Survey of Stereotactic Body Radiation Oncology for Early Staged Non-Small Cell Lung Cancer in China

Purpose: To evaluate the current status of stereotactic body radiotherapy (SBRT) for early staged non-small cell lung cancer (NSCLC) at main cancer hospitals in China. Methods and Materials: The questionnaire was sent by mail and email to 21 hospitals, which include the patient enrollment, treatment technique, dose and fractionation, quality control, disease control and side effects. Results: Nineteen hospitals responded. It was found that SBRT has been used for early staged NSCLC in most of the hospitals participating in the survey. The patient characteristics and techniques were relatively consistent, but there were many controversies regarding dose fractionation and quality control. Conclusions: SBRT for early staged NSCLC has been applied at main cancer hospitals in China. However, considerable variation exists. The establishment of clinical guidelines and standardized quality control are crucial for further improvement.

Lx2-32c,a novel semi-synthetic taxane,exerts antitumor activity against prostate cancer cells in vitro and in vivo

Tubulin has been shown to be an effective target for the development of cytotoxic agents against prostate cancer. Previously, we reported that Lx2-32 c is an anti-tubulin agent with high binding affinity to tubulin. In this study, we investigated the potential of Lx2-32 c to act as an effective cytotoxic agent in the treatment of prostate cancer. MTT assays showed that Lx2-32 c was cytotoxic to all tested prostate cancer cell lines. The Lx2-32c-treated cells typically exhibited a rounded morphology associated with the onset of apoptosis, as evidenced by immunocytochemical staining. Human prostate cancer cell lines treated with Lx2-32 c arrest in the G2/M phase of the cell cycle and the treatment is associated with an increased ratio of cells in the sub-G0/G1 phase as determined by flow cytometry. Furthermore, expression of the cleaved form of poly(ADP-ribose) polymerase in prostate cancer cell lines treated with Lx2-32 c was shown by Western blotting assay. Xenograft implants of LNCa P and PC3-derived tumors in nude mice showed that Lx2-32 c treatment significant inhibited tumor growth with effects equivalent to those of docetaxel. These findings demonstrate the potential of Lx2-32 c as a candidate antitumor agent for the treatment of prostate cancer.

Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells

Glioblastoma （GBM） is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM- derived cancer stem ceils （GSCs）. Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls （a neural stem cell （NSC） line and normal brain tissue） identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down-regulated in GBMs such as SPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM.

PCC0208017,a novel small-molecule inhibitor of MARK3/MARK4,suppresses glioma progression in vitro and in vivo

Gliomas are the most common primary intracranial neoplasms among all brain malignancies,and the microtubule affinity regulating kinases(MARKs)have become potential drug targets for glioma.Here,we report a novel dual small-molecule inhibitor of MARK3 and MARK4,designated as PCC0208017.In vitro,PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4,and strongly reduced proliferation in three glioma cell lines.This compound attenuated glioma cell migration,glioma cell invasion,and angiogenesis.Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau,disrupted microtubule dynamics,and induced a G2/M phase cell cycle arrest.In an in vivo glioma model,PCC0208017 showed robust anti-tumor activity,blood-brain barrier permeability,and a good oral pharmacokinetic profile.Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4.Taken together,our study describes for the first time that PCC0208017,a novel MARK3/MARK4 inhibitor,might be a promising lead compound for treatment of glioma.

Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection

Natural killer (NK) cells are indispensable components of both the innate and adaptive immune response. However,their precise roles in the cross-talk between innate and adaptive immunity during influenza virus infection remaincontroversial. By comparing NK cell dynamics and activity under a sub-lethal dose and high dose of influenza virusinfection, we showed that influenza virus PR8 directly infected NK cells during natural infection, which wasconsistent with our previous findings obtained from an in vitro investigation of human NK cells. The impairments incytotoxicity and IFN-γ production by spleen NK cells following high-dose infection were accompanied by decreasedvirus-specific killing mediated by cytotoxic T lymphocytes (CTLs). Importantly, the weakened CTL activity could bereversed by adoptive transfer of spleen NK cells harvested from low-dose-infected mice but not healthy donors.Taken together, our data provide direct evidence supporting the contribution of NK cells to antiviral T-cellresponses. This study also indicates that a novel NK-targeted immune evasion strategy is used by influenza virusto shrink both innate and adaptive immune responses.

Design,Synthesis and Biological Activities of Quinazoline Containing Sorafenib Analogs as Antitumor Agents

A series of novel sorafenib derivatives containing quinazoline moiety were designed and synthesized. Their anti-proliferative activities against HCT116 and HCT115 cell lines were evaluated using MTT assay. Most of the synthesized compounds showed significant cytotoxicity against the selected cell lines. These cytotoxicities were consistent with their inhibitory activity against the phosphorylation of c-Raf, MEK1/2 and ERK1/2. Compound GD-09 also showed much stronger anti-tumor activity than that of sorafenib in vivo by B16 melanoma xenograft model test.