Prediction of microvascular invasion and pathological differentiation of hepatocellular carcinoma based on a deep learning model.

PURPOSE: To develop a deep learning (DL) model based on preoperative contrast-enhanced computed tomography (CECT) images to predict microvascular invasion (MVI) and pathological differentiation of hepatocellular carcinoma (HCC). METHODS: This retrospective study included 640 consecutive patients who underwent surgical resection and were pathologically diagnosed with HCC at two medical institutions from April 2017 to May 2022. CECT images and relevant clinical parameters were collected. All the data were divided into 368 training sets, 138 test sets and 134 validation sets. Through DL, a segmentation model was used to obtain a region of interest (ROI) of the liver, and a classification model was established to predict the pathological status of HCC. RESULTS: The liver segmentation model based on the 3D U-Network had a mean intersection over union (mIoU) score of 0.9120 and a Dice score of 0.9473. Among all the classification prediction models based on the Swin transformer, the fusion models combining image information and clinical parameters exhibited the best performance. The area under the curve (AUC) of the fusion model for predicting the MVI status was 0.941, its accuracy was 0.917, and its specificity was 0.908. The AUC values of the fusion model for predicting poorly differentiated, moderately differentiated and highly differentiated HCC based on the test set were 0.962, 0.957 and 0.996, respectively. CONCLUSION: The established DL models established can be used to noninvasively and effectively predict the MVI status and the degree of pathological differentiation of HCC, and aid in clinical diagnosis and treatment.

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion: a case report.

BACKGROUND: Cutaneous Melanocytic Tumor with CRTC1::TRIM11 Fusion (CMTCT) represents a novel and rare entity in the realm of dermatological oncology, characterized by distinct melanocytic differentiation. This particular tumor type has yet to be officially recognized by the World Health Organization (WHO). CMTCT is generally perceived as a tumor with a relatively indolent nature; however, it is not devoid of metastatic potential. Therefore, ensuring complete surgical excision of the tumor, coupled with rigorous long-term follow-up, is paramount for patient management. In this context, we report the case of an 18-year-old female patient who presented with a dull red nodule on her left leg. Initial surgical intervention led to a pathological diagnosis of CMTCT, but it was determined that the tumor had not been fully excised. Consequently, a second surgical procedure was undertaken to achieve complete removal of the tumor. During a follow-up period of six months post-surgery, the patient showed no signs of local recurrence or metastasis, indicating a successful outcome. CASE PRESENTATION: An 18-year-old female patient noticed a dull red nodule on her left leg three years ago, which exhibited slow growth over time. She underwent a subcutaneous tumor resection. Histological examination under high-power magnification revealed that the neoplasm consisted of epithelioid cells arranged in nests, fascicles, bundles, or sheets. The tumor cells had round or ovoid nuclei with prominent nucleoli and visible mitotic figures. Notably, areas resembling nevus cell clusters were observed. Immunohistochemical analysis confirmed melanocytic differentiation. Next-generation sequencing (NGS) identified a CRTC1::TRIM11 fusion, and fluorescence in situ hybridization (FISH) for CRTC1 confirmed rearrangement. Consequently, a diagnosis of cutaneous melanocytic tumor with CRTC1::TRIM11 fusion was established. CONCLUSIONS: CMTCT is a rare tumor characterized by melanocytic differentiation. In this case, the tumor predominantly comprised epithelioid cells with localized nevus cell clusters. The expression of melanocyte markers could easily lead to a misdiagnosis as cutaneous melanoma. However, several distinguishing features were noted: the tumor was not connected to the epidermis, exhibited low cellular heterogeneity and proliferation index, and showed minimal cellular atypia. Additionally, tests for EWSR1 rearrangement (FISH) and BRAF V600E mutation (PCR-ARMS) were negative.This case underscores the importance of a comprehensive diagnostic approach when clinical, microscopic, immunohistochemical, and molecular findings do not align. The presence of nevus cell clusters morphology in the tumor cells enhances our understanding of this disease's histological spectrum and aids in avoiding misdiagnosis or missed diagnosis.

Clinicopathologic and mutational profiles of primary breast diffuse large B cell lymphoma in a male patient: case report and literature review.

INTRODUCTION: Primary breast lymphoma (PBL) is rare, and most cases occur in female patients, with few reported cases in male patients. The clinical presentation is similar to that of breast cancer, but the condition needs to be well understood, as treatment options and clinical course vary. Hence, we provide a relatively rare case of primary breast diffuse large B cell lymphoma (PB-DLBCL) in a male, including its complete clinicopathological features, radiological findings, genomic mutational profiles, and clinical course. CASE PRESENTATION: A 45-year-old male presented with a lump in his right breast for 1 week and was pathologically diagnosed with breast malignancy after a breast puncture biopsy at the local hospital. He came to our hospital for further treatment and underwent breast ultrasound and systemic positron emission tomography/computed tomography (PET/CT) imaging, followed by right mastectomy and sentinel lymph node biopsy. Histomorphology showed diffuse hyperplasia of tumor cells with clear boundaries and surrounding normal breast ducts. The adhesion of tumor cells was poor with obvious atypia. Immunohistochemical results showed that the tumor cells were positive for CD20, Bcl6, and MUM-1 but negative for CK (AE1/AE3), ER, PR, CD3, and CD10. Forty percent of the tumor cells were positive for c-Myc, and 80% of tumor cells were positive for Bcl2. The Ki-67 proliferation index was up to 80%. The tumor cells were negative for MYC and BCL2 rearrangements but positive for BCL6 rearrangement by fluorescent in situ hybridization. No abnormality was found in the pathological examination of bone marrow aspiration. Therefore, the male was diagnosed with PB-DLBCL, nongerminal center (non-GCB) phenotype, dual-expression type. The sample were sequenced by a target panel of 121 genes related to lymphoma. Next-generation sequencing revealed six tumor-specific mutated genes (IGH/BCL6, TNFAIP3, PRDM1, CREBBP, DTX1, and FOXO1). The patient was given six cycles of orelabrutinib plus R-CHOP chemotherapy and two cycles of intrathecal injection of cytarabine. The last follow-up was on April 13, 2023 (17 months). No recurrence or metastasis was found in laboratory and imaging examinations. CONCLUSION: We reported a relatively rare PB-DLBCL in a male, non-GBC phenotype, dual-expression type. It is worth mentioning that this case had IgH/BCL6 fusion, nonsense mutations in TNFAIP3, frameshift mutations in PRDM1, and missense mutations in CREBBP, DTX1, and FOXO1. To the best of our knowledge, this case is the first report of genomic mutational profiles of PB-DLBCL in males.

Insights into DNMT1 and programmed cell death in diseases.

DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is involved in various diseases, including cancer and nervous system diseases. Programmed cell death (PCD) is a fundamental mechanism that regulates cell proliferation and maintains the development and homeostasis of multicellular organisms. DNMT1 plays a regulatory role in various types of PCD, including apoptosis, autophagy, necroptosis, ferroptosis, and others. DNMT1 is closely associated with the development of various diseases by regulating key genes and pathways involved in PCD, including caspase 3/7 activities in apoptosis, Beclin 1, LC3, and some autophagy-related proteins in autophagy, glutathione peroxidase 4 (GPX4) and nuclear receptor coactivator 4 (NCOA4) in ferroptosis, and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3-mixed lineage kinase domain-like protein (RIPK1-RIPK3-MLKL) in necroptosis. Our study summarizes the regulatory relationship between DNMT1 and different types of PCD in various diseases and discusses the potential of DNMT1 as a common regulatory hub in multiple types of PCD, offering a perspective for therapeutic approaches in disease.

Effect of ABC Theory Model on Negative Emotion of Young Patients with Breast Cancer During Treatment.

Objective: To evaluate the effect of emotional ABC theory on anxiety and depression in young patients with breast cancer. Methods: A total of 200 eligible young patients with breast cancer were randomly divided into control group (N = 100) and experimental group (N = 100). The control group received routine treatment, while the experimental group received emotional ABC theory intervention at the same time. Results: The Self Rating Anxiety Scale (SAS) and Self Rating Depression Scale (SDS) scores of the two groups were observed before and after nursing. There was no significant difference between the two groups before nursing (P > 0.05), but there was significant difference between the two groups after nursing, the control group was significantly higher than the experimental group (P < 0.05). The satisfaction degree of the control group was significantly lower than that of the experimental group (P < 0.05). Conclusion: Young patients with breast cancer using emotional ABC theory can effectively improve negative emotions, clinical can promote the nursing program.

Deep learning-assisted LI-RADS grading and distinguishing hepatocellular carcinoma (HCC) from non-HCC based on multiphase CT: a two-center study.

OBJECTIVES: To develop a deep learning (DL) method that can determine the Liver Imaging Reporting and Data System (LI-RADS) grading of high-risk liver lesions and distinguish hepatocellular carcinoma (HCC) from non-HCC based on multiphase CT. METHODS: This retrospective study included 1049 patients with 1082 lesions from two independent hospitals that were pathologically confirmed as HCC or non-HCC. All patients underwent a four-phase CT imaging protocol. All lesions were graded (LR 4/5/M) by radiologists and divided into an internal (n = 886) and external cohort (n = 196) based on the examination date. In the internal cohort, Swin-Transformer based on different CT protocols were trained and tested for their ability to LI-RADS grading and distinguish HCC from non-HCC, and then validated in the external cohort. We further developed a combined model with the optimal protocol and clinical information for distinguishing HCC from non-HCC. RESULTS: In the test and external validation cohorts, the three-phase protocol without pre-contrast showed κ values of 0.6094 and 0.4845 for LI-RADS grading, and its accuracy was 0.8371 and 0.8061, while the accuracy of the radiologist was 0.8596 and 0.8622, respectively. The AUCs in distinguishing HCC from non-HCC were 0.865 and 0.715 in the test and external validation cohorts, while those of the combined model were 0.887 and 0.808. CONCLUSION: The Swin-Transformer based on three-phase CT protocol without pre-contrast could feasibly simplify LI-RADS grading and distinguish HCC from non-HCC. Furthermore, the DL model have the potential in accurately distinguishing HCC from non-HCC using imaging and highly characteristic clinical data as inputs. CLINICAL RELEVANCE STATEMENT: The application of deep learning model for multiphase CT has proven to improve the clinical applicability of the Liver Imaging Reporting and Data System and provide support to optimize the management of patients with liver diseases. KEY POINTS: • Deep learning (DL) simplifies LI-RADS grading and helps distinguish hepatocellular carcinoma (HCC) from non-HCC. • The Swin-Transformer based on the three-phase CT protocol without pre-contrast outperformed other CT protocols. • The Swin-Transformer provide help in distinguishing HCC from non-HCC by using CT and characteristic clinical information as inputs.

Identification and validation of novel biomarkers affecting bladder cancer immunotherapy via machine learning and its association with M2 macrophages.

Background: Immunotherapy has shown promising results in bladder cancer therapy options. Methods: Analysis of open-access data was conducted using the R software. Open-access data were obtained from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and IMvigor210 databases. Immunofluorescence and co-culture systems were utilized to validate the effect of PTHLH on M2 macrophage polarization. Results: Here, through the combined (TCGA, GSE128959, GSE13507, and GSE83586) and IMvigor210 cohorts, we comprehensively investigated the biological and immune microenvironment differences in patients with diverse immunotherapy responses. Meanwhile, we found that M2 macrophage could affect bladder cancer immunotherapy sensibility. Moreover, based on the machine learning algorithm (LASSO logistics regression), PTHLH, BHMT2, and NGFR were identified, which all have good prediction abilities for patient immunotherapy. Then, a logistics regression model was established based on PTHLH, BHMT2, and NGFR, and each patient was assigned a logistics score. Subsequently, we investigated the difference in patients with high low logistics scores, including biological enrichment, immune microenvironment, and genomic characteristics. Meanwhile, data from the Human Protein Atlas database indicated a higher protein level of PTHLH in bladder cancer tissue. Immunofluorescence indicated that the knockdown of PTHLH in bladder cancer cells can significantly inhibit the M2 polarization of co-culture M0 macrophages. Conclusions: Our study investigated the difference between bladder cancer immunotherapy responders and non-responders. Meanwhile, the PTHLH was identified as a novel biomarker for bladder cancer immunotherapy.

Sanggenon C Suppresses Tumorigenesis of Gastric Cancer by Blocking ERK-Drp1-Mediated Mitochondrial Fission.

Sanggenon C is a flavonoid extracted from the root bark of white mulberry, which is a traditional Chinese medicine with anti-inflammatory, antioxidative, and antitumor pharmacological effects. In this study, sanggenon C was found to inhibit human gastric cancer (GC) cell proliferation and colony formation, induce GC cell cycle arrest in the G0-G1 phase, and promote GC cell apoptosis. Moreover, sanggenon C was found to decrease the level of mitochondrial membrane potential in GC cells and inhibit mitochondrial fission. Mechanistically, RNA sequencing, bioinformatics analysis, and a series of functional analyses confirmed that sanggenon C inhibited mitochondrial fission to induce apoptosis by blocking the extracellular regulated protein kinases (ERK) signaling pathway, and constitutive activation of ERK significantly abrogated these effects. Finally, sanggenon C was found to suppress the growth of tumor xenografts in nude mice without obvious side effects to the vital organs of animals. This study reveals that sanggenon C could be a novel therapeutic strategy for GC treatment.

EIF3B Associates with Exacerbated Clinical Features, Poor Treatment Response and Survival in Adult Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia Patients.

Objective: This study was undertaken to investigate eukaryotic translation initiation factor 3 subunit B (EIF3B) expression and its clinical value for indicating disease progression and prognosis in adult Philadelphia chromosome negative acute lymphoblastic leukemia (Ph- ALL) patients. Methods: Totally, 76 adult Ph- ALL patients and 30 healthy donors (HDs) were included. Bone marrow (BM) samples before therapy (baseline), after 4-week therapy of Ph- ALL patients and the BM samples of HDs were collected. Then, EIF3B expression in BM was detected by reverse transcription quantitative polymerase chain reaction. Results: EIF3B expression was increased in Ph- ALL patients compared with HDs, which distinguished Ph- ALL patients from HDs (area under the curve [AUC]: 0.928; 95% confidence interval [CI]: 0.882-0.974) by receiver operating characteristic curve. Furthermore, higher baseline EIF3B expression was associated with elevated white blood cell and bone marrow blasts, while it was associated with lower complete remission (CR) within 4 weeks and less allogeneic hematopoietic stem cell transplant achievements in Ph- ALL patients. Additionally, higher baseline EIF3B expression was associated with decreased disease-free survival but not overall survival. However, it was associated with raised 1-year mortality and 3-year mortality in Ph- ALL patients. After 4-week therapy, EIF3B expression was reduced in total Ph- ALL patients. Notably, the reduction of EIF3B expression was more obvious in Ph- ALL patients who achieved CR within 4 weeks compared with Ph- ALL patients who did not achieve CR within 4 weeks. Conclusion: EIF3B overexpression is related to worsened clinical features, poor treatment response and survival in adult Ph- ALL patients.

Deciphering Antitumor Mechanism of Pien Tze Huang in Mice of Hepatocellular Carcinoma Based on Proteomics.

The Chinese formula Pien Tze Huang (PZH) has been used to treat hepatocellular carcinoma (HCC) and showed positive clinical effects. However, the antitumor mechanism of PZH in HCC remains unclear. In this study, HCC xenograft Balb/c mice were treated with PZH; then, proteomics detection and Ingenuity Pathway Analysis (IPA) were used to analyze the differentiated phosphorylated proteins in tumor tissues. The results indicated that PZH could inhibit tumor weight by 50.76%. Eighty-four upregulated and 11 downregulated phosphorylated proteins were identified in PZH-treated mice. Twenty signaling pathways were associated with inflammation (including the IL-6 and TNFR1/2 pathways), cancer growth (including the p53 and FAK pathways), and the cell cycle (including the G2/M and G1/S checkpoint regulation pathways). Moreover, TNF-α, IL-6, and several typical differentially expressed phosphorylated proteins (such as p-CCNB1, p-FOXO3, and p-STAT3) in tumor tissues, tumor cell viability, and cell cycle arrest assay in vitro further verify the results of IPA. These results revealed that PZH achieved antitumor activity in HCC; the underlying mechanisms of which were mainly through regulating the inflammation-associated cytokine secretion, cancer growth pathways, and induction of G2/M arrest. These data provided the potential molecular basis for PZH to act as a therapeutic drug or a supplement to chemotherapy drugs for human HCC in the future.

Study on the Release Potential of BPA and Steroid Estrogens in the Sediments of Erhai Lake, a Typical Plateau Lake of China.

On-site sampling analysis and laboratory-scale experiments were conducted to study the pollution status and release potential of EDCs in Erhai Lake. We found that nitrogen and phosphorus pollution in Erhai Lake sediment were both at a high level, as well as EDCs pollution. The concentrations of BPA, E2α, E1, E2ß, EE2, and E3 were 36.84 ng/g(DW), 13.04 ng/g(DW), 128.97 ng/g(DW), 52.57 ng/g(DW), 18.48 ng/g(DW) and 5.36 ng/g(DW), respectively. The concentrations of E2α, E1, E2ß and EE2 in the bottom water were higher than the surface water due to the impact of sediment release. The results of the 20 days release test indicated that BPA release from the sediment had a greater correlation with the original concentration and the particle size of sediment, while the steroid EDCs had no obvious correlation with these two factors, probably due to the difference in hydrophobicity between them. Under hydraulic disturbance and aerobic conditions, the release process of EDCs was accompanied by a large amount of microbial degradation, and degradation amount > released amount. BPA was released quickly, 9.56% was released in 20 days, but only 3.37% of steroid EDCs released. In comparison, the release process of steroids was longer and posed a greater threat to aquatic ecology.

Single-Cell Transcriptomic Atlas of Primate Ovarian Aging.

Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.

Data on Tougu Xiaotong capsules may inhibit p38 MAPK pathway-mediated inflammation in vitro.

The Tougu Xiaotong capsule (TXC) is a traditional herbal compound used to treat osteoarthritis (OA) in China. We performed fingerprint analysis with HPLC for the quality control of TXC. Its composition was identified by the comparison of the spectrogram and chromatographic peak of retention time with a reference substance. TXC was found to contain paeoniflorin, isofraxidin, ferulic acid, and rosmarinic acid. The chondrocytes were identified by immunohistochemical staining using collagen II. Chondrocytes that were positive for collagen II were stained brown in the cytoplasm. The toll-like receptor 4 (TLR4) was expressed on the chondrocyte membrane, which was observed using immunofluorescence microscopy. The nuclei were stained blue by 4',6-diamidino-2-phenylindole (DAPI) and TLR4 was stained green. These were observed using laser scanning confocal microscopy. The successful establishment of LPS-exposed chondrocytes was confirmed using enzyme-linked immunosorbent assay (ELISA). Lipopolysaccharide (LPS) administration significantly reduced the levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), and a maximum effect was observed at 8 h. We believe that these methods will be useful in future investigations of OA. This data article is related to the research article "Tougu Xiaotong capsules may inhibit p38 MAPK pathway-mediated inflammation: In vivo and in vitro verification" [1].

Identification of Constituents Affecting the Secretion of Pro-Inflammatory Cytokines in LPS-Induced U937 Cells by UHPLC-HRMS-Based Metabolic Profiling of the Traditional Chinese Medicine Formulation Huangqi Jianzhong Tang.

Within non-communicable diseases, chronic inflammatory conditions represent one of the biggest challenges for modern medicine. Traditional Chinese Medicine (TCM) has been practiced over centuries and has accumulated tremendous empirical knowledge on the treatment of such diseases. Huangqi Jianzhong Tang (HQJZT) is a famous TCM herbal formula composed of Radix Astragali, Ramulus Cinnamomi, Radix et Rhizoma Glycyrrhizae Praeparata cum Melle, Radix Paeoniae Alba, Rhizoma Zingiberis Recens, Fructus Jujubae and Saccharum Granorum (maltose), which has been used for the treatment of various chronic inflammatory gastrointestinal diseases. However, there is insufficient knowledge about its active constituents and the mechanisms responsible for its effects. The present study aimed at identifying constituents contributing to the bioactivity of HQJZT by combining in vitro cytokine production assays and LC-MS metabolomics techniques. From the HQJZT decoction as well as from its single herbal components, extracts of different polarities were prepared. Phytochemical composition of the extracts was analyzed by means of UPLC-QTOF-MS/MS. The inhibitory effects of the extracts on TNF-α, IL-1ß and IFN-γ production were studied in U937 cells. Phytochemical and pharmacological bioactivity data were correlated by orthogonal projection to latent structures discriminant analysis (OPLS-DA) in order to identify those HQJZT constituents which may be relevant for the observed pharmacological activities. The investigations resulted in the identification of 16 HQJZT constituents, which are likely to contribute to the activities observed in U937 cells. Seven of them, namely calycosin, formononetin, astragaloside I, liquiritigenin, 18ß-glycyrrhetinic acid, paeoniflorin and albiflorin were unambiguously identified. The predicted results were verified by testing these compounds in the same pharmacological assays as for the extracts. In conclusion, the anti-inflammatory activity of HQJZT could be substantiated by in vitro pharmacological screening, and the predicted activities of the OPLS-DA hits could be partially verified. Moreover, the benefits and limitations of MVDA for prediction pharmacologically active compounds contributing to the activity of a TCM mixture could be detected.

Radiological and clinical findings of isolated meningeal Rosai-Dorfman disease of the central nervous system.

Rosai-Dorfman disease (RDD) with isolated central nervous system (CNS) involvement is an extremely rare disease. Most RDD of the CNS present as dural-based mass mimicking meningioma and other common lesions, which makes preoperative accurate diagnosis of great difficulty. We searched the pathology database in our hospital and 3 cases of RDD with isolated CNS involvement were finally included in our study. Radiological and clinical findings of these three cases were retrospectively analyzed. The lesions of 2 cases were dura-based against the cerebral convexity, presenting as a sheet-shaped thickened dura mater, another case was located just across the cerebral falx, the dural display in the center was intact. The 3 cases showed low signal intensity on T2-weighted image, obviously enhanced, significantly surrounding edema and finger-like protuberance but no invasion of the brain parenchyma or no sign of hyperplasia or sclerosis of the surrounding cranial bones. In conclusion, when we come across a disease that mimicking meningioma, especially when it manifests as the above radiological features, we should considered it might be a kind of proliferative disease of the meninges, such as RDD.

Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis.

RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells. Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.

FOXO3-Engineered Human ESC-Derived Vascular Cells Promote Vascular Protection and Regeneration.

FOXO3 is an evolutionarily conserved transcription factor that has been linked to longevity. Here we wanted to find out whether human vascular cells could be functionally enhanced by engineering them to express an activated form of FOXO3. This was accomplished via genome editing at two nucleotides in human embryonic stem cells, followed by differentiation into a range of vascular cell types. FOXO3-activated vascular cells exhibited delayed aging and increased resistance to oxidative injury compared with wild-type cells. When tested in a therapeutic context, FOXO3-enhanced vascular cells promoted vascular regeneration in a mouse model of ischemic injury and were resistant to tumorigenic transformation both in vitro and in vivo. Mechanistically, constitutively active FOXO3 conferred cytoprotection by transcriptionally downregulating CSRP1. Taken together, our findings provide mechanistic insights into FOXO3-mediated vascular protection and indicate that FOXO3 activation may provide a means for generating more effective and safe biomaterials for cell replacement therapies.

Systems-Based Interactome Analysis for Hematopoiesis Effect of Angelicae sinensis Radix: Regulated Network of Cell Proliferation towards Hemopoiesis.

OBJECTIVE: To explore the molecular-level mechanism on the hematopoiesis effect of Angelicae sinensis Radix (ASR) with systems-based interactome analysis. METHODS: This systems-based interactome analysis was designed to enforce the workflow of "ASR (herb)→compound→target protein→internal protein actions→ending regulated protein for hematopoiesis". This workflow was deployed with restrictions on regulated proteins expresses in bone marrow and anemia disease and futher validated with experiments. RESULTS: The hematopoiesis mechanism of ASR might be accomplished through regulating pathways of cell proliferation towards hemopoiesis with cross-talking agents of spleen tyrosine kinase (SYK), Janus kinase 2 (JAK2), and interleukin-2-inducible T-cell kinase (ITK). The hematopoietic function of ASR was also validated by colony-forming assay performed on mice bone marrow cells. As a result, SYK, JAK2 and ITK were activated. CONCLUSION: This study provides a new approach to systematically study and predict the therapeutic mechanism for ASR based on interactome analysis towards biological process with experimental validations.

The Beneficial Effect of Human Amnion Mesenchymal Cells in Inhibition of Inflammation and Induction of Neuronal Repair in EAE Mice.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Currently, there is still lack of curative treatment for MS. Mesenchymal stem cell- (MSC-) based therapy is recently the subject of intense interest in autoimmune diseases. Here, we investigated the therapeutic effect and potential mechanism of human amnion mesenchymal cells (hAMC) on inflammation and remyelination in experimental autoimmune encephalomyelitis (EAE) mice. C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. hAMC were injected intraperitoneal when EAE was successfully established. The results demonstrated that application of hAMC significantly ameliorated the disease severity and histopathological changes in EAE mice. The production of proinflammatory cytokines such as IFN-γ, TNF-α, IL-1ß, and IL-17A in the spleen and CNS was dramatically inhibited. Moreover, CD4+ T cells and CD8+ T cells in the CNS were also significantly decreased in EAE mice after hAMC treatment. In addition, hAMC treatment also promoted the production of neuron-repair factors (NGF, CNTF, and BDNF) in the CNS of EAE mice. In conclusion, these results indicated that hAMC could attenuate the inflammation and promote the remyelination in EAE mice, which might be a promising cell source for the therapy of MS.