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Abstract Tumor organoids have emerged as powerful tools for in vitro cancer research due to their ability to retain the structural and genetic characteristics of tumors. Nevertheless, the absence of a complete tumor microenvironment (TME) limits the broader application of organoid models in immunological studies. Given the critical role of immune cells in tumor initiation and progression, the co-culture model of organoids and peripheral blood mononuclear cells (PBMCs) may provide an effective platform for simulating the interactions between immune and tumor cells in vitro. This model stands as a robust instrument for dissecting the TME, elucidating the molecular interactions, and exploring the therapeutic applications of chimeric antigen receptor (CAR)-engineered lymphocytes, as well as other cancer treatment modalities. This review systematically evaluates the advantages and disadvantages of the co-culture model, identifies its technical bottlenecks, and proposes corresponding optimization strategies. By summarizing the latest research advancements in this co-culture model, our goal is to provide valuable insights for further model optimization and clinical application, thereby promoting immunological research and bridging the gap between experimental outcomes and clinical practice.

Abstract Prostate cancer (PCa) is one of the most common and prevalent cancers in men worldwide. The majority of PCa-related deaths result from metastasis rather than primary tumors. Several studies have focused on the relationship between male-specific genes encoded on the Y chromosome and PCa metastasis; however, the relationship between the male specific protein encoded on the Y chromosome and tumor suppression has not been fully clarified. Here, we report a male specific protein of this type, the histone H3 lysine 4 (H3K4) demethylase JARID1D, which has the ability to inhibit the gene expression program related to cell invasion, and can thus form a phenotype that inhibits the invasion of PCa cells. However, JARID1D exhibits low expression level in advanced PCa, and which is related to rapid invasion and metastasis in patients with PCa. Curcumin, as a multi-target drug, can enhance the expression and demethylation activity of JARID1D, affect the androgen receptor (AR) and epithelial-mesenchymal transition (EMT) signaling cascade, and inhibit the metastatic potential of castration resistant cancer (CRPC). These findings suggest that using curcumin to increase the expression and demethylation activity of JARID1D may be a feasible strategy to inhibit PCa metastasis by regulating EMT and AR.

Abstract Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration‐resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron‐dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate‐specific membrane antigen (PSMA)‐targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane‐coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M‐gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA‐specific, CRPC‐targeting platform for ferroptosis induction with increased efficacy and safety.

Abstract Traumatic brain injury (TBI) is the main cause of disability, mental health disorder, and even death, with its incidence and social costs rising steadily. Although different treatment strategies have been developed and tested to mitigate neurological decline, a definitive cure for these conditions remains elusive. Studies have revealed that various neurotrophins represented by the brain‐derived neurotrophic factor are the key regulators of neuroinflammation, apoptosis, blood–brain barrier permeability, neurite regeneration, and memory function. These factors are instrumental in alleviating neuroinflammation and promoting neuroregeneration. In addition, neural stem cells (NSC) contribute to nerve repair through inherent neuroprotective and immunomodulatory properties, the release of neurotrophins, the activation of endogenous NSCs, and intercellular signaling. Notably, innovative research proposals are emerging to combine BDNF and NSCs, enabling them to synergistically complement and promote each other in facilitating injury repair and improving neuron differentiation after TBI. In this review, we summarize the mechanism of neurotrophins in promoting neurogenesis and restoring neural function after TBI, comprehensively explore the potential therapeutic effects of various neurotrophins in basic research on TBI, and investigate their interaction with NSCs. This endeavor aims to provide a valuable insight into the clinical treatment and transformation of neurotrophins in TBI, thereby promoting the progress of TBI therapeutics.

Abstract Background Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and receive effective chemotherapy have the best chance for long‐term survival. Unfortunately, because of the heterogeneity of pancreatic cancer, it is difficult to find a personalized treatment strategy for patients. Organoids are ideal preclinical models for personalized medicine. Therefore, we explore the cultivation conditions and construction methods of PDAC organoid models to screen the individualized therapy strategy. Methods Fresh PDAC tissues from surgical resection were collected and digested with digestive enzymes; then the tumor cells were embedded in Matrigel with a suitable medium to establish the PDAC organoid models. The genetic stability of the organoids was analyzed using whole exon sequencing; hematoxylin and eosin staining and immunohistochemistry of organoids were performed to analyze their consistency with the pathological morphology of the patient's tumor tissue; After 2 days of organoid culture, we selected four commonly used clinical chemotherapy drugs for single or combined treatment to analyze drug sensitivity. Results Two cases of PDAC organoid models were successfully established, and the results of their pathological characteristics and exome sequencing were consistent with those of the patient's tumor tissue. Both PDAC organoids showed more sensitivity to gemcitabine and cisplatin, and the combined treatment was more effective than monotherapy. Conclusion Both organoids better retained the pathological characteristics, genomic stability, and heterogeneity with the original tumor. Individual PDAC organoids exhibited different sensitivities to the same drugs. Thus, this study provided ideal experimental models for screening individualized therapy strategy for patients with PDAC.

Summary: Glycome in urine could be promising biomarkers for detecting pregnancy diagnosis and sex noninvasively for animals, especially for rare species. We explore the applicability of grouping golden snub-nosed monkeys by sex or diagnosing pregnancy based on their urinary glycopatterns, which are determined via lectin microarray combining mass spectrometry analysis. Sprague-Dawley rats are used to verify whether this approach and whether the glycomic biomarkers can be generalized to other mammalian species. The results show that, for both species, lectin microarray combining mass spectrometry can distinguish individuals’ pregnancy status and sex; significant differences are found in the types, amounts, and terminal modification of glycans between pregnant and non-pregnant females and between females and males. This indicates the approach could be generalized to other mammalian species to group sex and detect pregnancy, yet the glycopatterns appear to be species-specific and markers developed from one species may not be directly applicable to another.

Background: Angiogenesis constitutes a major mechanism responsible for exercise-induced beneficial effects. Our previous study identified a cluster of differentially expressed extracellular vesicle microRNAs (miRNAs) after exercise and found that some of them act as exerkines. However, whether these extracellular vesicle miRNAs mediate the exercise-induced angiogenesis remains unknown. Methods: A 9-day treadmill training was used as an exercise model in C57BL/6 mice. Liver-specific adeno-associated virus 8 was used to knock down microRNA-122-5p (miR-122-5p). Human umbilical vein endothelial cells were used in vitro. Results: Among these differentially expressed extracellular vesicle miRNAs, miR-122-5p was identified as a potent pro-angiogenic factor that activated vascular endothelial growth factor signaling and promoted angiogenesis both in vivo and in vitro. Exercise increased circulating levels of miR-122-5p, which was produced mainly by the liver and shuttled by extracellular vesicles in mice. Inhibition of circulating miR-122-5p or liver-specific knockdown of miR-122-5p significantly abolished the exercise-induced pro-angiogenic effect in skeletal muscles, and exercise-improved muscle performance in mice. Mechanistically, miR-122-5p promoted angiogenesis through shifting substrate preference to fatty acids in endothelial cells, and miR-122-5p upregulated endothelial cell fatty-acid utilization by targeting 1-acyl-sn-glycerol-3-phosphate acyltransferase (AGPAT1). In addition, miR-122-5p increased capillary density in perilesional skin tissues and accelerated wound healing in mice. Conclusion: These findings demonstrated that exercise promotes angiogenesis through upregulation of liver-derived extracellular vesicle miR-122-5p, which enhances fatty acid utilization by targeting AGPAT1 in endothelial cells, highlighting the therapeutic potential of miR-122-5p in tissue repair.

Abstract Background Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. Methods CD248 expression was examined in patients with liver cirrhosis and in mice with CCl4-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl4-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. Results CD248 expression was upregulated in patients with liver cirrhosis and in CCl4-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)+ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248+ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. Conclusions Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors. Graphic Abstract

Abstract Bladder cancer (BLCA) is the most common malignancy whose early diagnosis can ensure a better prognosis. However, the predictive accuracy of commonly used predictors, including patients’ general condition, histological grade, and pathological stage, is insufficient to identify the patients who need invasive treatment. Autophagy is regarded as a vital factor in maintaining mitochondrial function and energy homeostasis in cancer cells. Whether autophagy-related genes (ARGs) can predict the prognosis of BLCA patients deserves to be investigated. Based on BLCA data retrieved from the Cancer Genome Atlas and ARGs list obtained from the Human Autophagy Database website, we identified prognosis-related differentially expressed ARGs (PDEARGs) through Wilcox text and constructed a PDEARGs-based prognostic model through multivariate Cox regression analysis. The predictive accuracy, independent forecasting capability, and the correlation between present model and clinical variables or tumor microenvironment were evaluated through R software. Enrichment analysis of PDEARGs was performed to explore the underlying mechanism, and a systematic prognostic signature with nomogram was constructed by integrating clinical variables and the aforementioned PDEARGs-based model. We found that the risk score generated by PDEARGs-based model could effectively reflect deteriorated clinical variables and tumor-promoting microenvironment. Additionally, several immune-related gene ontology terms were significantly enriched by PDEARGs, which might provide insights for present model and propose potential therapeutic targets for BLCA patients. Finally, a systematic prognostic signature with promoted clinical utility and predictive accuracy was constructed to assist clinician decision. PDEARGs are valuable prognostic predictors and potential therapeutic targets for BLCA patients.

Gallbladder cancer is a highly aggressive malignancy with poor sensitivity to postoperative radiotherapy or chemotherapy; therefore, the development of individualized treatment strategies is paramount to improve patient outcomes. Both patient-derived tumor xenograft (PDX) and patient-derived tumor organoid (PDO) models derived from surgical specimens can better preserve the biological characteristics and heterogeneity of individual original tumors, display a unique advantage for individualized therapy and predicting clinical outcomes. In this study, PDX and PDO models of advanced gallbladder cancer were established, and the consistency of biological characteristics between them and primary patient samples was confirmed using pathological analysis and RNA-sequencing. Additionally, we tested the efficacy of chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitors using these two models. The results demonstrated that gemcitabine combined with cisplatin induced significant therapeutic effects. Furthermore, treatment with immune checkpoint inhibitors elicited promising responses in both the humanized mice and PDO immune models. Based on these results, gemcitabine combined with cisplatin was used for basic treatment, and immune checkpoint inhibitors were applied as a complementary intervention for gallbladder cancer. The patient responded well to treatment and exhibited a clearance of tumor foci. Our findings indicate that the combined use of PDO and PDX models can guide the clinical treatment course for gallbladder cancer patients to achieve individualized and effective treatment.

Owing to the high heterogeneity of pancreatic cancer, patient-derived xenografts (PDX) can compensate for the defects of cell line-derived xenografts (CDX) and also better preserve the heterogeneity and tumor microenvironment of primary tumors. Further, gemcitabine, which is used for the treatment of various cancers, is prone to tumor drug resistance, and this limits its sustained efficacy. Therefore, in this study, our objective was to screen appropriate individual therapeutic drugs for pancreatic cancer. To this end, we established pancreatic cancer PDX models from different patients and screened gemcitabine sensitivity regulatory molecules via high-throughput transcriptome sequencing and bioinformatics analysis. Based on the results obtained, gemcitabine was identified as the most suitable chemotherapeutic drug in a variety of PDX models. Additionally, our results indicated that Lipocalin 2 (LCN 2) may play an important role in the sensitivity of pancreatic cancer to gemcitabine treatment. Thus, the study provides a new potential intervention target for the treatment of pancreatic cancer in clinical practice.

Complex heterogeneity is an important characteristic in the development of prostate cancer (PCa), which further leads to the failure of known therapeutic options. PCa research has been hampered by the current in vitro model systems that cannot fully reflect the biological characteristics and clinical diversity of PCa. The tumor organoid model in three-dimensional culture retains the heterogeneity of primary tumor tissues in vitro well and enables high-throughput screening and genome editing. Therefore, the establishment of a PCa organoid model that recapitulates the diverse heterogeneity observed in clinical settings is of great significance for the study of PCa. In this review, we summarize the culture conditions, establishments, and limitations of PCa organoids and further review their application for the study of pathogenesis, drug screening, mechanism of drug resistance, and individualized treatment for PCa. Additionally, we look forward to other potential developmental directions of PCa organoids, such as the interaction between prostate cancer tumor cells and their microenvironment, clinical individualized treatments, heterogeneous transformation model, tumor immunotherapy, and organoid models combined with liquid biopsy. Through this, we provide more effective preclinical experimental schemes using the PCa organoid model.

Germline copy number variant (gCNV) has been studied as a genetic determinant for prognosis of several types of cancer, but little is known about how it affects non-small cell lung cancer (NSCLC) prognosis. We aimed to develop a prognostic nomogram for NSCLC based on gCNVs. Promising gCNVs that are associated with overall survival (OS) of NSCLC were sorted by analyzing the TCGA data and were validated in a small Chinese population. Then the successfully verified gCNVs were determined in a training cohort (n = 570) to develop a prognostic nomogram, and in a validation cohort (n = 465) to validate the nomogram. Thirty-five OS-related gCNVs were sorted and were reduced to 15 predictors by the Lasso regression analysis. Of them, only CNVR395.1 and CNVR2239.1 were confirmed to be associated with OS of NSCLC in the Chinese population. High polygenic risk score (PRS), which was calculated by the hazard effects of CNVR395.1 and CNVR2239.1, exerted a significantly higher death rate in the training cohort (HR = 1.41, 95%CI: 1.16–1.74) and validation cohort (HR = 1.42, 95%CI: 1.13–1.77) than low PRS. The nomogram incorporating PRS and surrounding factors, achieved admissible concordance indexes of 0.678 (95%CI: 0.664–0.693) and 0.686 (95%CI: 0.670–0.702) in predicting OS in the training and validation cohorts, respectively, and had well-fitted calibration curves. Moreover, an interaction between PRS and asbestos exposure was observed on affecting OS (Pinteraction = 0.042). Our analysis developed a nomogram that achieved an admissible prediction of NSCLC survival, which would be beneficial to the personalized intervention of NSCLC.

Immunotherapy has been used as a first-line treatment for a variety of advanced tumors, allowing remarkable progress to be made in cancer treatment. Nonetheless, only a small number of patients can benefit from immune checkpoint inhibitor monotherapy. To improve the effect of immunotherapy, the underlying mechanism of combination therapy was investigated in the context of an intact human tumor immune microenvironment using mice with a human immune system (HIS) bearing human tumors. Herein, we summarize and discuss strategies for the development and use of HIS mice models in tumor immunotherapies. Most importantly, this review proposes a method of t11umor identification and classification in HIS mice based on the tumor-infiltrating lymphocytes and PD-L1 expression, and according to this classification, we propose different combination treatment strategies that can be utilized to enhance the effect of immunotherapy. Thus, we provide effective experimental schemes for tumor immunotherapy in HIS mice models.

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.

Background: Renal cell carcinoma (RCC) is the most common malignancy in the urinary system. Despite substantial improvements in available treatment options, the survival outcome of advanced RCC is unsatisfactory. Identifying novel biomarkers to assist in early diagnosis and to screen patients who are sensitive to immunotherapy would be beneficial. CD248 is a promising candidate that deserves to be investigated.Methods: The Cancer Genome Atlas (TCGA) data set and clinical specimens were adopted to analyze the expression of CD248 between normal and tumor tissues. Univariate and multivariate Cox regression analyses were employed to identify independent prognostic factors and construct a CD248-based prognostic signature. The correlation among the present signature, tumor-infiltrating immune cells (TIICs), the tumor mutation burden (TMB), and immunomodulatory molecules was evaluated. The weighted gene co-expression network analysis (WGCNA), the enrichment analysis, and the miRNA correlation analysis were performed to explore the underlying mechanism of CD248 in the progression of RCC.Results: The overexpression of CD248 in RCC was related to a poor prognosis, and a CD248-based prognostic signature could precisely stratify patients with RCC with different survival outcomes regardless of the training or testing cohort. The present signature could reflect the immunosuppressive landscape of RCC (i.e., increased infiltration of regulatory T cells and upregulated immune checkpoints), accompanied by deteriorated clinicopathologic indexes. The TMB and immunostimulatory molecules expression also increased with the risk score generated from the present signature. CD248 co-expressed gene sets were identified through the WGCNA algorithm, and several immunosuppressive Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly enriched. The result of CD248-correlated miRNA further emphasized the importance of CD248 in RCC.Conclusion: CD248 is a valuable biomarker to improve the diagnostic and therapeutic efficiency of RCC. The immunosuppressive effect of CD248 co-expressed genes may provide insight for the present study, and miRNA would help to reveal the mechanism of the expressive regulation of CD248.

Abstract Background Even though multi-focused psychosocial residence rehabilitation intervention (MPRRI) programs are widely implemented by the Shanghai Cancer Rehabilitation Club, these programs have not been rigorously evaluated. In this study, we evaluated the effects of a 21-day MPRRI program, on the quality of life (QoL) among cancer survivors. Methods A total of 388 cancer patients were enrolled to either receive the 21-day MPRRI (n = 129) intervention or a waiting-list comparison (WLC) intervention (n = 259). The intervention group was offered community-based 21-day MPRRI program, combining supportive-expressive group, cognitive-behavioral therapy, and Guolin Qigong. QoL was measured using the European Organization for Research and Treatment Quality of Life Version 3 Questionnaire. Multivariable linear models were used to compare changes in QoL values between the two groups. Results After adjustment for the QoL score and other covariates at baseline, there was no significant difference in global health status (mean = 3.8, 95% CI − 1.3–9.0, P = 0.14) between the two groups after 6 months intervention. While compared with the WLC group, the intervention group showed significant improvements in the QoL score (all P

In this paper, we present an automated skeletal maturity recognition system that takes a single hand radiograph as an input and finally output the bone age prediction. Unlike the conventional manually diagnostic methods, which are laborious, fallible, and time-consuming, the proposed system takes input images and generates classification results directly. It first accurately detects the distal radius and ulna areas from the hand and wrist X-ray images by a faster region-based convolutional neural network (CNN) model. Then, a well-tuned CNN classification model is applied to estimate the bone ages. In the experiment section, we employed a data set of 1101 hand and wrist radiographs and conducted comprehensive experiments on the proposed system. We discussed the model performance according to various network configurations, multiple optimization algorithms, and different training sample amounts. After parameter optimization, the proposed model is finally achieved 92% and 90% classification accuracies for radius and ulna grades, respectively.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas)9 is a novel and convenient gene editing system that can be used to construct genetically modified animals. Recombination activating gene 2 (Rag2) is a core component that is involved in the initiation of V(D)J recombination during T- and B-cells maturation. Separately, the interleukin-2 receptor gamma chain gene (IL2rg) encoded the protein-regulated activity of natural killer (NK) cells and shared common receptors of some cytokines. Rag2 and IL2rg mutations cause immune system disorders associated with T-, B-, and NK cell function and some cytokine activities. In the present study, 2 single-guide RNAs (sgRNAs) targeted on Rag2 and IL2rg genes were microinjected into the zygotes of BALB/c mice with Cas9 messenger RNA (mRNA) to create Rag2/IL2rg-/- double knockout mice, and the biological characteristics of the mutated mice were subsequently analyzed. The results showed that CRISPR/Cas9-induced indel mutation displaced the frameshift of Rag2 and IL2rg genes, resulting in a decrease in the number of T-, B-, and NK cells and the destruction of immune-related tissues like the thymus and spleen. Mycobacterium tuberculosis 85B antigen could not induce cellular and humoral immune response in mice. However, this aberrant immune activity compromised the growth of several tumor heterogenous grafts in the mutated mice, including orthotopic and subcutaneous transplantation tumors. Thus, Rag2/IL2rg-/- knockout mice possessed features of severe combined immunodeficiency (SCID), which is an ideal model for human xenograft.

Birch veneers were coated with Ni-P films by a combined process of KBH4 activation and electroless plating. The plated veneers were further chemically corroded to obtain hydrophobic surfaces on wood. The effect of chemical corrosion on the contact angle of the veneers was investigated. The hydrophobic veneers were characterized by X-ray photo electron spectroscopy (XPS), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The surface contact angle of birch veneer before and after it was plated with Ni-P alloy coating was 41º and 121º, respectively. The contact angle reached 136.7º when the nickel-coated veneers were corroded in CuSO4 aqueous solution for 30 min. XPS analysis showed that Cu0 cluster doped with little CuO formed on the corroded surface of Ni-P alloy film after chemical corrosion. SEM and XRD showed that rough copper clusters formed on the surface of the wood veneer and revealed the reason of the surface hydrophobicity. This study provides a new pathway for fabricating hydrophobic wood.

A Ni-Fe-P alloy coating was applied to Triplochiton scleroxylon veneers to prepare a magnetic, corrosion-resistant, electromagnetism-shielding wood-based composite. The effects of solution pH on metal deposition, surface resistivity, crystal structure, and the chemical composition of the coatings were investigated. The electro-conductivity, anti-corrosion properties, and magnetic and electromagnetic shielding performances were also measured. The results showed that increasing the pH favored the co-deposition of nickel and iron; metal deposition increased and surface resistivity decreased. The Ni-Fe-P alloy coatings obtained at pH values between 8.8 and 9.6 were all crystalline. VSM data revealed that the addition of elemental Fe to the deposits remarkably increased the magnetic properties of the products. The anti-corrosion properties of Ni-Fe-P coatings were higher than those of Ni-P coatings prepared in 3.5 wt.% NaCl solution. The electromagnetic shielding effectiveness value of Ni-Fe-P plated veneer reached 45 to 60 dB at frequencies ranging from 9 kHz to 1.5 GHz.

Patients with pancreatic cancer (PC) receive limited benefits from immune checkpoint inhibitors (ICIs) alone. Recent studies have indicated that the combination of intestinal microflora regulators and ICI may be an effective strategy for enhancing the response to tumor immunotherapy. Resveratrol has been shown to regulate both intestinal microbiota and the immune microenvironment; therefore, we speculated that resveratrol may enhance the immunotherapeutic effect of α-PD-1 on PC. We constructed a double-humanized mouse model with both a humanized immune system and PC to evaluate the efficacy of different doses of resveratrol combined with anti-PD-1 mAb therapy and analyze the characteristics of the tumor immune microenvironment after treatment. In addition, I6S sequencing was performed on mouse fecal samples, and metabolomic analyses were performed on plasma samples to understand the characteristics of the intestinal microbiome and metabolites to explore the potential mechanism of anti-tumor immunity mediated by combined immunotherapy. Results suggested that the combination of resveratrol with anti-PD-1 mAb promoted the infiltration and activation of CD8+ T cells in tumor tissues, thus effectively inhibiting PC growth. Attentively, the effect emphasized the combined effect, dose-dependent nature and the involvement of gut microbiome. Furthermore, metabonomics showed that the combination therapy significantly increased the abundance of the metabolite prostaglandin D2 (PGD2), which was most likely related to the increased abundance of Desulfovibrio fairfieldensis. Finally, we confirmed that PGD2 amplified anti-tumor effect of α-PD-1 by activating prostaglandin D receptor 1 (DP1) to promote CD8 infiltration in double humanized PC mice and subcutaneously transplanted KPC mice. Overall, our data revealed resveratrol has the potential to enhance the efficacy of α-PD-1 by regulating the gut microbiome and its metabolites, and PGD2 was an effective molecular mediating the infiltration of CD8+T cells into tumor tissue to amplify the anti-tumor effect of α-PD-1.Significance The anti-PD-1 mAb may be further considered along with PGD2 or active molecules that can promote PGD2 synthesis to enhance the anti-tumor immune response

Reliable information processing in cells requires high sensitivity to changes in the input signal but low sensitivity to random fluctuations in the transmitted signal. There are often many alternative biological circuits qualifying for this biological function. Distinguishing theses biological models and finding the most suitable one are essential, as such model ranking, by experimental evidence, will help to judge the support of the working hypotheses forming each model. Here, we employ the approximate Bayesian computation (ABC) method based on sequential Monte Carlo (SMC) to search for biological circuits that can maintain signaling sensitivity while minimizing noise propagation, focusing on cases where the noise is characterized by rapid fluctuations. By systematically analyzing three-component circuits, we rank these biological circuits and identify three-basic-biological-motif buffering noise while maintaining sensitivity to long-term changes in input signals. We discuss in detail a particular implementation in control of nutrient homeostasis in yeast. The principal component analysis of the posterior provides insight into the nature of the reaction between nodes.

Tuberculosis (TB) remains a major worldwide health problem. The only vaccine against TB, Mycobacterium bovis Bacille Calmette-Guerin (BCG), has demonstrated relatively low efficacy and does not provide satisfactory protection against the disease. More efficient vaccines and improved therapies are urgently needed to decrease the worldwide spread and burden of TB, and use of a viable, metabolizing mycobacteria vaccine may be a promising strategy against the disease. Here, we constructed a recombinant Mycobacterium smegmatis (rMS) strain expressing a fusion protein of heparin-binding hemagglutinin (HBHA) and human interleukin 12 (hIL-12). Immune responses induced by the rMS in mice and protection against Mycobacterium tuberculosis (MTB) were investigated. Administration of this novel rMS enhanced Th1-type cellular responses (IFN-γ and IL-2) in mice and reduced bacterial burden in lungs as well as that achieved by BCG vaccination. Meanwhile, the bacteria load in M. tuberculosis infected mice treated with the rMS vaccine also was significantly reduced. In conclusion, the rMS strain expressing the HBHA and human IL-12 fusion protein enhanced immunogencity by improving the Th1-type response against TB, and the protective effect was equivalent to that of the conventional BCG vaccine in mice. Furthermore, it could decrease bacterial load and alleviate histopathological damage in lungs of M. tuberculosis infected mice.

Recently, traditional Chinese medicine and medicinal herbs have attracted more attentions worldwide for its anti-tumor efficacy. Celastrol and Triptolide, two active components extracted from the Chinese herb Tripterygium wilfordii Hook F (known as Lei Gong Teng or Thunder of God Vine), have shown anti-tumor effects. Celastrol was identified as a natural 26 s proteasome inhibitor which promotes cell apoptosis and inhibits tumor growth. The effect and mechanism of Triptolide on prostate cancer (PCa) is not well studied. Here we demonstrated that Triptolide, more potent than Celastrol, inhibited cell growth and induced cell death in LNCaP and PC-3 cell lines. Triptolide also significantly inhibited the xenografted PC-3 tumor growth in nude mice. Moreover, Triptolide induced PCa cell apoptosis through caspases activation and PARP cleavage. Unbalance between SUMOylation and deSUMOylation was reported to play an important role in PCa progression. SUMO-specific protease 1 (SENP1) was thought to be a potential marker and therapeutical target of PCa. Importantly, we observed that Triptolide down-regulated SENP1 expression in both mRNA and protein levels in dose-dependent and time-dependent manners, resulting in an enhanced cellular SUMOylation in PCa cells. Meanwhile, Triptolide decreased AR and c-Jun expression at similar manners, and suppressed AR and c-Jun transcription activity. Furthermore, knockdown or ectopic SENP1, c-Jun and AR expression in PCa cells inhibited the Triptolide anti-PCa effects. Taken together, our data suggest that Triptolide is a natural compound with potential therapeutic value for PCa. Its anti-tumor activity may be attributed to mechanisms involving down-regulation of SENP1 that restores SUMOylation and deSUMOyaltion balance and negative regulation of AR and c-Jun expression that inhibits the AR and c-Jun mediated transcription in PCa.