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Ibrutinib might improve the efficacy of anti‐CD19 chimeric antigen receptor (CD19 CAR) T‐cell therapy in chronic lymphocytic leukemia (CLL). We studied the possibility and mechanism of the synergistic effect of ibrutinib and CAR‐T cells in other types of lymphoma. In this study, we selected the CD19 CAR‐T cells of a patient with lymphoma who failed in his CD19 CAR‐T‐cell therapy and a dose of 8 mg/kg/d ibrutinib. Subcutaneous and tail vein tumorigenic mice were established with Raji cells. The differences in the synergistic effect between these 2 models were compared by bioluminescence imaging (BLI) monitoring and flow cytometry (FCM). The expression of the STAT‐3 signaling pathway was assessed by western blot analysis. There was no synergistic effect of ibrutinib and CD19 CAR‐T cells in vitro. Programmed cell death‐ligand 1 (PD‐L1) was expressed in 0.23 ± 0.06% of Raji cells. In the subcutaneous tumorigenic model, the luciferase signal was reduced significantly in the group receiving ibrutinib combined with CD19 CAR‐T cells. Moreover, the proportion of CD19 CAR‐T cells was higher in the polytherapy group than in the CAR‐T‐cell monotherapy group. However, we did not get an analogous synergistic effect in the tail vein tumorigenic model. STAT‐3 signaling pathway expression in the residual tumor cells did not differ between those with and those without ibrutinib, suggesting that the IL‐10/STAT‐3/PD‐L1 pathway was not involved in the synergistic effect. Therefore, some other mechanism might be a target for ibrutinib. Our results provide evidence for the use of ibrutinib in polytherapy for other types of B‐cell lymphoma., Our results might indicate that no IL‐10/STAT‐3/PD‐L1 pathways were involved in the synergistic effect. Then some other mechanism in the microenvironment might be a possible target for ibrutinib. We expect our results would provide evidence for the use of ibrutinib in polytherapy for other types of B‐cell lymphoma.

In breast cancer, the cancer stem cells (CSCs) are thought to be the main cause of metastasis and recurrence. Targeting of CSCs or cancer cells with stem cell-like properties has become a new approach for the treatment of breast cancer. Glabridin (GLA), a phytochemical from the root of Glycyrrhiza glabra, exhibited effective antitumor properties in various human cancer cells. However, the roles of GLA in the regulation of CSC-like properties and the underlying molecular mechanisms remain unclear. Here, we reported that GLA attenuated the CSC-like properties through microRNA-148a (miR-148a)/transforming growth factor beta (TGFβ)-SMAD2 signal pathway in vitro and in vivo. In MDA-MB-231 and Hs-578T breast cancer cell lines, GLA enhanced the expression of miR-148a through DNA demethylation. By targeting of the SMAD2-3'-UTR, miR-148a blocked the expression/activation of SMAD2, and in turn, restored the epithelial characteristics, adhesive abilities, and CSC-like properties. Furthermore, in mouse xenograft models, we also confirmed that GLA attenuated the tumor growth, mesenchymal characteristics, and CSCs-like properties via demethylation-activated miR-148a. Our findings suggested a potential treatment strategy to reduce the CSCs-like properties, and therefore enhance the effectiveness of breast cancer therapy.

Breast cancer is a major health problem worldwide. Current standard practices for treatment of breast cancer are less than satisfactory because of high rates of metastasis. Arsenic trioxide (As(2)O(3)), which induces demethylation of DNA and causes apoptosis, has been used as an anti-tumor agent. Little is known, however, regarding its anti-metastatic effects. The microRNA-200c (miR-200c), which is frequently lowly expressed in triple negative breast cancers (TNBCs), inhibits metastasis by inducing the mesenchymal to epithelial transition (MET). Here, we report that As(2)O(3) attenuates the migratory and invasive capacities of breast cancer cells, MDA-MB-231 and BT-549. Notably, As(2)O(3) induces an MET in vitro and in vivo, as determined by the increased expression of the epithelial marker, E-cadherin and decreased expressions of mesenchymal markers, N-cadherin and vimentin. Moreover, As(2)O(3) up-regulates the expression of miR-200c through demethylation. Over-expression of miR-200c enhances the expression of E-cadherin and decreases the expressions of N-cadherin and vimentin. Further, in MDA-MB-231 cells exposed to As(2)O(3), knockdown of miR-200c blocks the As(2)O(3) -induced MET. Finally, in MDA-MB-231 and BT-549 cells exposed to As(2)O(3), knockdown of miR-200c decreases the As(2)O(3) -induced inhibition of the migratory and invasive capacities. By identifying a mechanism whereby As(2)O(3) regulates miR-200c and MET, the results establish the anti-migration/invasion potential of arsenic trioxide.

Objectives Transfusional iron overload is of major concern in hematological disease. Iron-overload-related dyserythropoiesis and reactive oxygen species (ROS)-related damage to hematopoietic stem cell (HSC) function are major setbacks in treatment for such disorders. We therefore aim to investigate the effect of iron overload on hematopoiesis in the patients and explore the role of ROS in iron-induced oxidative damage in hematopoietic cells and microenvironment in vitro. Patients and methods The hematopoietic colony-forming capacity and ROS level of bone marrow cells were tested before and after iron chelation therapy. In vitro, we first established an iron overload model of bone marrow mononuclear cells (BMMNC) and umbilical cord-derived mesenchymal stem cells (UC-MSC). ROS level, cell cycle, and apoptosis were measured by FACS. Function of cells was individually studied by Colony-forming cell (CFC) assay and co-culture system. Finally, ROS-related signaling pathway was also detected by Western blot. Results After administering deferoxamine (DFO), reduced blood transfusion, increased neutrophil, increased platelet, and improved pancytopenia were observed in 76.9%, 46.2%, 26.9%, and 15.4% of the patients, respectively. Furthermore, the colony-forming capacity of BMMNC from iron overload patient was deficient, and ROS level was higher, which were partially recovered following iron chelation therapy. In vitro, exposure of BMMNC to ferric ammonium citrate (FAC) for 24 h decreased the ratio of CD34+ cell from 0.91 ± 0.12% to 0.39 ± 0.07%. Excessive iron could also induce apoptosis, arrest cell cycle, and decrease function of BMMNC and UC-MSC, which was accompanied by increased ROS level and stimulated p38MAPK, p53 signaling pathway. More importantly, N-acetyl-L-cysteine (NAC) or DFO could partially attenuate cell injury and inhibit the signaling pathway induced by excessive iron. Conclusions Our study shows that iron overload injures the hematopoiesis by damaging hematopoietic cell and hematopoietic microenvironment, which is mediated by ROS-related signaling proteins.

Melt treatment is widely used to mediate the structure of materials. Recently, it is evidenced to be a new way to improve the glass forming ability (GFA) and thermal stability of the amorphous alloys. Bulk metallic glass was obtained through this process in the Al-Ni-La alloy system. In this work, the mechanism of melt treatment on the GFA and thermal stability of the Al-Ni-La alloy was studied. A Ni-rich metastable high-melting-temperature-phase is found to occur to this alloy system. The elimination of the Ni-rich phase through the melt treatment is attributed to stabilize the thermal stability of the melt and, accordingly, enhances the GFA and thermal stability of the amorphous alloy.

More attention has been paid to bulk metallic glasses (BMGs) in recent years due to their superior properties, and they have already been developed successfully in many systems such as Zr-, Fe-, Mg-, Cu-, Ti-, Ni- and La-based alloys. [1–6] In the meantime, Al-based metallic glass has also received particular interest because of its low density and potential aerospace applications. [7] However, an Al-based metallic glassy rod with a diameter of 1 mm has not yet been produced. Mechanical properties of these materials are usually measured by examining wires and ribbons. [8,9] Therefore, the research and application of Al-based metallic glasses are limited to a large extent due to the sample size. It is important and significant to develop Al-based BMGs. Different methods, such as alloying for example, which are popular and effective in other alloy systems, [10] have been employed to improve the glass-forming ability (GFA) of Al-based metallic glasses. They have little effect on the GFA of Al-based alloy systems. [11,12] The low GFA of Al-based alloys results from the existence of local-ordering clusters and high-melting-temperature phases in the alloy melt, which usually act as nucleation sites. This further promotes crystallization: the precipitation of fcc-Al, and intermetallics, which deteriorate the GFA. In this paper, the successful preparation of an Al-based BMG with a diameter of 1 mm in the Al85.5Ni9.5La5 (in atomic percentage) alloy by a melt-treatment technique is described. The treatment is adapted to not only remove the pre-existing nuclei but also to realize a high cooling rate. The thermal and mechanical properties of the Al85.5Ni9.5La5 BMG, along with its compressive-fracture behavior are explored for the first time. This work will greatly promote the development and application of Al-based BMGs. Figure 1a shows a photograph of an Al85.5Ni9.5La5 BMG cylindrical rod with a diameter of 1 mm. The surface is smooth and lustrous, like other as-cast BMGs. Figure 1b shows X-ray diffraction (XRD) patterns of as-cast ribbons, sheets and rods. It can be seen that only one broad diffraction peak in the 2u range from 358 to 458, characteristic of an amorphous structure, is detected, without any crystalline peaks. Figure 2 shows differential scanning calorimetry (DSC) curves of the as-cast ribbons, sheets and rods. The three traces display similar glass-transition and crystallization behaviors and indicate similar amounts of exothermic heat, which is consistent with the XRD results. In comparison to the GFA of Al86Ni9La5 reported in ref. [13], we found that a larger size of amorphous alloy is obtained with our casting strategy than with the ordinary wedge-casting method. COMMUNICATION