-end code from GUI screenshots.It can be more suitable for using user interface(UI)design drafts that contain UI metadata.However,fragmented layers inevitably appear in the UI design drafts,which greatly reduces the quality of the generated code.None of the existing automated GUI techniques detects and merges the fragmented layers to improve the accessibility of generated code.In this paper,we propose UI layers merger(UILM),a vision-based method that can automatically detect and merge fragmented layers into UI components.Our UILM contains the merging area detector(MAD)and a layer merging algorithm.The MAD incorporates the boundary prior knowledge to accurately detect the boundaries of UI components.Then,the layer merging algorithm can search for the associated layers within the components’boundaries and merge them into a whole.We present a dynamic data augmentation approach to boost the performance of MAD.We also construct a large-scale UI dataset for training the MAD and testing the performance of UILM.Experimental results show that the proposed method outperforms the best baseline regarding merging area detection and achieves decent layer merging accuracy.A user study on a real application also confirms the effectiveness of our UILM.

Polylysine complexes and their biomedical applications

Poly-L-lysine(PLL)is a water-soluble biopolymer consist of repeating unit of L-lysine.It displays intrinsic non-antigenicity,antibacterial property,biocompatibility,and biodegradability,and facile synthesis procedure,there-fore has attracted particular attention in various biomedical and pharmaceutical applications.Following a brief introduction to PLL synthesis,this review focuses on the significant advances of PLL and PLL-derived complexes utilized in cargo delivery,tissue adhesives,and antibacterial materials.Meanwhile,this review summarized the modification and optimization of PLL complexes for further clinical translational studies.The final section dis-cusses the challenges and opportunities of PLL-based complexes in the biomedical areas.

Strategies for engineering neural cell alignment and their biomedical applications

Cell alignment plays a vital role in tissue regeneration,especially for neural cells like neurons.Recent progress in biomaterial technologies has enabled the creation of various approaches for engineering neural cell alignment,which has demonstrated significant effectiveness in several biomedical applications.This review primarily concentrates on the latest advancements for in vitro engineering of neural cell alignment.We also summarized their applications in biomedical research,particularly their potential in addressing nervous system injuries.Finally,we analyze the current challenges associated with engineering neural cell alignment and provide insights into future perspectives in this field.

The regulation of the Treg/Th 17 balance by mesenchyma stem cells in human systemic lupus erythematosus

Background and objective： Umbilical cord （UC）-derived mesenchymal stem cells （MSCs） have shown immunoregulation of various immune cells. The aim of this study was to investigate the mechanism of UC MSCs in the regulation of peripheral regulatory T cells （Treg） and T helper 17 （Th17） cells in patients with systemic lupus erythematosus （SLE）. Methods： Thirty patients with active SLE, refractory to conventional therapies, were given UC MSCs infusions. The percentages of peripheral blood CD4＋CD25＋Foxp3＋ regulatory T cells （Treg） and CD3＋CD8-1L17A＋ Th17 cells and the mean fluorescence intensities （MFI） of Foxp3 and IL- 17 were measured at I week, I month, 3 months, 6 months, and 12 months after MSCs transplantation （MSCT）. Serum cytokines, including transforming growth factor beta （TGF-β）, tumor necrosis factor alpha （TNF-α）, interleukin 6 （IL-6）, and IL-17A were detected using ELISA. Peripheral blood mononuclear cells from patients were collected and co-cultured with UC MSCs at ratios of 1：1, 10：1, and 50：1, respectively, for 72 h to detect the proportions of Treg and Th17 cells and the MFIs of Foxp3 and IL-17 were determined by flow cytometry. The cytokines in the supernatant solution were detected using ELISA. Inhibitors targeting TGF-β, IL-6, indoleamine 2,3-dioxygenase （IDO）, and prostaglandin E2 were added to the co-culture system, and the percentages of Treg and Th17 cells were observed. Results： The percentage of peripheral Treg and Foxp3 MFI increased 1 week, 1 month, and 3 months after UC MSCs transplantation, while the Th17 proportion and MFI of IL-17 decreased 3 months, 6 months, and 12 months after the treatment, along with an increase in serum TGF-β at I week, 3 months, and 12 months and a decrease in serum TNF-a beginning at I week. There were no alterations in serums IL-6 and IL-17A before or after MSCT. In vitro studies showed that the UC MSCs dose-dependently up-regulated peripheral Treg proportion in SLE patients, which was not depended on cell-cell contact. However, the down-regulation of Th17 cells was not dose-dependently and also not depended on cell-cell contact. Supernatant TGF-α and IL-6 levels significantly increased, TNF-a significantly decreased, but IL-17A had no change after the co-culture. The addition of anti-TGF-β antibody significantly abrogated the up-regulation of Treg, and the addition of PGE2 inhibitor significantly abrogated the down-regulation of Th17 cells. Both anti-lL-6 antibody and IDO inhibitor had no effects on Treg and Th17 cells. Conclusions： UC MSCs up-regulate Treg and down-regulate Th 17 cells through the regulation of TGF-β and PGE2 in lupus patients.

Transplantation of Human Bone Marrow Mesenchymal Stem Cell Ameliorates the Autoimmune Pathogenesis in MRL/lpr Mice

Recent evidence indicates that mesenchymal stem cells （MSC） possess immunosuppressive properties both in vitro and in vivo. We previously demonstrated the functional abnormality of bone marrow derived MSC in patients with systemic lupus erythematosus （SLE）. In this study, we aimed to investigate whether transplantation of human bone marrow derived MSC affects the autoimmune pathogenesis in MRL/Ipr mice. We found that human MSC from healthy donors reduced the proliferation of T lymphocytes from MRL/Ipr mice in a dose-dependent fashion. Two weeks after in vivo transfer of MSC, we detected significantly reduced serum levels of anti ds-DNA antibodies and 24 hour proteinuria in MRL/Ipr mice as compared with control groups without MSC transplantation. Moreover, flow cytometric analysis revealed markedly reduced number of CD4＋ T cells while increased Thl subpopulation in MSC group and MSC ＋ CTX group when compared with controls. Histopathological examination showed significantly reduced renal pathology in MSC-treated mice. Immunohistochemical studies further revealed reduced expression of TGF-~, FN, VEGF and the deposition of complement C3 in renal tissue after MSC and MSC ＋ CTX treatment. Taken together, we have demonstrated that transplantation of human MSC can significantly inhibit the autoimmune progression in MRL/Ipr mice. Cellular ＆ Molecular Immunology. 2008;5（6）：417-424.

MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus

Mesenchymal stem cells(MSCs)are critical for immune regulation.Although several microRNAs(miRNAs)have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function,the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear.Here,we show that patients with systemic lupus erythematosus(SLE)display a unique miRNA signature in bone marrow-derived MSCs(BMSCs)compared with normal controls,among which miR-663 is closely associated with SLE disease activity.MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper(Tfh)cells and upregulation of regulatory T(Treg)cells by targeting transforming growth factorβ1(TGF-β1).MiR-663 overexpression weakens the therapeutic effect of BMSCs,while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice.Thus,miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.

CD4^(+)CD25^(+)but not CD4^(+)Foxp3^(+) T cells as a regulatory subset in primary biliary cirrhosis

Increasing evidence indicates a role for regulatory T cells(Tregs)in the immune response and in autoimmune diseases,but the role of Tregs and cytokines in autoimmune hepatic diseases remains largely unclear and controversial,especially in patients with primary biliary cirrhosis(PBC).This study was undertaken to investigate Tregs and different cytokines in the liver and peripheral blood of PBC patients.We found that these patients demonstrated a reduction of CD4^(+)CD25^(+) T cells but elevated CD4^(+)Foxp3^(+) T cells in peripheral blood mononuclear cells(PBMCs)and CD41 T cells.The percentage of CD4^(+)CD25^(+) T cells in PBMCs was negatively correlated with elevated plasma interferon(IFN)-c levels.A liver-specific analysis showed that the frequency of Foxp31 Tregs,transforming growth factor(TGF)-b1 and IFN-c were increased in PBC patients.Our findings suggest that an imbalance between CD4^(+)CD25^(+) Tregs and cytotoxic cytokines plays a crucial role in the pathogenesis of PBC while the role of Foxp3 needs further investigation.

Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome

Immunoproteasome activation in immune cells is involved in the modulation of immune responses.Increasing evidence indicates that proteasome inhibitors show beneficial effects in treating autoimmune diseases,but it remains unclear whether proteasome inhibition is an effective approach for suppressing autoimmune development in Sjögren’s syndrome(SS).Our previous work has demonstrated a critical role for Th17 cells in the development of experimental SS(ESS)in mice.In this study,we detected high levels of low-molecular-weight protein 7(LMP7),a key subunit of the immunoproteasome,in Th17 cells from ESS mice.Moreover,treatment with bortezomib(BTZ),a proteasome inhibitor,markedly suppressed Th17 differentiation in both murine and human naive T cells in culture.Furthermore,ESS mice treated with BTZ displayed significantly higher saliva flow rates and a reduction in tissue destruction in the salivary glands compared with vehicle-treated ESS mice.Notably,BTZ-treated ESS mice showed markedly decreased Th17 cells,germinal center B cells and plasma cells in the peripheral lymphoid organs.In addition,adoptively transferred wild type naive CD4+T cells rapidly differentiated into Th17 cells and induced salivary dysfunction in IL-17-deficient mice immunized for ESS induction.However,BTZ treatment profoundly suppressed the donor T-cell-derived Th17 response and ameliorated the reduction in salivary secretion in IL-17-deficient recipient mice.Taken together,our findings demonstrate that proteasome inhibition can effectively ameliorate ESS by suppressing the Th17 response,which may contribute to the development of a novel therapeutic strategy for the treatment of SS.

SmartPaint:a co-creative drawing system based on generative adversarial networks

Artificial intelligence(AI) has played a significant role in imitating and producing large-scale designs such as e-commerce banners. However, it is less successful at creative and collaborative design outputs. Most humans express their ideas as rough sketches, and lack the professional skills to complete pleasing paintings. Existing AI approaches have failed to convert varied user sketches into artistically beautiful paintings while preserving their semantic concepts. To bridge this gap, we have developed Smart Paint, a co-creative drawing system based on generative adversarial networks(GANs), enabling a machine and a human being to collaborate in cartoon landscape painting. Smart Paint trains a GAN using triples of cartoon images, their corresponding semantic label maps, and edge detection maps. The machine can then simultaneously understand the cartoon style and semantics, along with the spatial relationships among the objects in the landscape images. The trained system receives a sketch as a semantic label map input, and automatically synthesizes its edge map for stable handling of varied sketches. It then outputs a creative and fine painting with the appropriate style corresponding to the human’s sketch. Experiments confirmed that the proposed Smart Paint system successfully generates high-quality cartoon paintings.

Ecto-mesenchymal stem cells: a new player for immune regulation and cell therapy

Extensive studies have demonstrated that mesenchymal stem cells(MSCs)are multipotent mesoderm-derived stromal cells that can differentiate into a variety of cell types,including adipocytes,osteoblasts,chondrocytes,myocytes and neuronal cells.1 MSCs are found in numerous organs and tissues,including bone marrow,heart,lung,muscle,peripheral blood,adipose tissue,cartilage,synovium,dental pulp,tonsil,umbilical cord,placenta,thymus and olfactory mucosa.1 MSCs have been shown to possess potent immunosuppressive functions and tissue repair capacities,which have facilitated the clinical applications of MSCs in treating a diverse range of disorders involving angiogenesis and fibrosis,including rheumatic diseases and graft-versus-host diseases.2,3 Here,we provide a brief commentary on newly emerging evidence of the immunoregulatory function and potential application of ecto-mesenchymal stem cells.