Selenide Heterostructure Nanosheets with Efficient Near-Infrared Photothermal Conversion for Therapy.

Photothermal therapy has been regarded as one of promising ways for tumor treatment. However, nanoagents with highly efficient thermal conversion and good bio-compatibility are still needed to be developed in biomedicine. In this work, we prepared two-dimensional heterostructures with bismuth selenide and tungsten selenide nanosheets as photothermal nanoagents. Near-infrared photothermal conversion of selenide heterostructure nanosheets can reach up to 40.75% under 808 nm excitation. It is known that selenium is a critical element to human health. More importantly, our experiments with mice show that the heterostructure nanosheets have low toxicity and high biocompatibility both in vitro and in vivo. The nanoagents based on heterostructures can effectively realize photothermal tumor ablation. It is suggested that the developed selenide nanosheets have great potential application in cancer therapy.

The new fast kilovoltage-switching dual-energy computed tomography for measuring bone mineral density.

Background: The update in technology may impact the accuracy in measuring bone mineral density (BMD). However, the application of the new fast kilovoltage (kV)-switching dual-energy computed tomography (DECT) for BMD measurement has not yet been reported. This study aimed to examine the accuracy and precision of the new fast kV-switching DECT in measuring BMD and to evaluate its applicability in clinical BMD measurement. Methods: Forty sets of the new fast kV-switching DECT scans and one quantitative computed tomography (QCT) scan were performed on the European Spine Phantom. Their relative errors and relative standard deviations were compared. A retrospective analysis was performed on patients who underwent chest plain DECT and abdominal monoenergetic plain CT at the same time. The relationship between hydroxyapatite-water and hydroxyapatite-fat measured using DECT and BMD measured using QCT was analyzed by multivariate regression analysis. Results: The relative errors of the new fast kV-switching DECT with low tube speeds (0.8 and 1.0 s/r) were all less than 6% and were less than those of QCT, except for those at 515 mA. The relative standard deviation values with high tube rotation speeds (0.5 and 0.6 s/r) were higher than those with low tube speeds (0.8 and 1.0 s/r) under most tube current conditions. The new fast kV-switching DECT-derived BMD values corrected by multiple linear regression (predicted hydroxyapatite) were significantly positively correlated with the QCT-based BMD values (R2=0.912; P<0.001). The results of the Bland-Altman analysis demonstrated high consistency between the 2 measurement methods. Conclusions: Results of the phantom measurements indicated that the new fast kV-switching DECT could measure BMD with relatively high accuracy and precision. The results of a subsequent clinical in vivo experiment demonstrated that vertebral BMD measurements derived from DECT and QCT were mostly consistent and highly accurate. Therefore, patients who undergo DECT for other clinical indications can simultaneously have their BMD determined.

Genetic testing and prognosis of sarcomatoid hepatocellular carcinoma patients.

Background: Sarcomatoid hepatocellular carcinoma (SHC) is a rare epithelial malignancy with high invasiveness and poor prognosis. However, the molecular characteristics and main driver genes for SHC have not been determined. The aim of this study is to explore the potentially actionable mutations of driver genes, which may provide more therapeutic options for SHC. Methods: In this study, DNA extraction and library preparation were performed using tumor tissues from 28 SHC patients. Then we used Miseq platform (Illumina) to sequence the target-enriched library, and we aligned and processed the sequencing data. The gene groups were tested for SNVs/Indels/CNVs. Tumor mutation burden (TMB) was assessed by the 425-cancer-relevant gene panel. Multivariate analysis of COX's model was used for survival analysis (OS) of patients' clinical characteristics. Result: The median overall survival (OS) of the patients was only 4.4 months. TP53, TERT, and KRAS were the top three frequently mutated genes, with frequencies of 89.3%, 64.3%, and 21.4%, respectively. A considerable number of patients carried mutations in genes involved in the TP53 pathway (96%) and DNA Damage Repair (DDR) pathway (21%). Multiple potentially actionable mutations, such as NTRK1 fusions and BRCA1/2 mutations, were identified in SHCs. Conclusions: This study shows a landscape of gene mutations in SHC. SHC has high mutation rates in TP53 pathway and DDR pathway. The potentially actionable mutations of driver genes may provide more therapeutic options for SHC. Survival analysis found that age, smoking, drinking, and tumor diameter may be independent prognostic predictors of SHC.

Tumor Microenvironment Analysis Identified Subtypes Associated With the Prognosis and the Tumor Response to Immunotherapy in Bladder Cancer.

Background: The efficiency of immune checkpoint inhibitors (ICIs) in bladder cancer (BLCA) treatment has been widely validated; however, the tumor response to ICIs was generally low. It is critical and urgent to find biomarkers that can predict tumor response to ICIs. The tumor microenvironment (TME), which may play important roles to either dampen or enhance immune responses, has been widely concerned. Methods: The cancer genome atlas BLCA (TCGA-BLCA) cohort (n = 400) was used in this study. Based on the proportions of 22 types of immune cells calculated by CIBERSORT, TME was classified by K-means Clustering and differentially expressed genes (DEGs) were determined. Based on DEGs, patients were classified into three groups, and cluster signature genes were identified after reducing redundant genes. Then TMEscore was calculated based on cluster signature genes, and the samples were classified to two subtypes. We performed somatic mutation and copy number variation analysis to identify the genetic characteristics of the two subtypes. Correlation analysis was performed to explore the correlation between TMEscore and the tumor response to ICIs as well as the prognosis of BLCA. Results: According to the proportions of immune cells, two TME clusters were determined, and 1,144 DEGs and 138 cluster signature genes were identified. Based on cluster signature genes, samples were classified into TMEscore-high (n = 199) and TMEscore-low (n = 201) subtypes. Survival analysis showed patients with TMEscore-high phenotype had better prognosis. Among the 45 differentially expressed micro-RNAs (miRNAs) and 1,033 differentially expressed messenger RNAs (mRNAs) between the two subtypes, 16 miRNAs and 287 mRNAs had statistically significant impact on the prognosis of BLCA. Furthermore, there were 94 genes with significant differences between the two subtypes, and they were enriched in RTK-RAS, NOTCH, WNT, Hippo, and PI3K pathways. The Tumor Immune Dysfunction and Exclusion (TIDE) score of TMEscore-high BLCA was statistically lower than that of TMEscore-low BLCA. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of TMEscore and tumor mutation burden (TMB) is 0.6918 and 0.5374, respectively. Conclusion: We developed a method to classify BLCA patients to two TME subtypes, TMEscore-high and TMEscore-low, and we found TMEscore-high subtype of BLCA had a good prognosis and a good response to ICIs.

FUS-induced circular RNA ZNF609 promotes tumorigenesis and progression via sponging miR-142-3p in lung cancer.

Circular RNAs (circRNAs) have been associated with lung cancer (LC), one of the most common cancers, but the underlying molecular mechanisms of the specific correlation with LC carcinogenesis remain unveiled. Quantitative real-time polymerase chain reaction was applied to examine the level of circZNF609. LC cells were transfected with silenced circZNF609 by siRNAs, and cell proliferation, migration, and apoptosis were evaluated to reflect the influences of circZNF609 knockdown in LC. Biotin-coupled circRNA capture, FISH and luciferase reporter assays were performed to study the relationship between circZNF609 and miR-142-3p. In current work, it was discovered that circZNF609 functioned as an onco-circRNA, which exhibited high expression as well as facilitated the proliferation and migration in LC cells. Next, we discovered that FUS RNA-binding protein, which could bind to the ZNF609 pre-mRNA, induced circZNF609 formation, and increased circZNF609 expression in LC. Furthermore, circZNF609 was verified to sponge and sequester miR-142-3p; circZNF609 enhanced LC cell proliferative and migrative ability via targeting miR-142-3p. Finally, G protein subunit beta 2 (GNB2) was figured out to involve in circZNF609/miR-142-3p axis-induced LC development. Conclusively, the results indicated that FUS-induced circZNF609 exerts promotional effects on LC cell proliferation and migration through modulation of the miR-142-3p/GNB2 axis, which could offer new insight for understanding LC.

Total Laparoscopic Uncut Roux-en-Y for Radical Distal Gastrectomy: An Interim Analysis of a Randomized, Controlled, Clinical Trial.

BACKGROUND: The traditional Billroth II and Roux-en-Y anastomosis after laparoscopic distal gastrectomy for gastric cancer are associated with bile reflux gastritis and roux stasis syndrome, respectively. The uncut Roux-en-Y gastrojejunostomy can decrease the incidence of these complications by blocking the entry of bile and pancreatic juice into the residual stomach and retaining the impulses originating from the duodenum. The purpose of the present study was to compare the short-term outcomes of uncut Roux-en-Y (URY) and Billroth II combined Braun (BB) anastomosis. METHODS: In this prospective, multi-center, two-arm randomized controlled trial, 124 patients with advanced distal gastric cancer were randomized into two groups: URY (n = 62) and BB (n = 62) groups. RESULTS: The mean gastric juice pH was significantly lower in the URY group compared with the BB group (3.94 ± 0.71 vs. 5.83 ± 0.91, P < 0.0001). The bile reflux gastritis at 3 months (P < 0.0001) and 6 months (P = 0.002) was significantly more frequent in the BB group. No recanalization occurred in the URY group, and no significant difference was found between the two groups in terms of mean operative time (P = 0.69), mean time to perform anastomosis (P = 0.86), mean estimated blood loss (P = 0.77), mean number of harvested lymph nodes (P = 0.90), time to first passage of flatus or defecation (P = 0.87), postoperative hospital stay (P = 0.83), and the incidence of postoperative complications (P = 0.70). CONCLUSIONS: URY anastomosis is associated with a significantly lower incidence of bile reflux gastritis and roux stasis syndrome compared with BB anastomosis.

Identification of novel diagnostic and prognostic biomarkers for hepatocellular carcinoma.

The differential expression of a featured set of genes may serve as a diagnostic biomarker in hepatocellular carcinoma (HCC) patients. The aim of this study was to identify prognostic biomarkers for the diagnosis and survival of HCC based on the analysis of a large cohort of patients. Clinical and RNA­seq data were obtained from The Cancer Genome Atlas (TCGA) database. A transcriptomics analysis was conducted to detect differentially expressed genes (DEGs). Samples from 53 tumors and 20 normal tissues of HCC patients were obtained to further analyze the connection between overall survival (OS) and DEG levels. Based on the OS and progression­free survival (PFS), 4 DEGs (GABRR1, SOX11, COL24A1 and MYLK2) were identified from the TCGA dataset. Using gene ontology (GO) analysis, it was demonstrated that the DEGs were associated with several biological processes, including multicellular organismal and single­multicellular organism processes, which are involved in the development and migration of HCC. In addition, the four genes were significantly upregulated in tumor tissues. Notably, the mRNA expression of the four genes had a negative association with OS and PFS in HCC patients determined using a Kaplan­Meir analysis. The four­gene signature is a potential novel biomarker for the prediction of HCC patient survival.

Design, synthesis and bioactivity evaluation of coumarin-chalcone hybrids as potential anticancer agents.

The selenoprotein thioredoxin reductases (TrxRs) have been extensively studied as a potential target for the development of anticancer drugs. Herein, we designed, synthesized, and evaluated a series of coumarin-chalcone hybrids as TrxR inhibitors. Most of them exhibited enhancing anticancer activity than Xanthohumol (Xn). The representative Xn-2 (IC50 = 3.6 µM) was a fluorescence agent, wherein drug uptake can be readily monitored in living cells by red fluorescence imaging. Xn-2 down-regulated the expression of TrxR, remarkedly induced ROS accumulation to activate mitochondrial apoptosis pathway. Furthermore, Xn-2 inhibited cancer cell metastasis and abolished the colony formation ability of cancer cells. Taken together, these results highlight that compound Xn-2 may be a promising theranostic TrxR inhibitor for human cancer therapy.

Spectral Computed Tomographic Parameters Predict the Therapeutic Efficacy and Overall Survival of the Angiogenesis Inhibitor AL3818 in Hepatic Lesions: Preliminary Animal Study.

OBJECTIVE: This study aimed to investigate the predictive and prognostic values of repeated spectral computed tomographic (CT) parameter changes for the prediction of treatment responses to the angiogenesis inhibitor AL3818 in hepatic tumors. METHODS: A total of 30 rabbits with VX2 hepatic tumors that underwent spectral contrast-enhanced abdominal CT before and during treatment were included in the study. The percent change (Δ, %) of the normalized iodine concentration (nIC) during the arterial phase (AP) and venous phase (VP) was used to predict the tumor response and to calculate the overall survival (OS). The threshold of the nIC for tumor response prediction and prognostic significance was determined by a receiver operating characteristic curve and Kaplan-Meier analysis. RESULTS: After treatment, there were 43% (13/30) responders and 57% (17/30) nonresponders. When ΔnICAP ≥ -13.10% was used as the threshold, the sensitivity and specificity for the prediction of tumor response were 82.41% and 92.31%, respectively. ΔnICVP resulted in 88.20% sensitivity and 76.92% specificity for cutoff values ≥10.78%. Kaplan-Meier analyses showed that high ΔnICAP and ΔnICVP were associated with improved OS. CONCLUSIONS: The current study shows the capability of the changes (Δ) in repeated spectral CT parameters to predict the tumor response during antiangiogenesis therapy in small hepatic tumors. ΔnICAP and ΔnICVP were predictors for treatment response and were associated with OS.

[Application of spectral CT in the differentiation of stage T3 and T4a gastric carcinoma].

OBJECTIVE: To investigate the application value of spectral CT in the differentiation of stage T3 and T4a gastric carcinoma. METHODS: Data of 62 gastric cancer patients of stage T3 and T4a undergoing abdominal spectral CT examination in the First Affiliated Hospital of Zhengzhou University from December 2013 to December 2014 were collected retrospectively. There were 38 male and 24 female patients, with age of 33 to 77(58.6±10.4) years old. Abdominal double-phase enhanced scanning in gemstone spectral imaging mode was used to measure Iodine concentration (IC, 100 µg/ml) and water concentration(WC, 100 µg/ml) of perigastric fat tissue adjacent to the lesion during arterial phase(AP) and venous phase(VP), and normalized iodine concentration (nIC) was calculated respectively(nIC=IC/IC of aorta on the same slice). IC, WC, nIC of arterial phase and venous phase between stage T3 and T4a lesions were compared with double independent sample t test and compared with pathology. The diagnostic efficacy was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: During arterial phase in stage T4a cases, IC (100 µg/ml) was -5.19±0.81 and nIC was -0.05±0.01, which was significantly higher than -3.44±1.54 (P=0.000) and -0.03±0.01 (P=0.000) in stage T3 cases. During venous phase in T4a cases, IC (100 µg/ml) was -3.78±0.94 and nIC was -0.04±0.01, which was significantly higher than -1.62±1.43 (P=0.000) and -0.02±0.02 (P=0.000) in stage T3 cases. As compared to arterial phase, IC and nIC of stage T4a and T3 of venous phase were more significantly different (all P<0.05). WC of stage T4a during arterial and venous phase was 955.72±15.68 and 949.86±17.36 respectively, while WC of stage T3 during arterial and venous phase was 947.77±18.43 and 942.46±18.53 respectively. There were no significant differences in WC between two stage cases during arterial and venous phase (P=0.106, P=0.143). ROC analysis showed that area under the ROC of IC and nIC during arterial phase was 0.829 and 0.867 respectively, and cut-off value of nIC was -0.039 for differentiation of stage T3 and T4a with corresponding 83.3% of sensitivity and 75.0% of specificity; area under the ROC of IC and nIC during venous phase was 0.873 and 0.905 respectively, and cut-off value of nIC was -0.031 for differentiation of stage T3 and T4a with corresponding 81.0% of sensitivity and 85.0% of specificity. CONCLUSIONS: Abdominal spectral CT scan is useful in the differentiation of stage T3 and T4a gastric carcinoma. The IC of perigastric fat tissue is significantly higher in stage T4a gastric carcinoma compared to stage T3 gastric carcinoma. Higher diagnostic efficacy can be obtained when taking -0.031 as the cut-off value of nIC during venous phase.

[Computed tomography features and pathological correlations of primitive neuroectodermal tumor of the kidney].

OBJECTIVE: To explore the computed tomography (CT) features and pathological correlations of primitive neuroectodermal tumor (PNET) of the kidney. METHODS: The CT features of 5 cases of pathologically confirmed PNETs were retrospectively reviewed along with a literature review to analyze the CT features and pathological correlations. RESULTS: The age range was 19-78 years. CT image showed solitary mass of heterogeneous density with ill-defined margins. One case had multifocal necrosis. Among 3 cases of cystic changes, there were mural nodule (n = 2) and patchy calcification (n = 1). Four cases showed invasive growth into renal cortex and pelvis with cortical interruption (n = 3) and destruction of renal capsule and invasion into perirenal fat space (n = 1). The tumors were confined to kidney contour with enlarged kidney (n = 3). All 5 cases showed slight heterogenous enhancement in cortico-medullary phase with persistent moderate enhancement (n = 4) and persistent mild enhancement (n = 1) in nephrographic phase. CONCLUSION: Renal PNET is common in young patients with a high degree of malignancy. CT features include large mass with heterogenous density and poor-defined border confined within renal contour. Necrosis and cystic changes occur commonly with invasive growth. Persistent enhancement is found during nephrographic phase. A definite diagnosis is dependent upon pathological and immunohistochemical examinations.

Evaluation of neovascularization with spectral computed tomography in a rabbit VX2 liver model: a comparison with real-time contrast-enhanced ultrasound and molecular biological findings.

OBJECTIVE: To validate the feasibility of using the parameters of spectral CT and CT perfusion and the dynamic features of real-time contrast-enhanced ultrasound (CEUS) to evaluate the vascularization of VX2 hepatic tumours. METHODS: Spectral CT imaging, CT perfusion and CEUS analysis were performed on rabbits implanted with VX2 hepatic tumours, 7 and 14 days after implantation. The perfusion parameters of CT, normalized iodine concentration (NIC) and dynamic features of CEUS were measured in the rim of the tumour (TR) and the normal liver region. The expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) was also determined. RESULTS: Increased perfusion parameters of CT were found in the TR. In addition, the NIC was elevated in TR during the arterial phase, and the peak intensity of the CEUS of the TR was reached significantly earlier than that on normal liver region. At 14 days, the perfusion parameters of CT (blood volume, permeability surface and hepatic arterial fraction) offered higher accuracy and stability in differentiating the TR from the normal liver region. Furthermore, CEUS was more accurate in diagnosing tumours <1.0 cm in diameter. In addition, VEGF and FGF2 expression was higher in the TR and were positively correlated with CT and CEUS parameters, except mean transit time, rise time, washout time and peak time. CONCLUSION: Use of spectral CT with perfusion techniques, iodine-based material-decomposition analysis and dynamic CEUS changes may reflect the angiogenesis and haemodynamic information of hepatic tumours. ADVANCES IN KNOWLEDGE: It is feasible to assess vascularization in hepatic cancer using CT or CEUS.

CT Features and Pathological Correlation of Primitive Neuroectodermal Tumor of the Kidney.

The purpose of the study was to analyze the computed tomography (CT) findings of primitive neuroectodermal tumor (PNET) of the kidney and correlate them pathologically. Ten cases of pathologically confirmed renal PNET were collected and retrospectively reviewed. The CT features that were analyzed include tumor size, shape, margins, density, nature of enhancement, presence of thrombosis, and metastasis, etc. These parameters were correlated with pathological findings and combined with literature review. The median age of the patients was 30 years. CT images showed solitary, large, ill-defined, irregular, or lobulated heterogeneous mass. Invasive growth toward the renal cortex and pelvis with renal cortical interruptions were seen in eight cases with one case exhibiting invasion that extended beyond the renal capsule with soft tissue seen in the perirenal fat pace. The tumors were confined to the kidney contour with enlargement of kidney in six of the cases. Cystic changes with mural nodules were detected in three cases. Eight cases showed persistent moderate enhancement during the nephrographic phase. Irregular septum-like structures were seen in four cases. Thrombosis was detected in eight cases. Lymph node metastasis was detected in eight cases with bilateral lung metastasis in two and bone metastasis in one. Renal PNET is a rare highly aggressive disease affecting younger people. It should be considered as a strong differential when well confined, yet large tumors that cause enlargement of the kidney are seen and also when tumors expressing cystic changes along with mural nodules are seen. Although renal PNET has certain other characteristic CT features, pathological and immunohistochemistry report must also be sought for definitive diagnosis.

Analysis of the discriminative methods for diagnosis of benign and malignant solitary pulmonary nodules based on serum markers.

BACKGROUND: Screening indexes of tumor serum markers for benign and malignant solitary pulmonary nodules (SPNs) were analyzed to find the optimum method for diagnosis. METHODS: Enzyme-linked immunosorbent assays, an automatic immune analyzer and radioimmunoassay methods were used to examine the levels of 8 serum markers in 164 SPN patients, and the sensitivity for differential diagnosis of malignant or benign SPN was compared for detection using a single plasma marker or a combination of markers. The results for serological indicators that closely relate to benign and malignant SPNs were screened using the Fisher discriminant analysis and a non-conditional logistic regression analysis method, respectively. The results were then verified by the k-means clustering analysis method. RESULTS: The sensitivity when using a combination of serum markers to detect SPN was higher than that using a single marker. By Fisher discriminant analysis, cytokeratin 19 fragments (CYFRA21-1), carbohydrate antigen 125 (CA125), squamous cell carcinoma antigen (SCC) and breast cancer antigen (CA153), which relate to the benign and malignant SPNs, were screened. Through non-conditional logistic regression analysis, CYFRA21-1, SCC and CA153 were obtained. Using the k-means clustering analysis, the cophenetic correlation coefficient (0.940) obtained by the Fisher discriminant analysis was higher than that obtained with logistic regression analysis (0.875). CONCLUSION: This study indicated that the Fisher discriminant analysis functioned better in screening out serum markers to recognize the benign and malignant SPN. The combined detection of CYFRA21-1, CA125, SCC and CA153 is an effective way to distinguish benign and malignant SPN, and will find an important clinical application in the early diagnosis of SPN.