Radiomics combined with clinical features in distinguishing non-calcifying tuberculosis granuloma and lung adenocarcinoma in small pulmonary nodules.

Aim: To evaluate the performance of radiomics models with the combination of clinical features in distinguishing non-calcified tuberculosis granuloma (TBG) and lung adenocarcinoma (LAC) in small pulmonary nodules. Methodology: We conducted a retrospective analysis of 280 patients with pulmonary nodules confirmed by surgical biopsy from January 2017 to December 2020. Samples were divided into LAC group (n = 143) and TBG group (n = 137). We assigned them to a training dataset (n = 196) and a testing dataset (n = 84). Clinical features including gender, age, smoking, CT appearance (size, location, spiculated sign, lobulated shape, vessel convergence, and pleural indentation) were extracted and included in the radiomics models. 3D slicer and FAE software were used to delineate the Region of Interest (ROI) and extract clinical features. The performance of the model was evaluated by the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC). Results: Based on the model selection, clinical features gender, and age in the LAC group and TBG group showed a significant difference in both datasets (P < 0.05). CT appearance lobulated shape was also significantly different in the LAC group and TBG group (Training dataset, P = 0.034; Testing dataset, P = 0.030). AUC were 0.8344 (95% CI [0.7712-0.8872]) and 0.751 (95% CI [0.6382-0.8531]) in training and testing dataset, respectively. Conclusion: With the capacity to detect differences between TBG and LAC based on their clinical features, radiomics models with a combined of clinical features may function as the potential non-invasive tool for distinguishing TBG and LAC in small pulmonary nodules.

Correction to Preparation of Engineered Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells with Ultrasonication for Skin Rejuvenation.

[This corrects the article DOI: 10.1021/acsomega.9b03561.].

Single high dose irradiation induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cells through the Ras/Raf/MEK/ERK pathways.

Purpose: Stereotactic body radiation therapy (SBRT) is emerging as a new noninvasive treatment in patients with primary liver carcinoma or liver-confined metastatic cancer. However, the radiobiological targets remain a subject of debate. Here, we investigated the potential biological effects of the radiation on the human hepatocellular carcinoma HepG2 cells.Materials and methods: Firstly, HepG2 cells were divided into three groups: control group, 3.5 Gy*8f group (L group), and 15 Gy*1f group (H group). After treatment, cell proliferation was examined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and plate colony formation assays. Cell cycle and apoptosis were assessed using propidium iodide and Hoechst 33258 staining, respectively. Furthermore, the mechanisms underlying irradiation-induced cell cycle arrest and cell apoptosis were investigated by Western blot assay.Results: Irradiation could effectively inhibit the proliferation and colony formation of HepG2 cells, and the single high dose irradiation showed stronger inhibitory effects. Irradiation-induced cell cycle arrest at G2/M phase in HepG2 cell, during which the expression levels of cyclin B1, CDK1, and p-CDK1 proteins were downregulated, whereas expression of p21 was upregulated in the irradiated HepG2 cells. After irradiation, typical morphological changes of apoptosis in HepG2 cells were observed; the number of cell apoptosis and the expression of apoptosis associated proteins were significantly increased in HepG2 cells by high dose irradiation compared with low dose irradiation. Additionally, compared with low dose irradiation, high dose irradiation significantly downregulated the phosphorylated proteins in the Ras/Raf/MEK/ERK signaling pathway.Conclusions: Our results suggest that irradiation applied in SBRT, particularly single high dose irradiation, mediates its anti-tumor effects by inducing cell cycle arrest and apoptosis via modulation of the Ras/Raf/MEK/ERK signaling pathway.

Anti-LDLR modified TPZ@Ce6-PEG complexes for tumor hypoxia-targeting chemo-/radio-/photodynamic/photothermal therapy.

Hypoxia, a state of low oxygen tension in solid tumors, is not only closely correlated with resistance to both radiotherapy and chemotherapy, but also associated with poor prognosis of tumors and regional lymph node status. Herein, based on the analysis of cell samples from tumor patients, low-density lipoprotein receptor (LDLR) was found to be overexpressed on the surface of hypoxic tumor cell membranes, and confirmed to be an effective hypoxia marker through specific binding with anti-LDLR antibody in solid tumors. In addition, using the special therapeutic microenvironment of hypoxia, tirapazamine (TPZ, which can be used as both a hypoxia-activated chemotherapy prodrug and radiotherapy sensitizer) was integrated with PEGylated photosensitizer chlorin e6 (Ce6-PEG) by self-assembly, and anti-LDLR was then modified on the surface to form tumor hypoxia-targeting multifunctional nanoparticles (CPTA). CPTA possesses a multimodal antitumor effect via a simultaneous photothermal therapy (PTT)/photodynamic therapy (PDT) effect generated by Ce6, and chemotherapy/radiotherapy actions sensitized by TPZ. It is noteworthy that tumor oxygen was consumed in the process of PDT and the hypoxia was subsequently exacerbated, which can greatly increase the TPZ-sensitized chemotherapy and lead to a synergistic antitumor effect. Both in vitro and in vivo experiments demonstrated that CPTA possesses an excellent therapeutic effect through PTT, PDT, and TPZ sensitized radiotherapy and chemotherapy. This hypoxic tumor targeting synergetic therapeutic strategy has great potential for future clinical transformation.

Ultrasound-guided percutaneous microwave ablation versus surgical resection for recurrent intrahepatic cholangiocarcinoma: intermediate-term results.

OBJECTIVE: The aims of this study were to compare the clinical outcomes between ultrasound-guided percutaneous microwave ablation (US-PMWA) and surgical resection (SR) in patients with recurrent intrahepatic cholangiocarcinoma (ICC) and to identify the prognostic factors associated with the two treatment methods. METHODS: This retrospective study was institutional review board approved. A total of 121 patients (102 men and 19 women) with 136 ICCs after hepatectomy from April 2011 to January 2017 were reviewed. Fifty-six patients underwent US-PMWA and 65 patients underwent SR. Survival, recurrence and liver function were compared between the two groups. Effect of changes in key parameters [i.e., overall survival (OS) and recurrence-free survival (RFS)] was statistically analyzed with the log-rank test. Univariate and multivariate analysis were performed on clinicopathological variables to identify factors affecting long-term outcome. RESULTS: The OS and RFS after MWA were comparable to that of SR (p = .405, and p = .589, respectively). Estimated 5-year OS rates were 23.7% after MWA and 21.8% after SR; for RFS, estimated 3-year RFS rates were 33.1% after MWA and 30.6% after SR. Major complication rates in SR group were higher than that in MWA (p < .001) (SR, 13.8% vs. MWA, 5.3%). Multivariate analysis showed tumor number (p = .012), ALBI grade (p = .007), and metastasis (p = .016), may become OS rate predictors. CONCLUSIONS: US-PMWA had comparable oncologic outcomes with SR and could be a safe and effective treatment for recurrent ICC after hepatectomy.

Preparation of Engineered Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells with Ultrasonication for Skin Rejuvenation.

Extracellular vesicles (EVs) are lipid-bilayer-enclosed vesicles of submicron size that are secreted by various cells. As mediators of intercellular communication, EVs can alter the physiological state of recipient cells by delivering encapsulated proteins and nucleic acids. Incontestably, growing evidence has shown important biological roles and the clinical relevance of EVs. The use of stem cell-derived EVs as a cell-free therapeutic modality for skin treatment has emerged as a promising application in dermatology. However, the moderate isolation efficiency of prevalent ultracentrifugation and low secretion rate make the massive low-cost production of EVs difficult. Here, we report development of engineered EVs (eEV) derived from human umbilical cord mesenchymal stem cells (hucMSCs) for skin treatment. Ultrasonication was used to shear intact hucMSCs for only 1 min, followed by regular centrifugation and filtration for producing nanoscale eEVs. This approach has ∼20-fold higher yield and ∼100-fold faster production than that of naturally secreted EVs (nsEV), while the production cost decreased to less than 10%. The eEVs have similar morphology, size distribution, and typical protein markers compared to nsEVs. Moreover, in vitro, both nsEVs and eEVs promote the proliferation and migration of dermal fibroblasts and increase in the expression of collagen, elastin, and fibronectin, whereas the matrix metalloproteinases-1 (MMP-1) and MMP-3 production can be significantly reduced. The wound-healing study in mice showed that both nsEVs and eEVs promote wound recovery in comparison with the controls. In sum, our results indicate that hucMSC-derived eEVs prepared by ultrasonication potentially can be used to increase skin extracellular matrix and enhance skin rejuvenation.

Aptamer-Conjugated Extracellular Nanovesicles for Targeted Drug Delivery.

Extracellular nanovesicles (ENV) released by many cells contain lipids, proteins, and nucleic acids that contribute to intercellular communication. ENVs have emerged as biomarkers and therapeutic targets but they have also been explored as drug delivery vehicles. However, for the latter application, clinical translation has been limited by low yield and inadequate targeting effects. ENV vectors with desired targeting properties can be produced from parental cells engineered to express membrane-bound targeting ligands, or they can be generated by fusion with targeting liposomes; however, neither approach has met clinical requirements. In this study, we demonstrate that mechanical extrusion of approximately 107 cells grafted with lipidated ligands can generate cancer cell-targeting ENV and can be prepared in approximately 1 hour. This rapid and economic approach could pave the way for clinical implementation in the future.Significance: A new and rapid method for production of drug-targeting nanovesicles has implications for cancer treatment by chimeric antigen receptor T cells and other therapies. Cancer Res; 78(3); 798-808. ©2017 AACR.

Fine Particulate Matter and Sulfur Dioxide Coexposures Induce Rat Lung Pathological Injury and Inflammatory Responses Via TLR4/p38/NF-κB Pathway.

Fine particulate matter (PM2.5) and sulfur dioxide (SO2) are 2 common air pollutants, but their toxicological effects of coexposure are still not fully clear. In this study, SO2 exposure (5.6 mg/m3) couldn't cause obvious inflammatory responses in rat lungs. The PM2.5 exposure (1.5 mg/kg body weight) increased inflammatory cell counts in bronchoalveolar lavage fluid (BALF) and some inflammation damage. Importantly, SO2 and PM2.5 (1.5, 6.0, and 24.0 mg/kg) coexposure induced pathological and ultrastructural damage and raised inflammatory cells in BALF compared with the control. Also, they significantly elevated the levels of pro-inflammatory cytokines, adhesion molecule, and nitric oxide (NO) and promoted the gene expression of nuclear factor kappa B (NF-κB), phosphorylated p38 (p-p38), and Toll-like receptor 4 (TLR4) in rat lungs treated with higher dose of PM2.5 (6.0 and 24.0 mg/kg) plus SO2 relative to the control or SO2 group, along with the decreased inhibitor of NF-κBα and increased inhibitor of NF-κB kinase ß expressions. The changes in the inflammatory markers in the presence of PM2.5 plus SO2 were not significant compared with the PM2.5 group. The results indicated that inflammatory injury and pathological and ultrastructural damage in rat lungs exposed to PM2.5 plus SO2 were involved in TLR4/p38/NF-κB pathway activation accompanied by oversecretion of pro-inflammatory cytokine, adhesion molecule, and NO. It provides more useful evidence to understand the possible toxicological mechanism that PM2.5 and SO2 copollution exacerbate lung disease.

Synthesis of novel galactose functionalized gold nanoparticles and its radiosensitizing mechanism.

BACKGROUND: Biocompatible gold nanoparticles (GNPs) are potentially practical and efficient agents in cancer radiotherapy applications. In this study, we demonstrated that GNPs can significantly modulate irradiation response of hepatocellular carcinoma cells in vitro and investigated the underlying mechanisms. We co-grafted galactose (GAL) targeting hepatocyte specific asialoglycoprotein receptor and Polyethylene Glycol (PEG) onto GNPs surfaces to increase GNPs targeting specificity and stability. RESULTS: This novel GAL-PEG-GNPs and bare GNPs show similar appearance and cytotoxicity profiles, while more GAL-PEG-GNPs can be effectively uptaken and could enhance cancer cell killing. CONCLUSION: GAL-PEG-GNPs have better radiosensitization to HepG2. The sensitization mechanism of GAL-PEG-GNPs is related to the apoptotic gene process activated by generation of a large amount of free radicals induced by GNPs.

The role and mechanisms of nanoparticles to enhance radiosensitivity in hepatocellular cell.

OBJECTIVE: This work aimed to investigate whether nanosilver and nanogold could modulate irradiation response of hepatocellular carcinoma cells (HepG2) in vitro and the underlying mechanisms. METHODS: Cell viability of the HCC cell lines (HepG2) was examined by the 3-(4,5-dimethylthiazol-yl)-5(3-carboxymethoxyphenyl)-2H-terazolium (MTT) assays. Clonogenic growth assays of HepG2 were determined by colony formation assays. Cell apoptosis and cell cycle distribution changes were analyzed by flow cytometry (FCM). DNA damage was assessed by monitoring γ-H2AX foci in irradiated cells with immunofluorescence microscopy. The expression of regulating molecules was analyzed by using western blotting for Bax, caspase-3, and Bcl-2, and the content of catalase (Catalase CAT), superoxide dismutase (SOD), glutathione (Total of GSH) were determined. RESULTS: Our results show that nanosilver and nanogold reduced the viability of HepG2 cells. Nanosilver and nanogold significantly enhanced the radiosensitivity of HepG2 cells. Obtained by Dq, the SER of 1/5 silver+irradiation group, 1/10 silver+irradiation group, 1/5 gold+irradiation group, 1/10 gold+irradiation group, respectively, were 1.977, 1.823, 1.762, 1.597. Immunofluorescence assays showed that there was 32.2±1.2% of irradiated HepG2. And 48.1±0.1% of 1/5 IC50 nanogold+6Gy group, 43.7±0.8% of 1/10 IC50 nanogold+6Gy group, 48.8±1.2% of 1/5 IC50 nanosilver+6Gy group,41.5±1.5% of 1/10 IC50 nanosilver+6Gy group. Nanosilver and nanogold could upregulate the expression of Bax, caspase-3 and downregulate the expression of Bcl-2. Moreover, the content of CAT, SOD and Total GSH were significantly reduced. CONCLUSION: Nanosilver and nanogold could enhance the radiationsensitivity of hepatocellular carcinoma cells. Elevated DNA damage levels and apoptosis may be responsible for this.

Nanoparticle surface and nanocore properties determine the effect on radiosensitivity of cancer cells upon ionizing radiation treatment.

For correctly selected and reasonably designed nanoscale radiosensitizers, it is necessary to investigate whether nanoparticle (NPs) coatings, nanocores (we defined it as naked NPs) or other precursors cause cellular response upon ionizing radiation (IR) at first. In this paper, we mainly discussed the effect of nanoparticle surface and nanocore properties on anti-proliferation of cancer cells upon IR treatment. We examined different kinds of modifiers of the same nanocores, as well as distinct nanocores with the same surface. We obtained some different results and demonstrated silver NPs would have significant radiosensitization on cancer cells in virtue of the nanocore property.

An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.

Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment.

Detection of single tumor cell resistance with aptamer biochip.

In this study, a novel RNA aptamer biochip was developed for tumor cell capture and detection of single cell resistance. This biochip consists of a polydimethylsiloxane (PDMS) cover containing a channel for introducing cells and sustaining their activity and microelectrode matrix on a silicon dioxide layer. Epidermal growth factor receptor (EGFR) aptamers which specifically identify and isolate tumor cells were attached in the gap between two electrodes. After cell biochip incubation, surplus tumor cells were removed, and those dwelling on the intervals were further analyzed. When resistance measurement was completed, these cells were flushed away via controlled flow acceleration, and were collected for further analysis. The results demonstrate the convenience and efficiency of using anti-EGFR aptamer biochips for the detection of single cell resistance. This novel aptamer biochip may be used for the isolation of circulating tumor cells from peripheral blood and cell counting, or be assembled with other lab-on-a-chip components for follow-up gene and protein analysis.

A novel magnetic nanoparticle hyperthermia combined with ACMF-dependant drug release by DAMMs injection in VX-2 liver tumors.

In this paper, we investigated the feasibility and effect of a novel combination therapy of magnetic nanoparticles (MNPs) hyperthermia with anticancer drugs for solid malignancies using doxorubicin-loaded alginate-templated magnetic microcapsules (DAMMs) in an animal liver cancer model. Firstly, DAMMs containing 18 nm gamma-Fe2O3 with doxorubicin (Dox) were synthesized and characterized. Then, the particular behavior of Dox release under external alternating current magnetic filed (ACMF) was tested in vitro. Moreover, to obtain accurate thermotherapy, the dose of DAMMs and temperature rise were computed by Hyperthermia treatment plan (HTP) and a fiber optic temperature sensor (FOTS) was used to monitor the temperature rise during treatments on VX-2 liver tumor-bearing rabbits. Furthermore, the therapeutic effect was studied by histopathological examinations and animal survival. The results showed that ACMF can induce Dox fast release during the treatment and the high MNPs content of DMMAs guaranteed the temperature rise for hyperthermia in tumors. The rabbits bearing VX-2 tumors in the magnetic hyperthermia using DMMAs group gained the most tumor necrosis and survival time. It was indicated that DAMMs-based magnetic hyperthermia could be a feasible and effective remedy which could be targeted at liver tumors by dual effects of hyperthermia and chemotherapy.

Expression of p16 in non-small cell lung cancer and its prognostic significance: a meta-analysis of published literatures.

The prognostic value of p16 for survival of patients with non-small cell lung cancer (NSCLC) remains controversial. we performed a meta-analysis of the literatures in order to clarify its impact. Published studies in English were identified using an electronic search in order to aggregate the available survival results. To be eligible, a study had to have dealt with p16 protein assessment in NSCLC patients on the primary site and have reported survival data according to p16 expression. Twenty trials, comprising 1995 patients, provided sufficient information for the meta-analysis. Seventeen assessed any non-small cell lung cancer subtype, three assessed adenocarcinoma only. Eight identified high p16 expression as a favourable prognostic factor and one linked it with poor prognosis, Eleven trials were not significant. The overall combined hazard ratio (HR) calculated using a random-effects model suggested that high p16 expression has a favourable impact on survival in all NSCLC [0.69, 95% CI: 0.59-0.81]; The studies were categorized according to histology, disease stage and laboratory technique. The aggregated survival data showed a poor survival prognosis in squamous cell cancer with lower p16 expression [0.34, 95% CI: 0.13-0.91]. The adenocarcinoma subgroup had an HR of 0.91 [95% CI 0.76-1.10] without statistical significance. In early stage NSCLC (I-II), the aggregated HR was 0.42 [95% CI: 0.28-0.63], showing a worse survival for NSCLC with abnormal p16 expression; Results were significant with the HR of 0.61 [95% CI: 0.45-0.82] for five studies detecting p16 by immunohistochemistry with antibody clone G175-405. In conclusion, our meta-analysis shows that the p16 expression status is an independent prognostic factor in NSCLC, and this tendency is also found in the subgroups of squamous cell lung cancer and early stage NSCLC (I-II), but not in lung adenocarcinoma.

(18)F-DG PET/CT in detection of recurrence and metastasis of colorectal cancer.

AIM: To evaluate the value of (18)F-DG PET/CT in detecting recurrence and/or metastasis of colorectal cancer (CRC). METHODS: Combined visual analysis with semiquantitative analysis, the (18)F-DG PET/CT whole-body imaging results and the corresponding clinical data of 68 postoperative CRC patients including 48 male and 20 female with average age of 58.1 were analyzed retrospectively. RESULTS: Recurrence and/or metastasis were confirmed in 56 patients in the clinical follow-up after the PET/CT imaging. The sensitivity of PET/CT diagnosis of CRC recurrence and/or metastasis was 94.6%, and the specificity was 83.3%. The positive predictive value (PPV) was 96.4% and the negative predictive value (NPV) was 76.9%. PET/CT imaging detected one or more occult malignant lesions in 8 cases where abdominal/pelvic CT and/or ultrasonography showed negative findings, and also detected more lesions than CT or ultrasonography did in 30.4% (17/56) cases. Recurrence and/or metastasis was detected in 91.7% (22/24) cases with elevated serum CEA levels by (18)F-DG PET/CT imaging. CONCLUSION: (18)F-DG PET/CT could detect the recurrence and/or metastasis of CRC with high sensitivity and specificity.