Glioblastoma is the most common and deadly primary brain tumor in adults. Low-dose,metronomic (LDM) temozolomide (TMZ) displays improved efficacy in the treatment of glioblastoma by targeting angiogenesis, but has a limited effect on recurrence. The antiangiogenesis drug ginsenoside Rg3 (RG3) is the main active ingredient of ginseng, a popular herbal medicine. Using an in vitro and a rat model of an orthotopic glioma allograft, this study was to determine whether RG3 enhanced the antiangiogenesis activity of LDM TMZ in the treatment of glioblastoma. Our results showed that combined use of TMZ with RG3 displayed additive inhibition on proliferation of both human umbilical vein endothelial cells (HUVEC) and rat C6 glioma cells in vitro. They additively arrested cell cycle, increased apoptosis, and decreased VEGF-A and BCL-2 expression in HUVEC. Antiangiogenesis effect was also evaluated in the rat model of orthotopic glioma allograft, based upon markers including relative cerebral blood volume (rCBV) by magnetic resonance imaging (MRI), VEGF levels and microvessel density (MVD)/CD34 staining. LDM TMZ alone was potent in suppressing angiogenesis and tumor growth, whereas RG3 alone only had modest antiangiogenesis effects. Combined treatment significantly and additively suppressed angiogenesis, without additive inhibitory effects on allografted tumor growth. These data provide evidence showing the efficacy of LDM TMZ on glioma treatment. The combined additive antiangiogenesis effect suggests that RG3 has the potential to further increase the efficacy of LDM TMZ in the treatment of glioblastoma.

Cell cycle regulatory pathway is a well-established pathway mainly dependent on cyclin-dependent kinases (CDKs), which are regulated positively by cyclins and negatively by cyclin-dependent kinase inhibitors(CKIs). Cyclin-dependent kinase 2 associate protein 1(CDK2-AP1) is a specific negative regulatory protein for CDK2, is important in the cancer cell cycle. However, the function of CDK2-AP1 in breast cancer remains unclear. We designed therefore explored the effects of CDK2-AP1 on breast cancer growth and its chemo-sensitivity. Expression of CDK2-AP1, CDK2 and CyclinD1 in 209 cases of pathological specimens using IHC staining was measured. Lost-of-function and Gain-of-function assays were used in vivo and in vitro relating to the specific role of CDK2-AP1 in breast cancer. We analyzed in vivo and in vitro the impact of CDK2-AP1 on chemotherapy sensitivity in breast cancer. The positive ratio of CDK2-AP1 expression was reduced successively in normal breast tissue, DCIS, invasive breast cancer and relapsed breast cancer, however, with CDK2 and CyclinD1 it was suggested that CDK2-AP1 was correlated closely with the tumorigenesis and progress, and might work as a tumor suppressor. After down-regulating CDK2-AP1 in breast cancer cells, the cell cycle was accelerated and cell proliferation enhanced. The cell cycle was arrested in G0/G1 phase and G2/M phase after up-regulating CDK2-AP1 in breast cancer cells, inhibiting cell proliferation. The expression of CDK2 and CyclinD1 changed accordingly after downregulation or upregulation of CDK2-AP1 by western blot, suggesting a role of the CDK2-AP1/CDK2/CyclinD1 cell cycle pathway in the initiation and progression of breast cancer. Similar results were obtained in animal assays. The data indicates that CDK2-AP1 can induce sensitivity to docetaxel treatment in breast cancer cells. CDK2-AP1 affects tumorigenesis, tumor growth and chemo-sensitivity by cell cycle regulation, which can potentially to be a therapeutical agent in breast cancer.

Introduction: Angiogenesis is an essential feature of liver cancer. Tumor hypoxia results from abnormal vessel architecture. Numerous studies have sufficiently demonstrated that Tanshinone IIA (Tan IIA) can increase blood flow and enhance microcirculation. The objectives of this study are to: 1 assess the impact of Tan IIA on tumor angiogenesis and architecture, 2 determine the impact of Tan IIA on tumor hypoxia and susceptibility to Sorafenib, and 3 clarify the relevant mechanisms.Methods: CCK8 and flow cytometry measured cell proliferation and apoptosis, respectively. Tube creation assay was used to investigate medication effects on angiogenesis and structure. Drug effects on tumor development, metastasis, and hypoxic tumor microenvironment are assessed in an orthotopic xenograft model of liver tumors. Protein expression was measured by Western blotting and immunohistochemistry.Results: Our results demonstrated that Tan IIA could not reduce tumor proliferation or enhance Sorafenib’s anti-tumor effect in vitro. Nevertheless, it can prevent Sorafenib from demolishing the typical vascular structure and aid sorafenib in blocking the recruitment of vascular endothelial cells by liver cancer cells. Although Tan IIA cannot inhibit tumor growth in vivo, it can significantly boost Sorafenib’s inhibitory effect on liver cancer, alleviate tumor microenvironment hypoxia, and minimize lung metastasis. This effect may be achieved by reducing HIF-1α and HIF-2α expression via the PI3K-AKT signal pathway.Discussion: Our results reveal the mechanism of Tan IIA in normalizing tumor blood vessels, provide innovative concepts and approaches to overcome chemotherapy resistance, and provide a theoretical basis for the clinical transformation and usage of Tan IIA.

Axillary lymph node dissection is an indispensable step in modified radical mastectomy for breast cancer. It is the most reliable method and the golden standard to determine the status of axillary lymph nodes. It is also of great importance to evaluate the prognosis and develop treatment plans for breast cancer patients. Axillary lymph node dissection can be anatomically divided into levels I, II, and III. Level I and Level II axillary lymph dissection is the standard clinical treatment of axillary lymph nodes positive breast cancer, whereas level III axillary lymph node dissection has been controversial. Level III axillary lymph node metastasis is one of the important factors that can easily cause distant metastasis and recurrence. It is also an important index to estimate the prognosis of breast cancer patients. To facilitate the decision of whether or not to perform level III lymph node dissection, we reviewed the indications, complications, and surgical procedures of level III lymph node dissection.

Regulatory T cells (Tregs), particularly the CD4+CD25+Foxp3+ Tregs, down regulate immunity and promote tumor cell growth by directly suppressing CD8+ and CD4+ T cells. Alternatively they can promote tumor growth by generating interleukin-10 (IL-10) and transforming growth factor β (TGFβ) in situ, which help tumor cells to evade the immune system. In vivo tumor models were prepared via subcutaneous injection with a suspension of B16 melanoma cells into the left upper flank of C57BL/6 J mice. The mice were randomized into five groups: radiotherapy (RT), chemotherapy (CT), radiochemotherapy (RCT), Inteferon α (INFα) groups, and a control group. Flow cytometry was used to determine the Tregs levels in the spleen and peripheral blood, and immunohistochemistry was performed to determine the expression levels of TGFβ and IL-10 in the tumor microenvironment. Tumor weight was significantly reduced in the CT or RCT groups (40.91 % and 41.83 %, respectively), while the reduction in tumor weight was relatively lower for the RT and IFNα groups (15.10 % and 13.15 %, respectively). The flow cytometry results showed that the ratios of CD4+CD25+Foxp3+ Tregs to lymphocytes and CD4+ cells in the spleen and in peripheral blood were significantly decreased after treatment with IFNα (P < 0.05). Expression of TGFβ and IL-10 in the tumor microenvironment in the CT and RT groups was higher compared with the control group (P < 0.01), while the expression of TGFβ and IL-10 in the INFα group was not significantly different (P > 0.05). The results show that INFα-2b inhibits cancer cell immune evasion by decreasing the levels of CD4+CD25+Foxp3+ Tregs and suppressing the expression of TGFβ and IL-10 in the tumor microenvironment.

Background: Phosphoinositide 3-kinases (PI3Ks) are lipid enzymes that regulate a wide range of intracellular functions. In contrast to Class I and Class III PI3K, which have more detailed descriptions, Class II PI3K has only recently become the focus of functional research. PIK3C2A is a classical member of the PI3Ks class II. However, the role of PIK3C2A in cancer prognosis and progression remains unknown.Methods: The expression pattern and prognostic significance of PIK3C2A in human malignancies were investigated using multiple datasets and scRNA-seq data. The PIK3C2A expression in renal clear cell carcinoma (KIRC) was then validated utilizing Western blot. The functional role of PIK3C2A in KIRC was assessed using combined function loss experiments with in vitro experiments. Furthermore, the correlation of PIK3C2A expression with tumor immunity was investigated in KIRC. The TCGA database was employed to investigate PIK3C2A functional networks.Results: Significant decrease in PIK3C2A expression in KIRC, demonstrated that it potentially influences the prognosis of diverse tumors, particularly KIRC. In addition, PIK3C2A was significantly correlated with the T stage, M stage, pathologic stage, and histologic grade of KIRC. Nomogram models were constructed and used to predict patient survival based on the results of multivariate Cox regression analysis. PIK3C2A knockdown resulted in significantly increased KIRC cell proliferation. Of note, PIK3C2A expression demonstrated a significant correlation with the infiltrating levels of primary immune cells in KIRC.Conclusion: These findings support the hypothesis that PIK3C2A is a novel biomarker for tumor progression and indicates dynamic shifts in immune infiltration in KIRC. Furthermore, aberrant PIK3C2A expression can influence the biological activity of cancer cells.