Radiation-Induced Endothelial Ferroptosis Accelerates Atherosclerosis via the DDHD2-Mediated Nrf2/GPX4 Pathway.

This study sought to explore potential roles of endothelial ferroptosis in radiation-associated atherosclerosis (RAA) and molecular mechanisms behind this phenomenon. Here, an in vivo RAA mouse model was used and treated with ferroptosis inhibitors. We found that the RAA group had a higher plaque burden and a reduction in endothelial cells with increased lipid peroxidation compared to the control group, while ameliorated by liproxstatin-1. In vitro experiments further confirmed that radiation induced the occurrence of ferroptosis in human artery endothelial cells (HAECs). Then, proteomics analysis of HAECs identified domain-containing protein 2 (DDHD2) as a co-differentially expressed protein, which was enriched in the lipid metabolism pathway. In addition, the level of lipid peroxidation was elevated in DDHD2-knockdown HAECs. Mechanistically, a significant decrease in the protein and mRNA expression of glutathione peroxidase 4 (GPX4) was observed in HAECs following DDHD2 knockdown. Co-immunoprecipitation assays indicated a potential interaction between DDHD2 and nuclear factor erythroid 2-related factor 2 (Nrf2). The downregulation of Nrf2 protein was also detected in DDHD2-knockdown HAECs. In conclusion, our findings suggest that radiation-induced endothelial ferroptosis accelerates atherosclerosis, and DDHD2 is a potential regulatory protein in radiation-induced endothelial ferroptosis through the Nrf2/GPX4 pathway.

AS-NeSt: A Novel 3D Deep Learning Model for Radiation Therapy Dose Distribution Prediction in Esophageal Cancer Treatment With Multiple Prescriptions.

PURPOSE: Implementing artificial intelligence technologies allows for the accurate prediction of radiation therapy dose distributions, enhancing treatment planning efficiency. However, esophageal cancers present unique challenges because of tumor complexity and diverse prescription types. Additionally, limited data availability hampers the effectiveness of existing artificial intelligence models. This study developed a deep learning model, trained on a diverse data set of esophageal cancer prescriptions, to improve dose prediction accuracy. METHODS AND MATERIALS: We retrospectively collected data from 530 patients with esophageal cancer, including single-target and simultaneous integrated boost prescriptions, for model building. The proposed Asymmetric ResNeSt (AS-NeSt) model features novel 3-dimensional (3D) ResNeSt blocks and an asymmetrical architecture. We constructed a loss function targeting global and local doses and validated the model's performance against existing alternatives. Model-assisted experiments were used to validate its clinical benefits. RESULTS: The AS-NeSt model maintained an absolute prediction error below 5% for each dosimetric metric. The average Dice similarity coefficient for isodose volumes was 0.93. The model achieved an average relative prediction error of 2.02%, statistically lower than Hierarchically Densely Connected U-net (4.17%), DoseNet (2.35%), and Densely Connected Network (3.65%). It also demonstrated significantly fewer parameters and shorter prediction times. Clinically, the AS-NeSt model raised physicians' ability to accurately preassess appropriate treatment methods before planning from 95.24% to 100%, reduced planning time by over 61% for junior dosimetrists and 52% for senior dosimetrists, and decreased both inter- and intra-dosimetrist discrepancies by more than 50%. CONCLUSIONS: The AS-NeSt model, developed with innovative 3D ResNeSt blocks and an asymmetrical encoder-decoder structure, has been validated using clinical esophageal cancer patient data. It accurately predicts 3D dose distributions for various prescriptions, including simultaneous integrated boost, showing potential to improve the management of esophageal cancer treatment in a clinical setting.

A planning strategy may reduce the risk of heart diseases and radiation pneumonia: Avoiding the specific heart substructures.

BACKGROUND: Dose to heart substructures is a better predictor for major adverse cardiac events (MACE) than mean heart dose (MHD). We propose an avoidance planning strategy for important cardiac substructures. MATERIAL AND METHODS: Two plans, clinical and cardiac substructure-avoidance plan, were generated for twenty patients. Five dose-sensitive substructures, including left ventricle, pulmonary artery, left anterior descending branch, left circumflex branch and the coronary artery were chosen. The avoidance plan aims to meet the target criteria and organ-at-risk (OARs) constraints while minimizing the dose parameters of the above five substructures. The dosimetric assessments included the mean dose and the maximum dose of cardiac substructures and several volume parameters. In addition, we also evaluated the relative risk of coronary artery disease (CAD), chronic heart failure (CHF), and radiation pneumonia (RP). RESULTS: Pearson correlation coefficient and R2 value of linear regression fitting demonstrated that MHD had poor prediction ability for the mean dose of the cardiac substructures. Compared to clinical plans, an avoidance plan is able to statistically significantly decrease the dose to key substructures. Meanwhile, the dose to OARs and the coverage of the target are comparable in the two plans. In addition, it can be observed that the avoidance plan statistically decreases the relative risks of CAD, CHF, and RP. CONCLUSIONS: The substructure-avoidance planning strategy that incorporates the cardiac substructures into optimization process, can protect the important heart substructures, such as left ventricle, left anterior descending branch and pulmonary artery, achieving the substantive sparing of dose-sensitive cardiac structures, and have the potential to decrease the relative risks of CAD, CHF, and RP.

Blood flow characterization in nailfold capillary using optical flow-assisted two-stream network and spatial-temporal image.

The blood flow velocity in the nailfold capillary is an important indicator of the status of microcirculation. The conventional manual processing method is both laborious and prone to human artifacts. A feasible way to solve this problem is to use machine learning to assist in image processing and diagnosis. Inspired by the Two-Stream Convolutional Networks, this study proposes an optical flow-assisted two-stream network to segment nailfold blood vessels. Firstly, we use U-Net as the spatial flow network and the dense optical flow as the temporal stream. The results show that the optical flow information can effectively improve the integrity of the segmentation of blood vessels. The overall accuracy is 94.01 %, the Dice score is 0.8099, the IoU score is 0.6806, and the VOE score is 0.3194. Secondly, The flow velocity of the segmented blood vessel is determined by constructing the spatial-temporal (ST) image. The blood flow velocity evaluated is consistent with the typical blood flow speed reported. This study proposes a novel two-stream network for blood vessel segmentation of nailfold capillary images. Combined with ST image and line detection method, it provides an effective workflow for measuring the blood flow velocity of nailfold capillaries.

Insights into prognosis and immune infiltration of cuproptosis-related genes in breast cancer.

Introduction: Breast cancer (BC) has been ranking first in incidence and the leading cause of death among female cancers worldwide based on the latest report. Regulated cell death (RCD) plays a significant role in tumor initiation and provides an important target of cancer treatment. Cuproptosis, a novel form of RCD, is ignited by mitochondrial stress, particularly the lipoylated mitochondrial enzymes aggregation. However, the role of cuproptosis-related genes (CRGs) in tumor generation and progression remains unclear. Methods: In this study, the mRNA expression data of CRGs in BC and normal breast tissue were extracted from TCGA database, and protein expression patterns of these CRGs were analyzed using UALCAN. The prognostic values of CRGs in BC were explored by using KaplanMeier plotter and Cox regression analysis. Genetic mutations profiles were evaluated using the cBioPortal database. Meanwhile, we utilized CIBERSORT and TIMER 2.0 database to perform the correlation analysis between CRGs and immune cell infiltration. Results: Our results indicated that CRGs expression is significantly different in BC and normal breast tissues. Then we found that upregulated PDHA1 expression was associated with worse endpoint of BC. Moreover, we also performed immune infiltration analysis of CRGs, and demonstrated that PDHA1 expression was closely related to the infiltration levels of CD4+ memory T cell, macrophage M0 and M1 cell and mast cell in BC. Conclusions: Our results demonstrated the prognostic and immunogenetic values of PDHA1 in BC. Therefore, PDHA1 can be an independent prognostic biomarker and potential target for immunotherapy of BC.

Pan-cancer analysis of FBXW family with potential implications in prognosis and immune infiltration.

Background: The F-box and WD repeat domain containing (FBXW) family of SCF E3 complexes has 10 members that are responsible for ubiquitination and degradation of substrate proteins involved in cell cycle regulation and tumorigenesis. Among them, FBXW1 (also called b-TrCP1/BTRC) and FBXW7 are the central proteins in this category. However, there is still a lack of elaborate exploration of the contribution of FBXW family members, especially FBXW1 and FBXW7, in various tumor types. Methods: In this present study, we preliminarily analyzed the genetic structure characteristics of the FBXW family, and systematically investigated their expression patterns and clinical correlations based on the TCGA pan-cancer data. Survival analysis of FBXWs was also conducted through the Kaplan-Meier method. In addition, we assessed their immune infiltration level through immune-related algorithms like Timer and xCell. Results: There were obvious genetic heterogeneity and different clinical traits in FBXW family members. Moreover, we found that FBXW family genes may be useful in predicting prognosis and therapeutic efficacy using survival analysis. In addition, the immune infiltration of FBXW family was also clearly illustrated in this study. The results showed these genes were closely involved in immune components such as immune score, immune subtypes, tumor-infiltrating lymphocytes and immune checkpoints. Notedly, FBXW1 as an oncogene and FBXW7 as a tumor suppressor gene also show opposite relationships on immune cells. Conclusion: Our results provided valuable strategies to guide the therapeutic orientation concerning the role of FBXW family genes in cancer.

Photodynamic therapy reduces metastasis of breast cancer by minimizing circulating tumor cells.

Cancer metastasis after traditional surgery introduces a high barrier to therapy efficacy. Photodynamic therapy (PDT) for cancer is based on a photochemical process of photosensitizers that concentrate in tumors and release oxidant species under light excitation to destroy cells. Compared with traditional surgery, PDT provides minimal invasion and targeted therapy. In this in vivo study, we monitor the real-time and long-term dynamics of circulating tumor cells (CTCs) after a single round of PDT and after surgical resection in a breast cancer animal model. The CTC level is low after PDT treatment, and the recurrence of the primary tumor is postponed in the PDT group compared with the resection group. We find that metastasis is correlated with the CTC level, and the PDT-treated mice show no metastasis in the lung or liver. Our results suggest PDT can effectively reduce metastasis by minimizing CTCs after treatment and is a great technology for breast cancer therapy.

Real-time monitoring of single circulating tumor cells with a fluorescently labeled deoxy-glucose by in vivo flow cytometry.

Circulating tumor cells (CTCs) play an essential role in metastasis and serve as an important prognostic biomarker. The technology of CTC labeling and detection in vivo can greatly improve the research of cancer metastasis and therapy. However, there is no in vivo technology to detect CTCs in clinic. In this study, we demonstrate that 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG), a 2-deoxy-glucose analog, can work in vivo to indicate CTCs and metastases fluorescently by direct intravenous injection. During the development of an implanted tumor in mice, the spontaneous CTCs released from the primary tumor into blood vessels can be labeled by 2-NBDG due to the abnormal metabolism of CTCs. The green fluorescence of 2-NBDG from CTCs is then noninvasively detected by an in vivo flow cytometry system. Due to the high uptake of glucose by tumor cells, the CTCs in mice can maintain a high 2-NBDG level and thus be distinguished by 2-NBDG fluorescence in vivo efficiently, enabling tumor detection in vivo like positron emission tomography (PET) but at the single-cell resolution. Our results suggest 2-NBDG, a glucose analog with high biosafety, holds promising potential in clinical applications, similar to the widely-used contrast medium 2-F18 -fluorodeoxyglucose in PET.

Corrigendum: EXOSC5 as a Novel Prognostic Marker Promotes Proliferation of Colorectal Cancer via Activating the ERK and AKT Pathways.

[This corrects the article DOI: 10.3389/fonc.2019.00643.].

The Plasma Levels and Polymorphisms of Vitronectin Predict Radiation Pneumonitis in Patients With Lung Cancer Receiving Thoracic Radiation Therapy.

PURPOSE: Our previous findings have identified vitronectin (VTN) as a potential biomarker for radiation pneumonitis (RP) through proteomics and molecular mechanism studies. In a recent study, we further explored associations of plasma level and single nucleotide polymorphisms of VTN with the risk of RP in patients with lung cancer receiving radiation therapy. METHODS AND MATERIALS: A total of 165 patients with lung cancer were prospectively enrolled with detection of VTN concentration before radiation therapy. VTN reference single nucleotide polymorphisms, rs704 and rs2227721, were genotyped by Taqman probe method. Cox proportional hazard models were performed to identify clinical variables and genotypes associated with the risk of RP on univariate and multivariate analyses, and t tests and analysis of variance were conducted to evaluate the expression level of VTN. RESULTS: The baseline secretion level of VTN in patients with grade ≥3 RP was significantly higher than that in grade <3 RP patients (P < .0001), and elevated levels were observed in patients having the AA genotype compared with GA/GG genotypes of rs704. The VTN rs704 GA/GG and rs2227721 AA/AC genotypes had a significantly lower risk of RP (hazard ratio [HR], 0.448, P = .005; HR, 0.419, P = .008, respectively). In addition, combining cut-off values of mean lung dose (MLD) and VTN plasma level, grade ≥3 RP risk groupings were as follows: high risk: MLD ≥12 Gy and VTN level ≥132 µg/mL (RP rate, 10 of 16 patients, 62.5%); intermediate risk: MLD ≥12 Gy and VTN level <132 µg/mL or MLD <12 Gy and VTN level ≥132 µg/mL (8 of 70 patients, 11.4%); and low risk: MLD <12 Gy and VTN level <132 µg/mL (1 of 79 patients, 1.3%) (P < .0001). CONCLUSIONS: Among patients receiving radiation therapy, relatively high plasma levels of VTN before radiation therapy were associated with the higher incidence of RP, and VTN rs704 and rs2227721 each had a significant effect on predicting RP risk. Combining VTN concentration with MLD appeared to facilitate stratification of patients with lung cancer who received radiation therapy into low-, intermediate-, and high-risk RP groups. This study indicated that VTN may serve as a blood biomarker for susceptibility to RP in patients with lung cancer.

Treatment of stage III non-small cell lung cancer in the era of immunotherapy: pathological complete response to neoadjuvant pembrolizumab and chemotherapy.

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. The expected 5-year survival of stage III NSCLC ranges from 13% to 36% for stage III. Due to the heterogeneity and poor efficacy of stage III patients, there is great controversy on how to optimize the therapy strategy. Immunotherapy is providing better clinical efficacy to more NSCLC patients, and is rapidly extending its range of care from advanced stage to locally advanced stage and early stage NSCLC. Due to the patient's strong treatment intention, drug availability, and a few encouraging results from clinical trials (NADIM, NCT02716038, etc.), the authors observed a case of stage III NSCLC that achieved complete remission after receiving neoadjuvant chemotherapy combined with immunotherapy. In view of such a satisfactory result in neoadjuvant therapy, this article discusses how comprehensive treatment for stage III NSCLC patients may be conducted and the manner in which various therapeutic techniques can be mastered in the era of immunotherapy. Immunotherapy has opened the exploratory space for finding resolutions to numerous challenges of treating stage III NSCLC. Further clinical studies and exploration of personalized treatment, guided by imaging data, and clinical and pathological biomarkers are imperative for the benefit of these patients.

WITHDRAWN: Circular RNA circUBA1 promotes gastric cancer proliferation and metastasis by acting as a competitive endogenous RNA through sponging miR-375 and regulating TEAD4.

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EXOSC5 as a Novel Prognostic Marker Promotes Proliferation of Colorectal Cancer via Activating the ERK and AKT Pathways.

Background and Objective: Exosome component 5 (EXOSC5) is a novel cancer-related gene that is aberrantly expressed in various malignances. However, the molecular mechanism and biological role of EXOSC5 have not been explored in colorectal cancer (CRC). In this study, we investigated the functions and mechanisms by which EXOSC5 promotes the progression of CRC. Methods: EXOSC5 expressions in CRC cell lines and paired CRC and adjacent normal tissues were measured via quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry (IHC). In vitro experiments including colony formation, Cell Counting Kit-8 (CCK-8), and flow cytometry and in vivo tumorigenesis assay were performed to explore the effects of EXOSC5 on growth of CRC. The impacts of EXOSC5 on ERK and Akt signaling pathways were measured by Western blot. Results: The mRNA and protein expression levels of EXOSC5 were up-regulated in CRC as compared to adjacent normal tissues. IHC analysis indicated that high EXOSC5 level was positively associated with poor prognosis. EXOSC5 overexpression facilitated the growth of CRC cells, while EXOSC5 knockdown led to decreased proliferation, G1/S phase transition arrest. The oncogenic functions of EXOSC5 were associated with activation of the ERK and Akt pathways in CRC. Conclusion: EXOSC5 is overexpressed in CRC and promotes CRC growth partly through activation of ERK and Akt signaling pathways. Accordingly, EXOSC5 may be a novel oncogene, and acts as a therapeutic target, or prognostic factor for CRC.

Carboxypeptidase A4 promotes cell growth via activating STAT3 and ERK signaling pathways and predicts a poor prognosis in colorectal cancer.

Carboxypeptidase A4 (CPA4) is a novel cancer-related gene that is aberrantly expressed in various malignant tumors. However, the roles and mechanisms of CPA4 have not been explored in colorectal cancer (CRC). In this study, we investigated the functions and mechanisms by which CPA4 promotes CRC progression. Quantitative real-time PCR (qRT-PCR) and western blot showed that CPA4 mRNA and CPA4 protein levels were up-regulated in CRC compared to levels in adjacent normal tissue. Immunohistochemistry (IHC) results indicating high CPA4 levels were positively associated with poor prognoses. In addition, Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and transwell assays demonstrated that CPA4 overexpression facilitated the growth of CRC cells, whereas CPA4 knockdown resulted in decreased proliferation, G1/S phase transition arrest, and apoptosis. Subcutaneous tumorigenesis was performed in nude mice to confirm the tumor-promoting effects of CPA4 in vivo. Western blot revealed that activation of the STAT3 and ERK pathways is one of the oncogenic functions of CPA4 in CRC. Accordingly, CPA4 promotes CRC cell growth via activating the STAT3 and ERK pathways and may be a prognostic factor or therapeutic target for CRC.

Identification and development of long non-coding RNA-associated regulatory network in colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-associated death globally. Long non-coding RNAs (lncRNAs) have been identified as micro RNA (miRNA) sponges in a competing endogenous RNA (ceRNA) network and are involved in the regulation of mRNA expression. This study aims to construct a lncRNA-associated ceRNA network and investigate the prognostic biomarkers in CRC. A total of 38 differentially expressed (DE) lncRNAs, 23 DEmiRNAs and 27 DEmRNAs were identified by analysing the expression profiles of CRC obtained from The Cancer Genome Atlas (TCGA). These RNAs were chosen to develop a ceRNA regulatory network of CRC, which comprised 125 edges. Survival analysis showed that four lncRNAs, six miRNAs and five mRNAs were significantly associated with overall survival. A potential regulatory axis of ADAMTS9-AS2/miR-32/PHLPP2 was identified from the network. Experimental validation was performed using clinical samples by quantitative real-time PCR (qRT-PCR), which showed that expression of the genes in the axis was associated with clinicopathological features and the correlation among them perfectly conformed to the 'ceRNA theory'. Overexpression of ADAMTS9-AS2 in colon cancer cell lines significantly inhibited the miR-32 expression and promoted PHLPP2 expression, while ADAMTS9-AS2 knockdown had the opposite effects. The constructed novel ceRNA network may provide a comprehensive understanding of the mechanisms of CRC carcinogenesis. The ADAMTS9-AS2/miR-32/PHLPP2 regulatory axis may serve as a potential therapeutic target for CRC.

Visualizing Interactions of Circulating Tumor Cell and Dendritic Cell in the Blood Circulation Using In Vivo Imaging Flow Cytometry.

OBJECTIVE: Visualizing cell interactions in blood circulation is of great importance in studies of anticancer immunotherapy or drugs. However, the lack of a suitable imaging system hampers progress in this field. METHODS: In this work, we built a dual-channel in vivo imaging flow cytometer to visualize the interactions of circulating tumor cells (CTCs) and dendritic cells (DCs) simultaneously in the bloodstream. Two artificial neural networks were trained to identify blood vessels and cells in the acquired images. RESULTS AND CONCLUSION: Using this technique, single CTCs and CTC clusters were readily distinguished by their morphology. Interactions of CTCs and DCs were identified, while their moving velocities were analyzed. The CTC-DC clusters moved at a slower velocity than that of single CTCs or DCs. This may provide new insights into tumor metastasis and blood rheology. SIGNIFICANCE: This in vivo imaging flow cytometry system holds great potential for assessing the efficiency of targeting CTCs with anticancer immune cells or drugs.

Monitoring circulating prostate cancer cells by in vivo flow cytometry assesses androgen deprivation therapy on metastasis.

It remains controversial whether surgical castration prolongs survival rate and improves therapy prospects in patients suffering from prostate cancer. We used PC3 cell line to establish prostate tumor models. In vivo flow cytometry and ultrasonic imaging were used to monitor the process of prostate cancer growth, development and metastasis. We found out that the number of circulating tumor cells (CTCs) in orthotopic tumor model was higher than that in subcutaneous tumor model. The CTC number in orthotopic tumor model was due to burst growth, while CTC number in subcutaneous tumor model showed a gradual increase with tumor size. After androgen deprivation therapy (ADT) through testicular extraction, we constructed GFP-PC3 subcutaneous tumor models and orthotopic tumor models. We found dramatically decreased CTC number, relieved symptoms caused by the tumor, and significantly prolonged survival time after testicular extraction in orthotopically transplanted prostate tumor model, while the carcinogenesis process and metastases were little influenced by ADT in subcutaneous tumor model. ADT treatment can restrict tumor growth, decrease the CTC number significantly and inhibit distant invasion through inhibition of tumor proliferation and tumor angiogenesis in orthotopical prostate tumor model. © 2018 International Society for Advancement of Cytometry.

Protective effects of cyclic helix B peptide on aristolochic acid induced acute kidney injury.

BACKGROUND: Aristolochic acid (AA) injuries remain a serious condition associated with acute renal dysfunction. Herein, the effect and mechanism of a novel tissue protective peptide, cyclic helical B-peptide (CHBP) derived from erythropoietin, were investigated in a mice model. METHODS: Mice were randomly divided into four groups, receiving the following treatments (1: saline; 2: AA 10mg/kg; 3: AA 10mg/kg +CHBP 4nmol/kg; 4: AA 10mg/kg +CHBP 8nmol/kg). RESULTS: Blood urea nitrogen and serum creatinine was increased by AA but decreased by CHBP in a dose-dependent fashion. CHBP also significantly improved renal tubular injury and inflammatory infiltration, which was gradually increased by AA. Apoptotic cells, infiltrating inflammatory cells, and active caspase-3+ cells were greatly reduced by CHBP. In addition, CHBP inhibited caspase-3, 9 and improved bcl-2, bcl-xl protein expression in vivo. CONCLUSION: Taken together, we demonstrated, for the first time, that CHBP effectively improved renal function and tissue damage caused by AA, which maybe through reducing caspase-3 activation, apoptosis, and inflammation.

MicroRNA-191 acts as a tumor promoter by modulating the TET1-p53 pathway in intrahepatic cholangiocarcinoma.

Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003). CONCLUSION: Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. (Hepatology 2017;66:136-151).

Systemically Infused Mesenchymal Stem Cells Show Different Homing Profiles in Healthy and Tumor Mouse Models.

Bone marrow-derived mesenchymal stem cells (MSCs) can localize in injured, inflamed, and cancerous tissues after systemic infusion. However, the dynamic homing profile of MSCs in the peripheral blood is not well characterized. Here, using in vivo flow cytometry to noninvasively monitor the dynamics of fluorescence-labeled cells, we found different clearance kinetics of systemically infused MSCs between healthy and tumor mouse models. The circulation times of MSCs in healthy mice and mice with subcutaneous tumors, orthotopically transplanted liver tumors, or metastatic lung tumors were 30, 24, 18, and 12 hours, respectively, suggesting that MSCs actively home to tumor environments. MSCs infiltrated into hepatocellular carcinoma (HCC) sites and preferentially engrafted to micrometastatic regions both in vivo and in vitro. The expression of epidermal growth factor, CXCL9, CCL25, and matrix metalloproteinases-9 by HCC cells differed between primary tumor sites and metastatic regions. By characterizing the homing profiles of systemically perfused MSCs under physiological and cancerous conditions, these findings increase our understanding of the migration of MSCs from the circulation to tumor sites and constitute a basis for developing MSC-based anti-cancer therapeutic strategies. Stem Cells Translational Medicine 2017;6:1120-1131.