Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway.

Lung cancer is one of the most significant malignancies, with both high morbidity and mortality. CDK10 is closely related to cancer progression and metastasis. However, its role in lung cancer radioresistance demands further clarification. In this study, we demonstrated that CDK10 was downregulated in lung cancer tissues, and CDK10 expression level was associated with the clinical prognosis in lung cancer patients. We also found that silencing CDK10 promoted lung cancer cell proliferation, migration, and radioresistance. We further verified that silencing CDK10 facilitated the activation of JNK/c-Jun signaling, and c-Jun depletion could reverse the effects of CDK10 knockdown in lung cancer cells. Our findings revealed that CDK10 plays an important role in cell growth and radioresistance by inhibiting JNK/c-Jun signaling pathway in lung cancer. Therefore, CDK10 might be a promising therapeutic target in lung cancer.

Malignant gastrointestinal neuroectodermal tumor: a case report and literature review.

Introduction and importance: A malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare primary malignant mesenchymal tumor of the gastrointestinal tract characterized by EWSR1 gene rearrangement. An optimal systemic treatment strategy for advanced/recurrent GNET has not yet been identified. Case presentation: A 24-year-old male patient was hospitalized with abdominal pain and underwent two operations for a tumor in his small intestine. Immunohistochemistry (IHC) showed strong expression of S-100 protein and SOX 10. Fluorescence in situ hybridization analysis and next-generation sequencing analysis indicated that there were EWSR gene rearrangements and the presence of EWSR-ATP1 gene fusions, respectively. The diagnosis of GNET in the small intestine was confirmed by pathology. The young patient received the fifth-line of apatinib mesylate and the sixth-line of apatinib combined with temozolomide. The two apatinib-containing regimens showed stable disease and progression-free survival of 4.7 months and 3.1 months with single-agent apatinib or apatinib combined with temozolomide, respectively. Clinical discussion: To our best knowledge, this is the first report of malignant GNET treated with apatinib and temozolomide. Apatinib-containing regimens might has antineoplastic activity against GNET. The authors reviewed the relevant reports of previous GNET treatment, summarized the clinicopathological characteristics of GNET, and found that there are no reports of apatinib for backline treatment of GNET. Conclusion: Containing apatinib may provide an additional treatment option for patients with chemotherapy-resistant GNET tumors.

Higher thymocyte selection-associated high mobility group box (TOX) expression predicts poor prognosis in patients with ovarian cancer.

BACKGROUND: Ovarian cancer is one of the most lethal gynecologic malignancies with a dismal prognosis that poses a serious threat to human health, highlighting the need for more knowledge about what is required for identifying some biomarkers for early diagnosis, prediction of prognosis and disease monitoring. TOX, a critical transcription factor related to the development of malignancies that contributing to lymphocytes not just T cells, had been proved prognostic value in some spectrum of cancers. Here, we aimed to study the prognostic role of TOX in ovarian cancer. RESULTS: We found that TOX was not only expressed in CD8 T cells but also tumor cells. TOX expression score was higher in ovarian cancer tissues and correlated with survival status. Survival analysis revealed that ovarian cancer patients with high TOX expression score generally shorter overall survival and disease-free survival times. Univariate and Multivariate Cox demonstrated that TOX expression score could be used as an independent prognostic factor for patients with ovarian cancer. CONCLUSION: TOX expression in ovarian cancer could be a promising tool for predict overall survival of ovarian cancer patients.

A Quassinoid Diterpenoid Eurycomanone from Eurycoma longifolia Jack Exerts Anti-Cancer Effect through Autophagy Inhibition.

Eurycomanone (EN) is one of the representative quassinoid diterpenoids from roots of Eurycoma longifolia Jack, a natural medicine that is widely distributed in Southeast Asia. Previous studies showed that EN induces cancer cell apoptosis and exhibits anti-cancer activity, but the molecular mechanism of EN against cancer has still not been elucidated. In this study, we examined the regulatory effect of EN on autophagy to reveal the mechanism of EN-mediated colon cancer growth inhibition. First, we found that EN is able to inhibit colon cancer cell proliferation and colony formation. The angiogenesis level in cancer cells was inhibited as well. Next, the treatment of EN led to the suppression of autophagy, which was characterized by the downregulation of the LC3-II level and the formation of GFP-LC3 puncta under EN treatment in colon cancer. Moreover, we revealed that the mTOR signaling pathway was activated by EN in a time- and concentration-dependent manner. Finally, autophagy induction protected colon cancer cells from EN treatment, suggesting that autophagy improves cell survival. Taken together, our findings revealed the mechanism of EN against colon cancer through inhibiting autophagy and angiogenesis in colon cancer, supporting that the autophagy inhibitor EN could be developed to be a novel anti-cancer agent.

Tumor Vessel Normalization: A Window to Enhancing Cancer Immunotherapy.

Hostile microenvironment produced by abnormal blood vessels, which is characterized by hypoxia, low pH value and increasing interstitial fluid pressure, would facilitate tumor progression, metastasis, immunosuppression and anticancer treatments resistance. These abnormalities are the result of the imbalance of pro-angiogenic and anti-angiogenic factors (such as VEGF and angiopoietin 2, ANG2). Prudent use of anti-angiogenesis drugs would normalize these aberrant tumor vessels, resulting in a transient window of vessel normalization. In addition, use of cancer immunotherapy including immune checkpoint blockers when vessel normalization is achieved brings better outcomes. In this review, we sum up the advances in the field of understanding and application of the concept of tumor vessels normalization window to treat cancer. Moreover, we also outline some challenges and opportunities ahead to optimize the combination of anti-angiogenic agents and immunotherapy, leading to improve patients' outcomes.

Identification of DNA hydroxymethylation associated genes in osteoarthritis by combined analysis of hydroxymethylation and gene expression.

BACKGROUND: Our study aimed to explore more mechanistic insights into the epigenetic regulation of osteoarthritis (OA). METHODS: The expression profiles (accession number: GSE64393 and GSE64394) were downloaded from the Gene Expression Omnibus database. The differentially hydroxymethylated regions (DhMRs) and differentially expressed genes (DEGs) between OA and control groups were identified. The distribution of DhMRs in the whole genome and the correlation between DhMRs and DEGs were analyzed. Functional module mining for the DEGs and DhMRs was conducted, followed by protein-protein interaction (PPI) analysis. The transcriptional factor (TF) was predicted. RESULTS: Total 52,282 DhMRs were obtained, among which 31,452 ones were annotated to 9726 genes. Additionally, 1806 DEGs were selected. Hydroxymethylation mainly occurred in gene body region. Correlation analysis revealed that more than 70% of DhMRs were uncorrelated with DEGs expression. Functional module mining for the DEGs and DhMRs identified 2 functional modules, which were involved in pathways of regulation of actin cytoskeleton, and TGF-ß signaling pathway. A PPI network was constructed, and ITGB3 had the highest degree. Furthermore, 7 TFs were predicted, which regulated 12 candidate genes, such as HES1-PTEN. CONCLUSIONS: The onset and progression of OA may be associated with the upregulated hydroxymethylation in gene body region of PTEN. HES1 may be important TF in the pathogenesis of OA. Additionally, pathways of regulation of actin cytoskeleton, and TGF-beta signaling pathway may also play important roles in OA progression.

Employing graphene acoustoelectric switch by dual surface acoustic wave transducers.

We implement a logic switch by using a graphene acoustoelectric transducer at room temperature. We operate two pairs of inter-digital transducers (IDTs) to launch surface acoustic waves (SAWs) on a LiNbO3 substrate and utilize graphene as a channel material to sustain acoustoelectric current Iae induced by SAWs. By cooperatively tuning the input power on the IDTs, we can manipulate the propagation direction of Iae such that the measured Iae can be deliberately controlled to be positive, negative, or even zero. We define the zero-crossing Iae as [Formula: see text], and then demonstrate that Iae can be switched with a ratio [Formula: see text] at a rate up to few tens kHz. Our device with an accessible operation scheme provides a means to convert incoming acoustic waves modulated by digitized data sequence onto electric signals with frequency band suitable for digital audio modulation. Consequently, it could potentially open a route for developing graphene-based logic devices in large-scale integration electronics.

Synergistic Suppression Effect on Tumor Growth of Colorectal Cancer by Combining Radiotherapy With a TRAIL-Armed Oncolytic Adenovirus.

The combination of gene therapy and radiation is a promising new treatment for cancer. This study aimed to clarify the synergistic effect of targeted oncolytic adenovirus (radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand) and radiotherapy on colorectal cancer cells and elucidate the mechanisms of the underlying antitumor activity. Viability, cell cycle status, and apoptosis of treated colorectal cancer cells were determined via MTT and flow cytometric assays. The molecular mechanism underlying apoptotic pathway activation was elucidated through Western blot analysis of caspase-8, caspase-3, and PARP proteins. Combination treatment with radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand and radiotherapy displayed significantly greater antitumor activity than either of the monotherapies. The primary mechanism behind the antitumor activity in the SW480 and Lovo colorectal cancer cell lines was apoptosis induction through the caspase pathway and G1 phase arrest. In an SW480 xenograft model of colorectal cancer, the combination therapy achieved a significantly greater reduction in tumor volume than the monotherapies. Overall, in this study, we demonstrate that the oncolytic radiotherapy-tumor necrosis factor-related apoptosis-inducing ligand construct can sensitize human colorectal cancer cells to radiation-induced apoptosis both in vitro and in vivo. Therefore, our findings point toward a novel synergistic approach to colorectal cancer treatment.

Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 predicts poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fifth leading cause of cancer-related death worldwide. Novel prognostic biomarkers are urgently needed for patients with HCC. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) overexpression may promote tumor metastasis in HCC. However, few studies investigate the prognosis predictive role of LGR5 in patients with HCC. Herein, we aimed to examine the expression level of LGR5 in tumors and its correlation with clinical characteristics and survivals of patients with HCC. LGR5 expression in tumor specimens and adjacent tissue resected from 66 patients were detected by immunohistochemistry. The results showed that the expression of LGR5 was markedly higher in HCC than in normal adjacent tissues (P = .006). High expression of LGR5 was significantly correlated with later disease stage (P = .009). In addition, high LGR5 expression was remarkably correlated with short overall survival than those with low LGR5 expression (P < .05). The median overall survival of patients with high LGR5 expression was 12 months, whereas that of patients with low LGR5 expression was still not reached (longer than 70 months). Notably, in our limited cases, we did not detect any difference in tumor size, lymphatic invasion, or metastasis in patients with high or low expression of LGR5. In conclusion, high protein level of LGR5 was associated with poor prognosis of these patients. LGR5 appears to be a valuable prognostic predictor clinically and a potential target in HCC therapy.

Effects of Kanglaite Injection on Serum miRNA-21 in Patients with Advanced Lung Cancer.

BACKGROUND Lung cancer is the most common type of cancer throughout the world, and the morbidity of lung cancer is continuously increasing. Patients with advanced lung cancer often cannot tolerate chemoradiotherapy. The decrease of the expression of miRNA-21 can be used as an indicator of the therapeutic effect of lung cancer. In this study, the effect of Kanglaite injection on serum miRNA-21 in patients with advanced lung cancer was investigated, providing reliable and important evidences. MATERIAL AND METHODS From March 2016 to March 2017, 120 patients with advanced lung cancer were examined; we collected detailed information and serum samples. The patients were treated by intravenous drip of Kanglaite, which was provided by Zhejiang Kanglaite Pharmaceutical Co., Ltd., China. We administered 200 ml intravenous drip once per day for a total of 21 days. Serum samples were collected from patients after treatments. In this study, 4 observation indexes were considered - KPS (Karnofsky performance score, KPS), body weight, adverse effects, and miRNA-21 level - evaluated before and after the Kanglaite treatment. RESULTS Among 120 patients with advanced lung cancer, the KPS of 75 patients (63.1%) was increased after the treatment, and body weight was increased by 55.9%. In addition, serum miRNA-21 level after the Kanglaite treatment was 2.45±0.15, which was significantly lower than before treatment (3.87±0.54), (P<0.05). CONCLUSIONS The effect of Kanglaite injection on serum miRNA-21 in patients with advanced lung cancer was shown to significantly reduce the expression of miRNA-21, providing objective evidence for the effect of Kanglaite injection in patients with advanced lung cancer.

Histone deacetylase inhibitor trichostatin A and autophagy inhibitor chloroquine synergistically exert anti-tumor activity in H-ras transformed breast epithelial cells.

Histone deacetylase inhibitors (HDACIs) cause oncogene­transformed mammalian cell death. Our previous study indicated that HDACIs activate forkhead box O1 (FOXO1) and induce autophagy in liver and colon cancer cells. However, whether FOXO1 is involved in HDACI­mediated oncogene­transformed mammalian cell death remains unclear. In the present study, H­ras transformed MCF10A cells were used to investigate the role of FOXO1 in this pathway. Results showed that trichostatin A (TSA), a HDACI, activated apoptosis in MCF10A­ras cells, but not in MCF10A cells. Furthermore, TSA activated FOXO1 via P21 upregulation, whereas the knockdown of FOXO1 reduced TSA­induced cell death. In addition, TSA induced autophagy in MCF10A and MCF10A­ras cells by blocking the mammailian target of rapamycin signaling pathway. Furthermore, autophagy inhibition lead to higher MCF10A­ras cell death by TSA, thus indicating that autophagy is essential in cell survival. Taken together, the present study demonstrated that TSA causes oncogene­transformed cell apoptosis via activation of FOXO1 and HDACI­mediated autophagy induction, which served as important cell survival mechanisms. Notably, the present findings imply that a combination of HDACIs and autophagy inhibitors produce a synergistic anticancer effect.

CYFRA 21-1 is an early predictor of chemotherapeutic effectiveness in advanced nonsmall cell lung cancer: An observational study.

Serum cytokeratin 19 fragment (CYFRA21-1) has been found to be a useful prognostic marker in lung cancer. Previous studies have revealed that change in CYFRA21-1 synchronously predicted therapeutic effectiveness in advanced nonsmall cell lung cancer (NSCLC) after the second cycle of chemotherapy. The objective of this study was to investigate the early predictive value of percentage change in serum CYFRA21-1 from pretreatment to completion of the first cycle of chemotherapy for chemotherapeutic effectiveness in advanced NSCLC patients.Ninety-seven advanced NSCLC patients with elevated serum CYFRA21-1 level (≥3.8 µg/L), who received 2 platinum-containing drugs, were included in this retrospective study. Serum CYFRA21-1 had been assayed before and after the first cycle of chemotherapy. To evaluate the effectiveness of chemotherapy, patients were allocated to disease control (DC) and progressive disease groups. The percentage changes of serum CYFRA21-1 concentration before and after first-cycle chemotherapy that occurred in each group were evaluated for their ability to predict achievement of radiologic DC, that is, to predict therapeutic effectiveness.The percentage change of serum CYFRA21-1 and the prevalence of ≥5% weight loss were higher in patients with progressive disease than in those with DC. The differences in other clinical and pathological variables including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, cigarette smoking, histological type, gross type, clinical stage, and chemotherapy regimens of the 2 groups were not significant. Both multiple generalized linear model analysis and linear trend tests indicated that the percentage change of serum CYFRA21-1 concentration was independently and negatively linked to the effectiveness of chemotherapy for NSCLC (P < 0.01). The area under the receiver-operating characteristic curve of the percentage change in prediction of DC was 0.84 and the optimal cut-off value was17.5% (P < 0.001).The percentage change of serum CYFRA21-1 after completing the first cycle of chemotherapy was predictive of treatment effects and might be helpful in making early decisions to change chemotherapy regimens in patients with advanced NSCLC.

Circulating tumor cell clusters: What we know and what we expect (Review).

The major cause of cancer-associated mortality is tumor metastasis, a disease that is far from understood. Many studies have observed circulating tumor cells (CTCs) in patients' circulation systems, and a few latest investigations showed that CTC clusters have a potentially high capacity of metastasis. The capture and analysis of CTC clusters offer new insights into tumor metastasis and can facilitate the development of cancer treatments. We reviewed the research history of the CTC clusters, as well as the technologies used for detecting and isolating CTC clusters. In addition, we discuss the characteristics of CTC clusters and their roles in tumor dissemination. Clinical relevance of CTC clusters was also implicated in currently limited data. Moving forward, the next frontier in this field is to develop more efficient capture methods and decipher conundrums of characterization of CTC clusters. This will ultimately identify the clinical value of CTC clusters as a biomarker and therapeutic target.

Phenotype of circulating tumor cell: face-off between epithelial and mesenchymal masks.

Most patients with cancers died of distant metastasis. It is always difficult to find cancer metastasis in early time, let alone to prevent or cure it. Currently, oncologists place high hopes on circulating tumor cell (CTC), which, compared to current imaging methods, is found more sensitive for early metastasis. Recently, techniques for CTC enrichment and identification are developing quickly. However, there are great challenges in the clinical interpretation of CTC assessments. Increasing studies have shown the heterogeneity of CTCs, which may play different roles in cancer metastasis. Epithelial-mesenchymal transition is not only the main mechanism of the cancer cells invading the circulation system but also a distinguished characteristic of CTCs. Investigators are trying to differentiate specific subgroups of CTCs that are truly responsible for cancer metastasis. Here, we reviewed the current evidences on epithelial-mesenchymal transition of CTCs from perspectives of enrichment methods, biology, and its subgroups.

A circulating tumor cell cluster-based model for tumor metastasis (Hypothesis).

Metastasis is the major cause of mortality in patients with malignancies; however, the mechanisms of tumor cell dissemination and metastasis formation are obscure. Circulating tumor cells (CTCs) are believed to be a critical step for distant metastasis and are associated with a poor patient prognosis. The precise processes of metastasis formation from CTCs are vague. In the present study, we hypothesize that two CTC cluster-based mechanisms of tumor cell inoculation in ectopic organs may be viable: i) Formation of a micro-cancer embolus due to interception of CTC clusters by small vessels; and ii) formation of micrometastasis in an extravasation-dependent or -independent manner. Pathological evidence of micro-cancer emboli is critical for the verifications of this hypothesis. If proved true, this hypothesis will provide a novel perspective for cancer metastasis and has valuable clinical implications.

Immunotherapy for hepatocellular carcinoma: From basic research to clinical use.

Hepatocellular carcinoma (HCC) is a common cancer worldwide with a poor prognosis. Few strategies have been proven efficient in HCC treatment, particularly for those patients not indicated for curative resection or transplantation. Immunotherapy has been developed for decades for cancer control and is attaining more attention as a result of encouraging outcomes of new strategies such as chimeric antigen receptor T cells and immune checkpoint blockade. Right at the front of the new era of immunotherapy, we review the immunotherapy in HCC treatment, from basic research to clinical trials, covering anything from immunomodulators, tumor vaccines and adoptive immunotherapy. The mechanisms, efficacy and safety as well as the approach particulars are unveiled to assist readers to gain a concise but extensive understanding of immunotherapy of HCC.

A case report of different degrees of the left anterior, septal and posterior fascicular branch block.

We present a rare case of various conduction defects involving the left anterior, septal, and posterior branch in one patient. The different degrees of block of anterior, septal, and posterior fascicular of the left bundle branch indicate pathological changes in left ventricle. However, the values of this electrocardiographic presentation indicating the left ventricular function still need more investigations.