Currently, the two approved T cell products with chimeric antigen receptors (CAR) are from autologous T cells. These CAR T cells approved for clinical use must be generated on a custom-made basis. This case-by-case autologous T cell production platform remains a significant limiting factor for large-scale clinical application due to the costly and lengthy production process. There is also an inherent risk of production failure. The individualized, custom-made autologous CAR T cell production process also posts constriction on the wide application on diverse tumor types. Therefore, universal allogeneic T cells are needed for the preparation of universal CAR T cells that can serve as the “off-the-shelf” ready-to-use therapeutic agents for large-scale clinical applications. Genome-editing technologies including ZFN (zinc finger nuclease), TALEN (transcription activator-like effector nuclease), and CRISPR-Cas9 are being used to generate the universal third-party T cells. In addition, split, universal, and programmable (SUPRA) CARs are being developed to enhance the flexibility and controllability of CAR T cells. The engineered universal T cells and universal CARs are paving the road for a totally new generation of CAR T cells capable of targeting multiple antigens and/ or being delivered to multiple recipients without re-editing of T cells. This may escalate to a new wave of revolution in cancer immunotherapy. This review summarized the latest advances on designs and development of universal CARs, universal T cells, and clinical application of universal CAR T cells.

Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies have dramatically changed the natural history of multiple myeloma (MM). However, most patients eventually suffer a relapse and succumb to the disease. Chimeric antigen receptor (CAR) engineered T cells targeting B cell maturation antigen (BCMA), CD138, CS1 glycoprotein antigen (SLAMF7) and light chains are in active development for therapy of refractory /relapsed (RR) MM. CD19- targeted CAR T cells in conjunction with autologous stem cell transplantation also showed activity in RRMM. Dual- target CAR T cells are in clinical trials for RRMM. This review summarized the recent updates of ongoing CAR T clinical trials for multiple myeloma.

Severe GVHD is a lethal complication to ASCT, and a number of approaches are therefore being evaluated. Recently, Le Blanc et al. reported a case of grade IV therapy-resistant acute GVHD of the gut and liver that showed rapid improvement after infusion of mesenchymal stem cells. Here we describe two pediatric patients who developed severe refractory acute GVHD following ASCT and were successfully treated with AMSC from HLA-mismatched unrelated donors.

In many countries, floods are the leading natural disaster in terms of damage and losses per year. Early prediction of such events can help prevent some of those losses. Artificial neural networks (ANN) show a strong ability to deal quickly with large amounts of measured data. In this work, we develop an ANN for outputting flood inundation maps based on multiple discharge inputs with a high grid resolution (4 m × 4 m). After testing different neural network training algorithms and network structures, we found resilience backpropagation to perform best. Furthermore, by introducing clustering for preprocessing discharge curves before training, the quality of the prediction could be improved. Synthetic flood events are used for the training and validation of the ANN. Historical events were additionally used for further validation with real data. The results show that the developed ANN is capable of predicting the maximum flood inundation extents. The mean squared error in more than 98 and 86% of the total area is smaller than 0.2 m 2 in the prediction of synthetic events and historical events, respectively.

Background: The pathogenesis of multiple myeloma (MM) is not completely known. Uncovering the potential mechanism of MM initiation and progression is essential for identifying novel diagnostic and therapeutic targets. Herein, we explored the function and the working mechanism of circular RNA circ_0007841 in MM progression. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expression of circ_0007841, microRNA-338-3p (miR-338-3p) and bromodomain containing 4 (BRD4). Cell proliferation ability was analyzed through cell counting kit-8 (CCK8) assay, colony formation assay and flow cytometry. Transwell assays were conducted to measure the migration and invasion abilities of MM cells. Cell apoptosis was also assessed by flow cytometry. The interaction between miR-338-3p and circ_0007841 or BRD4 was confirmed by dual-luciferase reporter assay and RNA-pull down assay. Results: Circ_0007841 was highly expressed in bone marrow (BM)-derived plasma cells of MM patients and MM cell lines than that in healthy volunteers and normal plasma cell line nPCs. Circ_0007841 promoted the proliferation, cell cycle and metastasis and impeded the apoptosis of MM cells. miR-338-3p was a direct target of circ_0007841 in MM cells and circ_0007841 accelerated the progression of MM through targeting miR-338-3p. BRD4 could directly bind to miR-338-3p in MM cells and miR-338-3p exerted an anti-tumor role through targeting BRD4. Circ_0007841 promoted the activation of PI3K/AKT signaling via miR-338-3p/BRD4 axis. Exosomes generated from mesenchymal stromal cells (MSCs) elevated the malignant behaviors of MM cells via circ_0007841. Conclusion: Circ_0007841 acted as an oncogene to promote the proliferation, cell cycle and motility and restrain the apoptosis of MM cells through sequestering miR-338-3p to up-regulate the expression of BRD4.

Circular RNAs (circRNAs) possess important regulatory effects on multiple myeloma (MM) progression. Here, we aimed at exploring the function of circ_0007841 in MM and the underlying molecular mechanism. Expression of circ_0007841, microRNA (miR)-129-5p and Jagged1 (JAG1) was determined via qRT-PCR or western blot assay. Methyl thiazolyl tetrazolium (MTT) assay was applied to examine cell viability and IC50 value of MM cells to bortezomib (BTZ). Colony formation assay was performed to analyze cell proliferation. Moreover, cell apoptosis was assessed by flow cytometry and western blot analysis. Cell metastasis was evaluated by wound healing assay and Transwell assay. Function of circ_0007841 in vivo was determined by xenograft tumor assay. Target relationship between miR-129-5p and circ_0007841 or JAG1 was confirmed via dualluciferase reporter, RNA immunoprecipitation (RIP) and pull-down assays. The up-regulation of circ_0007841 and JAG1, and the down-regulation of miR-129-5p were detected in MM bone marrow aspirates and cells. Circ_0007841 knockdown significantly repressed cell proliferation, chemoresistance, and metastasis, while contributed to apoptosis of MM cells in vitro, and reduced tumor growth in vivo. Circ_0007841 targeted miR-129-5p, and miR-129-5p inhibition reversed impact of silencing of circ_0007841 on MM cells. JAG1 was a mRNA target of miR-129-5p, whose overexpression could undermine the miR-129-5p-mediated effects on MM cells. Circ_0007841 positively regulated JAG1 expression via absorbing miR-129-5p. Circ_0007841 knockdown inhibited MM cell proliferation, metastasis and chemoresistance through modulating miR-129-5p/JAG1 axis, suggesting that circ_0007841 might serve as a potential therapeutic target of MM.

To the Editor, Chimeric antigen receptor (CAR) T-cell targeted multiple myeloma antigens such as CD138, kappa-light chain, and Bcell maturation antigen (BCMA) as well as CD19 had been widely adopted. More and more CART clinical trials for MM presented encouraging results [1-3]. However, current CART treatment still faces the adverse reactions as cytokine release syndrome (CRS), myelosuppression, and other complications, especially, severe myelosuppression is often a fatal threat to patients. We adopted the stem cell infusion to promote hematopoietic recovery for a relapsed MM patient developing severe and persistent myelosuppression after CART cell therapy. A male patient with 56 years old was diagnosed with multiple myeloma, IgG, lambda type, stage II for ISS stage, and III for RISS stage. He had received nine courses of treatment including one course of PD regimen (bortezomib combined with dexamethasone) and eight courses of PAD regimen (bortezomib, epirubicin, and dexamethasone) before auto-stem cell transplantation (ASCT) and achieved the complete remission according to the evaluation criteria of the IMWG. Sufficient number of hematopoietic stem cells (6.2 × 10 8 /kg for MNC and 5.6 × 10 8 /kg for CD34 + cells) were harvested. On November 23, 2017, the patient received highdose melphalan (200 mg/m 2) and performed ASCT, hematopoiesis recovered 15 days after stem cell infusion.

The occurrence of primary extranodal non-Hodgkin's lymphoma (NHL) of soft tissue is rare, particularly in skeletal muscle. The present study describes a case of diffuse large B cell lymphoma of the right lower extremity and provides a detailed review of the literature associated with this disorder, with the aim of improving the future diagnosis and therapy of extranodal NHL. The present case report was of a 76-year-old woman who presented with a right thigh and calf mass. In view of the tumor's location and the patient's age, soft tissue tumors were considered to be soft tissue sarcoma. Imaging scans were performed to determine the location and size of the tumor, followed by a biopsy of the muscle. Histopathological examination then yielded a diagnosis of diffuse large B cell lymphoma. The patient then underwent 4 cycles of chemotherapy. There was evident relief of pain and swelling in the right extremity; however, positron emission tomography/computed tomography (PET/CT) determined insufficient treatment efficacy. Chemotherapy was adjusted for 2 cycles; however, the patient suffered an aggravation of edema, so a different chemotherapy regimen of bleomycin, cytarabine, vincristine, cyclosphamide and dexamethasone (BCOAD) was performed for a further 2 cycles. The edema was alleviated and magnetic resonance imaging revealed shrinkage of the lower limb mass and the right thigh mass was undetectable. In conclusion, the present case report demonstrated that PET/CT may help determine the efficacy of chemotherapy treatment and that the BCOAD chemotherapy regimen may be more effective than standard treatments in certain cases.