Exosome miR-101-3p derived from bone marrow mesenchymal stem cells promotes radiotherapy sensitivity in non-small cell lung cancer by regulating DNA damage repair and autophagy levels through EZH2.

BACKGROUND AND OBJECTIVE: The morbidity rate of non-small cell lung cancer (NSCLC) increases with age, highlighting that NSCLC is a serious threat to human health. The aim of this study was mainly to describe the role of exosomal miR-101-3p derived from bone marrow mesenchymal stem cells (BMSCs) in NSCLC. METHODS: A549 or NCI-H1703 cells (1×105/mouse) were injected into nude mice to establish an NSCLC animal model. RTqPCR, Western blotting and comet assays were used to assess the changes in gene expression, proteins and DNA damage repair. RESULTS: miR-101-3p and RAI2 were found to be expressed at low levels in NSCLC, while EZH2 was highly expressed. In terms of function, miR-101-3p downregulated EZH2. In addition, exosomal miR-101-3p derived from BMSCs promoted the expression of RAI2, inhibited DNA damage repair, and inhibited the activation of the PI3K/AKT/mTOR signaling pathway by inhibiting EZH2, thereby promoting autophagy and decreasing cell viability and finally enhancing the sensitivity of NSCLC to radiotherapy and inhibiting the malignant biological behavior of NSCLC. CONCLUSION: Exosomal miR-101-3p derived from BMSCs can inhibit DNA damage repair, promote autophagy, enhance the radiosensitivity of NSCLC, and inhibit the progression of NSCLC by inhibiting EZH2.

The DMRTA1-SOX2 positive feedback loop promotes progression and chemotherapy resistance of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is among the most prevalent causes of cancer-related death in patients worldwide. Resistance to immunotherapy and chemotherapy results in worse survival outcomes in ESCC. It is urgent to explore the underlying molecular mechanism of immune evasion and chemoresistance in ESCC. Here, we conducted RNA-sequencing analysis in ten ESCC tissues from cisplatin-based neoadjuvant chemotherapy patients. We found that DMRTA1 was extremely upregulated in the non-pathologic complete response (non-pCR) group. The proliferation rate of esophageal squamous carcinoma cells was markedly decreased after knockdown of DMRTA1 expression, which could increase cisplatin sensitivity in ESCC. Additionally, suppression of DMRTA1 could decrease the immune escape of esophageal squamous carcinoma cells. Further mechanistic studies suggest that DMRTA1 can promote its expression by binding to the promoter of SOX2, which plays important roles in the progression and chemoresistance of ESCC in the form of positive feedback. Therefore, DMRTA1 could be a potential target to suppress immune escape and overcome chemoresistance in ESCC.

Convex compressive beamforming with nonconvex sparse regularization.

The convex sparse penalty based compressive beamforming technique can achieve robust high resolution in direction-of-arrival (DOA) estimation tasks, but it often leads to an insufficient sparsity-inducing problem due to its convex loose approximation to ideal ℓ0 nonconvex penalty. On the contrary, the nonconvex sparse penalty can tightly approximate ℓ0 penalty to effectively enhance DOA estimation accuracy, but it incurs an initialization sensitivity problem due to its multiple local minimas. Leveraging their individual advantages, a minimax-concave penalty (MCP) regularized DOA estimation algorithm is proposed to achieve a maximally sparse level while maintaining the convex property of the overall objective function. Moreover, an accelerated block gradient descent-ascent algorithm with convergence guarantee is developed to rapidly achieve its one optimal point. Simulation results demonstrate that MCP penalty improves DOA estimation accuracy compared with popular sparse compressive beamforming techniques in strong noise scenarios and weak source confirmation. Ocean experimental results also validate that it retains more stable DOA estimation accuracy and incurs less artificial interferences.

Doppler chirplet transform for the velocity estimation of a fast moving acoustic source of discrete tones.

An extended chirplet transform method termed as Doppler chirplet transform is proposed to estimate the velocity of a discrete tone source in uniform linear motion. This method directly uses the relation of the observed instantaneous frequency to the source velocity as the kernel of the chirplet transform. It is tested on a set of 30-s truck noise recordings and also on simulated data from a statistical perspective. The results show that the Doppler chirplet transform significantly reduces the run time that the polynomial chirplet transform [Xu, Yang, and Yu, J. Acoust. Soc. Am. 137(4), EL320-EL326 (2015)] costs to produce similarly accurate estimates of the source velocity.

Second-order cone programming with probabilistic regularization for robust adaptive beamforming.

Probabilistic regularization (PR) is introduced to make superdirective array beamforming robust against sensor characteristic mismatches. The objective is to enlarge the directivity while ensuring robustness with high probability. The PR problem is solved via the second-order cone programming where the regularization parameter is chosen through a statistical analysis of the system perturbations, based on Monte Carlo simulations. Experiments are carried out on a miniaturized 3 × 3 uniform rectangular array without calibration. The results show that for this particular array, the PR method is robust to sensor mismatches and achieves a higher level of directivity compared with other robust adaptive beamforming approaches.

An upper bound for the directivity index of superdirective acoustic vector sensor arrays.

Approximate analytical expressions of the white noise gain (WNG) for two superdirective acoustic vector sensor arrays are provided, which disclose the strong dependence of the tradeoff between the WNG and the directivity index (DI) on the highest order of the modes for the pattern synthesis. The considered arrays are a uniform linear array and a uniform circular array. A condition on the WNG that ensures a high array gain in the two-dimensional homogeneous and isotropic noise field is deduced. Using this condition, an upper bound on the highest order of the modes for the pattern synthesis can be derived, and hence the maximum DI can be determined. The presented results are not strictly limited to the two array geometries considered herein, and can be extended to other superdirective acoustic array designs.

On the dynamics of ocean ambient noise: Two decades later.

Two decades ago, it was shown that ambient noise exhibits low dimensional chaotic behavior. Recent new techniques in nonlinear science can effectively detect the underlying dynamics in noisy time series. In this paper, the presence of low dimensional deterministic dynamics in ambient noise is investigated using diverse nonlinear techniques, including correlation dimension, Lyapunov exponent, nonlinear prediction, and entropy based methods. The consistent interpretation of different methods demonstrates that ambient noise can be best modeled as nonlinear stochastic dynamics, thus rejecting the hypothesis of low dimensional chaotic behavior. The ambient noise data utilized in this study are of duration 60 s measured at South China Sea.

Low-frequency beamforming for a miniaturized aperture three-by-three uniform rectangular array of acoustic vector sensors.

This paper proposes a mode domain beamforming method for a 3 × 3 uniform rectangular array of two-dimensional (2D) acoustic vector sensors with inter-sensor spacing much smaller than the wavelengths in the working frequency band. The acoustic modes are extracted from the particle velocity observations in light of the source-sink pictures of the Taylor's series multipoles [Wikswo and Swinney, J. Appl. Phys. 56(11), 3039-3049 (1984)]. Then, similar to other mode domain methods, the modes are synthesized to obtain the desired beam pattern. The proposed method is limited to the cases where five is the maximum order of the modes for pattern synthesis, meaning that the directivity index in the 2D isotropic noise case can reach up to 10.4 dB. The proposed method has been validated by field experiments.

Serum anti-osteopontin autoantibody as a novel diagnostic and prognostic biomarker in patients with hepatocellular carcinoma.

Osteopontin (OPN) is a secreted phosphorylated and glycosylated protein, which plays an important role in carcinogenesis and metastasis. In hepatocellular carcinoma (HCC), OPN is being investigated either as a therapeutic target gene or as a biomarker for diagnosis. Yet, the role of the anti-OPN autoantibody in HCC remains unclear. In the present study, the level of serum anti-OPN autoantibody in HCC was analyzed by enzyme-linked immunosorbent assay. Immunohistochemistry (IHC) was also performed to analyze protein expression profiles and the prognostic significance of OPN in HCC. In this study, the prevalence and titer of anti-OPN autoantibodies in HCC were significantly higher than these values in normal human serum (NHS) (P=0.001, P=0.000, respectively). When both α-fetoprotein and the autoantibody against OPN were used simultaneously as diagnostic biomarkers, the sensitivity was up to 65%. In IHC, 59 of the 83 (65.6%) HCC specimens expressed OPN with cytoplasmic positive staining. The overall survival (OS) of HCC patients with OPN-positive tumors was 28.81 months compared to 39.37 months for HCC patients with OPN-negative tumors (P<0.01). Furthermore, multivariate analysis showed that OPN overexpression was the strongest independent adverse prognostic factor for OS (P=0.02). Taken together, our data indicate that the anti-OPN autoantibody may be a supplementary serological biomarker for HCC, and is correlated with poor prognosis in HCC patients.

The intensity of radiotherapy-elicited immune response is associated with esophageal cancer clearance.

Radiation therapy is one of the standard therapeutic modalities for esophageal cancer, achieving its main antitumor efficacy through DNA damage. However, accumulating evidence shows that radiotherapy can substantially alter the tumor microenvironment, particularly with respect to its effects on immune cells. We hypothesized that the immune response elicited by radiotherapy may be as important as the radiation itself for successful treatment. More specifically, immunomodulatory cytokines may enhance the effectiveness of radiotherapy. To investigate this hypothesis, we measured changes in the serum interferon-gamma (IFN- γ ) and interleukin-2 (IL-2) concentrations during radiotherapy and compared these modifications with outcomes. We found that serum concentrations of IL-2 and IFN- γ were positively associated with local response to radiotherapy in esophageal cancer. More generally, the intensity of the radiotherapy-elicited immune response was positively associated with local response to radiotherapy in esophageal cancer. Changes in serum IL-2 and IFN- γ concentrations were further associated with increased risks of acute hematologic toxicity and acute organ toxicity of the esophagus, lung, and skin. These results suggest that deciphering the mechanisms of radiotherapy-elicited immune response may help in the development of therapeutic interventions that would enhance the efficacy of radiotherapy and convert some ineffective responses to effective responses.

Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma.

PURPOSE: Yes-associated protein (YAP) and PDZ-binding motif (TAZ) are two important effectors of Hippo pathway controlling the balance of organ size and carcinogenesis. Amphiregulin (AREG) is a member of the epidermal growth factor family, a direct target gene of YAP and TAZ. The role of these proteins in hepatocellular carcinoma (HCC) is unclear. METHODS: The expression of YAP, TAZ, and AREG in HCC was analyzed by immunohistochemical staining. The level of secreted serum AREG was also assayed by enzyme-linked immunosorbent (ELISA) assay. RESULTS: YAP, TAZ, and AREG were expressed in 69.2% (27/39), 66.7% (26/39), and 61.5% (24/39) of HCC patients. The expression of YAP was significantly correlated with Edmondson stage (P>0.05), serum AFP level (P>0.05), and HCC prognosis (P>0.05). AREG expression was also significantly correlated with Edmondson stage (P>0.05) and serum AFP level (P>0.05). In addition, the expression of serum AREG was higher than serum AFP in HCC patients. Further multivariate analysis showed that YAP expression was an independent prognostic factor that significantly affected the overall survival of HCC patients. CONCLUSIONS: YAP maybe an independent prognostic indicator for HCC patients and serum AREG may be a serological biomarker of HCC.

Serum SALL4 is a novel prognosis biomarker with tumor recurrence and poor survival of patients in hepatocellular carcinoma.

AIM: Sal-like protein 4 (SALL4), is reexpressed in tissues of a subgroup of HCC associated with poor prognosis. Reports of SALL4 serological levels linked to HCC patients are meager and unclear in the prognosis of this malignancy. METHODS: Immunohistochemistry and optical microscopy protocols were used to examine the presence of SALL4 in liver tissues from the following patients: 38 HCC, 11 chronic hepatitis B virus (HBV), 13 liver cirrhosis, and 12 healthy controls. Additionally, enzyme-linked immunosorbent assay (ELISA) was used to measure the SALL4 levels in serum samples isolated from patients as follows: 127 with HCC, 27 with HBV, 24 with liver cirrhosis, and 23 normal controls. RESULTS: Analysis of liver tissues sections from HCC patients (18 out 38; 47.4%) showed positive staining for SALL4 and its expression did no correlate with any of the clinicopathologic characteristics. HCC patients displayed higher levels (50.4%) of SALL4 protein in serum, compared with the three control groups. Moreover, SALL4 concentration reached the maximum level after one week after treatment and dropped quickly after one month. These HCC patients showing high SALL4 serum levels had poor prognosis, evidenced by both tumor recurrence and overall survival rate. CONCLUSIONS: High SALL4 serum levels are a novel biomarker in the prognosis of HCC patients.

The role of PAM4 in the management of pancreatic cancer: diagnosis, radioimmunodetection, and radioimmunotherapy.

PAM4, a new monoclonal antibody (MAb) known as clivatuzumab, is highly reactive with pancreatic cancer and precursor lesions. It is absent from the normal tissues and has limited reactivity with nonpancreatic cancer. The detailed characteristic of the PAM4 epitope is unknown but recent studies have shown that it is dependent on MUC1 glycosylation status. The limited PAM4 expression pattern makes it an attractive candidate for management of pancreatic adenocarcinoma. In addition, PAM4 is a serum biomarker for diagnosis of pancreatic cancer. Several different radiolabeled immunodiagnostic and immunotherapeutic agents of PAM4 have been developed and some are being evaluated in preclinical and/or clinical studies. The review will focus on PAM4 and its potential utility for the diagnosis, radioimmunodetection, and radioimmunotherapy of pancreatic cancer.

Gαs protein expression is an independent predictor of recurrence in prostate cancer.

BACKGROUND: T393C polymorphism in the gene GNAS1, which encodes the G-protein alpha s subunit (Gαs) of heterotrimeric G protein, is significantly associated with the clinical outcome of patients suffering from several cancers. However, studies on the role and protein expression of Gαs subunit in prostate cancer were still unavailable. METHODS: The immunohistochemical staining was used to assess Gαs expression through tissue microarray procedure of 56 metastatic PCas, 291 localized PCas, and 67 benign hyperplasia (BPH). Gαs expression was semiquantitatively scored and evaluated the correlation with pathologic parameters and biochemical recurrence of prostate-specific antigen (PSA). RESULTS: Gαs expression was localized in nuclear and cytoplasm in prostate cancer cells and downregulated in metastatic PCa compared to localized PCa and BPH (P < 0.001). Gαs was inversely associated with PSA level and Gleason scores; patients with low expression of Gαs had adverse clincopathological features. In multivariable Cox regression analysis, high Gαs expression and Gleason scores were independent predictors of both PSA progression-free and overall survival. CONCLUSIONS: Gαs down-expression is associated with adverse pathologic features and clinical PSA biochemical recurrence of prostate cancer. Gαs is an independent predictor to help determine the risk of PSA progression and death.

The role of RCAS1 as a biomarker in diagnosing CRC and monitoring tumor recurrence and metastasis.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) plays an important role in tumor progression by helping tumor cell to escape from host immunological surveillance or modifying the characteristics of connective tissue around. RCAS1 may appropriately reflect the development and prognosis of tumor. In the study, we sought to identify the clinical significance of RCAS1 in colorectal cancer (CRC) diagnosis and tumor recurrence monitoring. Immunohistochemistry (IHC) with tissue array slides was preformed to analyze RCAS1 protein expression in CRC, colorectal polyps, and normal colon tissues. RCAS1 levels in colorectal cancer were significantly higher than those in colorectal polyps and normal colon tissues (P<0.001). Silencing RCAS1 gene in human colonic adenocarcinoma cells decreased cell proliferation and enhanced apoptosis through the p53 signaling pathway. Further analysis by an enzyme-linked immunosorbent assay (ELISA) showed that serum RCAS1 levels in CRC are significantly higher than in healthy controls and polyps (P<0.05), in which the highest serum RCAS1 level is reported in the recurrence group. The serum RCAS1 levels have a significant correlation with clinical stage and pathologic grading. Furthermore, the positive rate of serum RCAS1 in CRC was 82.1 %, which was higher than carcinoembryonic antigen (CEA). Especially in CEA-negative cases, the sensitivity of RCAS1 was 88.2 %. Finally, CRC patients who were followed up showed a serum RCAS1 level which significantly decreased after surgery (P<0.001) and obviously increased in the recurrence group. Taken together, our data demonstrated that RCAS1 is not only a supplementary serological biomarker for CRC diagnosis but also useful for monitoring tumor recurrence. RCAS1 might be a supplementary serological marker for CRC.