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Background: What is the difference in efficacy and side effects of radiotherapy bridging CAR-T therapy versus CAR-T therapy followed by radiotherapy? Patients and methods: Fourteen R/R DLBCL patients received radiotherapy before CAR-T therapy (R-C group). R-C group was divided into: 1-3 months radiotherapy before CAR-T therapy (1-3 mons) group and more than 3 months before CAR-T therapy (more than 3 mons) group. Seventeen patients received radiotherapy 2-3 months after CAR-T therapy (C-R) group. Results: In R-C group, ORR was 81.82% and CR was 54.55%. In C-R group, ORR was 64.71% and CR was only 35.29% after CAR-T therapy, but CR became 64.71% after the following radiotherapy. CAR-T cell peaks were higher in R-C group than in C-R group, and higher in R-C (1-3 mons) group than that in R-C (more than 3 mons) group. Three patients in R-C group died of CRS, no patient in C-R group died of CRS. There was no difference in CRS and ICANS in R-C and C-R group. CRS and ICANS grades were higher in R-C (1-3 mons) group than that in R-C (more than 3 mons) group. Conclusions: Radiotherapy bridging CAR-T therapy had higher ORR. While, CAR-T therapy followed by radiotherapy might improve CR without higher CRS and ICANS. Trial registration number ChiCTR1800019622.

Haibo Zhu,1 Haobin Deng,2 Juan Mu,1 Cuicui Lyu,1 Yanyu Jiang,1 Qi Deng1 1Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, People’s Republic of China; 2The First Central Clinical College of Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Qi Deng No. 24, Fukang Road, Tianjin, People’s Republic of ChinaTel +8613612055872Email kachydeng@126.comBackground: To observe efficacy of the anti-CD22 chimeric antigen receptor modified (anti-CD22-CAR) T cell salvage therapy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and B cell acute lymphoid leukemia (B-ALL) patients whose disease did not reach CR or progressed again after anti-CD19-CAR T cell therapy.Methods: In our study, seven R/R DLBCL patients reached stable disease (SD) or progression of disease (PD) after their anti-CD19-CAR T cell therapy. Only three in all the six R/R B-ALL patients obtained complete response (CR)/CR with incomplete count recovery (Cri) in their anti-CD19-CAR T cell therapy, but they relapsed again in the following three, six and one months. Then, all these thirteen R/R DLBCL and B-ALL patients received anti-CD22 CAR-T cell salvage therapy because their disease did not reach CR or progressed again.Results: Four R/R DLBCL patients obtained CR, while two R/R DLBCL patients achieved PR and one patient achieved SD. But only two R/R B-ALL patients obtained Cri in their anti-CD22 CAR-T cell salvage therapy. The overall survival (OS) of R/R DLBCL patients after the anti-CD22 CAR-T cell therapy was 6.142± 3.395 months until August 31, 2020. There was no different of the median expansion peaks of the two kinds of CAR T cells (P=0.920). The time of anti-CD22-CAR T cell proportion peak days was later than that of the time of anti-CD19-CAR T cell peak days post infusion (P=0.022). Their cytokine release syndrome (CRS) was graded 2– 4 in their anti-CD19-CAR T cell therapy, while the notable CRS was graded 1– 2 in their anti-CD22-CAR T cell therapy. But there was no difference in the CRS and the immune effect or cell associated neurotoxic syndrome (ICANS) grades in the two kinds of therapies. And there was no difference in the hematological toxicity grades in the two kinds of therapies.Conclusion: The anti-CD22-CAR T cell salvage therapy is highly effective in R/R DLBCL patients than in R/R B-ALL patients who failed in anti-CD19-CAR T cell therapy before. We need to expand the number of R/R DLBCL or B-ALL patients and continue to observe.Trial Registration: ChiCTR-ONN-16009862 and ChiCTR1800019298.Keywords: chimeric antigen receptor, CAR, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, anti-CD19, anti-CD22

The addition of a small amount of oxygen improves the mechanical properties, especially plasticity, of Ti45.7Zr33Ni3Cu5.8Be12.5 amorphous alloy composites (AACs) at room temperature (298 K). Compared to the plasticity of AACs without added O (5%), the plasticity of the composites with 0.73 at.% O (nominal composition) was much higher (11 %). Even at O content higher than 0.73 at.%, the AACs exhibited good plasticity. The highest plasticity of ∼12.3 % was observed with 2.87 at.% O. Two distinct mechanisms are proposed to explain the enhanced plasticity of the AACs. At low O content, although deformation-induced phase transformation was suppressed, a substantial amount of α’’ martensite was formed. The microstructural features of α’’ martensite, such as thinner laths and homogeneous distribution, induced the formation of multiple shear bands in the amorphous matrix. At high O content, deformation-induced phase transformation was seriously suppressed. A dispersed nano ω phase was formed during rapid solidification in AACs with O content higher than 1.45 at.%. This resulted in a weakening in the anisotropy of β dendrites and led to their homogenous deformation. Furthermore, multiple shear bands were formed in the amorphous matrix. Apart from plasticity, the strength of the AACs also increased with an increase in the O content. This phenomenon was explained in terms of three mechanisms, viz. the solid-solution-strengthening effect of O, fine-grain strengthening of β dendrites, and secondary phase strengthening by the nano ω phase.

BackgroundPerivascular adipose tissue (PVAT), an active endocrine organ, exerts direct effect on vascular tone through paracrine. Activation of PVAT metabolism plays an inhibitory role in atherosclerosis via secreting relaxing factors. The present studies were designed to investigate the role of PVAT metabolism in regulation of hypertension.Materials and methodsApolipoprotein E (ApoE) knockout mice with BMP4 knockout in adipose tissue or brown adipose tissue (aP2-DKO or UCP1-DKO, respectively) were used for exploring the role of impaired PVAT metabolism in hypertension. Vascular function was assessed using wire myography. The potential regulatory factor of vascular function was explored using qPCR and ELISA and further confirmed in perivascular fat cell line.ResultsKnockout of BMP4 either in adipose tissue or specifically in BAT aggravates high-fat diet (HFD, 40% fat)-induced hypertension and endothelial dysfunction in ApoE–/– mice. In the meanwhile, deficiency of BMP4 also aggravates Ang II (angiotensin II) -induced hypertension and vascular remodeling in ApoE–/– mice. Moreover, deficiency of BMP4 inhibits NO release and induces ROS production. In vitro system, aortic rings pretreated with PVAT extracts from BMP4-DKO mice showed increased vasoconstriction and reduced endothelial-dependent relaxation compared with the controls. We further demonstrated that PVAT of BMP4-DKO mice expressed higher level of angiotensinogen (AGT) and Ang II compared with the controls.ConclusionImpaired PVAT metabolism aggravates hypertension, and this effect is dependent on the activation of local renin-angiotensin-aldosterone system (RAAS). The results of this study first demonstrate the regulatory role of PVAT metabolism in hypertension.

A luminescent Cd(II) coordination polymer, namely {[Cd(btic)(phen)]·0.5H2O}n (CP-1) (H2btic = 5-(2-benzothiazolyl)isophthalic acid, phen = 1,10-phenanthroline), was constructed through the mixed-ligand method under solvothermal conditions. CP-1 manifests a chain structure decorated with uncoordinated Lewis basic N and S donors. CP-1 exhibits high sensing towards Zn2+, Fe3+ and Cr2O72− ions with fluorescence enhancement or quenching. CP-1 exhibited a fluorescence enhancement for Zn2+ ions through weak binding to S and N atoms, and a fluorescence quenching for Fe3+ and Cr2O72− ions by an energy transfer process. The binding constants were calculated as 1.812 × 104 mol−1 for Zn2+, 4.959 × 104 mol−1 for Fe3+ and 1.793 × 104 mol−1 for Cr2O72−. This study shows CP-1 as a rare multi-responsive sensor material for the efficient detection of Zn2+, Fe3+ and Cr2O72− ions.

Nickel (Ni)/nickel oxide heterostructures have been demonstrated to be promising candidates to replace catalysts based on conventional noble metals for electrochemical water splitting. Here we report a universal, controlled scalable arc-discharge method to produce Ni/NiO nanoparticles encapsulated in graphene as multifunctional catalysts for the hydrogen evolution reaction (HER), urea oxidation reaction (UOR) and 5-hydroxymethylfurfural (HMF) oxidation reaction. We find that the catalytic activity of Ni/NiO@graphene can be altered dramatically by the electronic structure of the graphene layer which can be tuned by introducing oxygen dopants through a post-annealing process. Due to the synergistic effect of Ni nanoparticles, Ni/NiO heterostructures and the oxygen-doped graphene layer, the as-prepared catalysts show superior catalytic activity for the HER and UOR. The overall electrochemical water splitting in alkaline electrolyte with urea only requires 1.46 V. Moreover, the as-fabricated composites can catalyze the HMF oxidation reaction efficiently. This work provides a viable strategy to solve the energy challenge.

Background: Although anti-CD19 chimeric antigen receptor (CAR) T cell therapy has achieved satisfactory results in relapsed/refractory (R/R) Follicular lymphoma (FL), R/R FL patients with high-risk disease characteristics, previous HSCT, bulky disease, and POD24 had a low complete response (CR).Patients and methods: Twenty-seven R/R FL patients with higher advanced disease stage, higher tumor burden or higher previous treatment lines had already received Bruton tyrosine kinase (BTK) inhibitors prior to anti-CD19-CAR T-cell therapy, or received BTK inhibitors as combination/maintenance therapy in this study. The clinical response and adverse events (AEs) were observed in this study.Results: All R/R FL patients who received BTK inhibitors prior to the study had higher advanced disease stage, tumor burden, and previous treatment lines than those who did not receive BTK inhibitors. Patients who received combination/maintenance therapy with BTK inhibitors had higher advanced disease stage and tumor burden than those who did not receive BTK inhibitors. There was no difference of POD 24, TP53, tFL, IPI score in the three groups with or without BTK inhibitors. The clinical response was lower in POD 24 group than that of in no POD 24 group. But the other poor prognostic factors did not affect the clinical response with the methods of BTK inhibitors as a bridge to CAR-T cell therapy or a combination/maintenance treatment with CAR-T cell therapy. There was no difference of the mean peaks of anti-CD19-CAR T cells in three groups with or without BTK inhibitors. It was higher in no POD 24 group and in FL group. But it was no difference between the FLIPI 1 1-2 and FLIPI 1 3-5 group, the FLIPI 2 1-2 and FLIPI 2 3-5 group. The CRS grades were higher in BTK inhibitors before CAR-T cell therapy group, no POD 24 group, FL group, FLIPI 3-5 grade group. The ICANS grade was higher in BTK inhibitors before CAR-T cell therapy group.Conclusion: Other poor prognostic factors except POD 24 did not affect clinical response with the methods of BTK inhibitors as a bridge to anti-CD19-CAR T cell therapy or a combination/maintenance treatment with CAR-T cell therapy in R/R FL patients.Trial registration: The study was registered at http://www.chictr.org.cn/index.aspx as ChiCTR-ONN-16009862 and http://www.chictr.org.cn/index.aspx as ChiCTR1800019622.

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.

We studied the efficacy and safety of the combined treatment with programmed cell death 1 (PD-1) inhibitors and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and subsequent PD-1 inhibitor maintenance treatment in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and high tumor burden. Forty-four R/R DLBCL patients with high tumor burden were enrolled in this study. The experimental group of 26 patients received combined therapy with PD-1 inhibitors and anti-CD19-CAR T cells, while the control group of 18 patients received anti-CD19-CAR T-cell therapy alone. The objective response rate (ORR) was 65.39% and 61.11% in the combination and control groups, respectively. The PD-1 inhibitor maintenance therapy was selected for patients who achieved complete response or partial response in the combination therapy group. Progression-free survival and overall survival rates in the combination group were higher than those in the control group 3 and 12 months after CAR T-cell infusion. There was no significant difference in the grade of cytokine release syndrome or immune effector cell associated neurotoxic syndrome between the two groups. In the maintenance therapy group, only eight patients experienced grade 1 Common Terminology Criteria for Adverse Events (CTCAE) and three grade 2 CTCAE. Overall, we found that the ORR was not affected by the combination therapy with PD-1 inhibitors and anti-CD19-CAR T cells. However, patients who had achieved the ORR might benefit from PD-1 inhibitor maintenance therapy after combination therapy without increased side effects.

A patient with relapsed mantle cell lymphoma (MCL) showed stable disease after receiving ibrutinib therapy as a salvage therapy, after the failure of his first chimeric antigen receptor (CAR)-T 19 cell therapy.The combined effects of CAR-T 19 cells from the patient and ibrutinib on JeKo-1 cell were explored in vitro and in vivo.The expression of programmed death-1 (PD-1) receptor on CD3+ T cells in the peripheral blood decreased from 82.95% in the first CAR-T 19 cell therapy to approx. 40% after 14 months of ibrutinib therapy. When the disease progressed again during the ibrutinib therapy, the patient was enrolled into the same clinical trial of CAR-T 19 cell therapy.The efficacy of CAR-T 19 cells increased after the ibrutinib therapy. The mRNA expression level of PD-1 in CAR-T 19 cells after ibrutinib therapy was lower than in CAR-T 19 cells before the ibrutinib therapy. Nevertheless, CAR-T 19 cell therapy combined with ibrutinib had no synergistic effect in a short term in vitro and in the JeKo-1 cell mouse model.We expect our results to provide evidence for the combination treatment of ibrutinib for MCL or even other types of B-cell lymphomas. Moreover, the improvement in CAR-T 19 cell function was based on long-term ibrutinib therapy.

The H2020 MOSES project aims to significantly enhance the short sea shipping component of the European supply chain by developing the following innovations: an Innovative Feeder vessel outfitted with a Robotic Container-Handling System, an Autonomous Tugboat swarm that cooperates with an Automated Mooring System, and a Digital Matchmaking and Logistics Collaboration Platform. Towards this goal, the MOSES project implements a user-driven development approach that aims to ensure that the systems are designed to satisfy actual stakeholder needs. This paper aims to comprehensively map the needs of the MOSES stakeholders and translate them into formally structured user requirements for each innovation, which will be used at a later stage of development to determine system requirements and specifications. The employed MOSES User Requirements Extraction Methodology includes determining key design goals, identifying the stakeholder categories that affect the future operation of the MOSES innovations, eliciting stakeholder needs from the results of an online survey and two stakeholder workshops. The results show that the MOSES stakeholders focus on environmental impact, safety of automated and autonomous functionalities, and operational flexibility and dependability. Based on the identified needs, this paper documents essential requirements that determine the main functionalities of the MOSES innovations and relate to the project's broad objectives. These requirements provide the basis for elaborating the qualities and performance characteristics of the innovations at a later stage of development.

Background: Gestational diabetes mellitus (GDM) has significant short and long-term health consequences for both the mother and child. There is limited but suggestive evidence that inulin could improve glucose tolerance during pregnancy. This study assessed the effect of inulin on glucose homeostasis and elucidated the molecular mechanisms underlying the inulin-induced antidiabetic effects during pregnancy. Method: Female C57BL/6 mice were randomized to receive either no treatment, high-dose inulin and low-dose inulin for 7 weeks with measurement of biochemical profiles. A real-time2 (RT2) profiler polymerase chain reaction (PCR) array involved in glycolipid metabolism was measured. Results: Inulin treatment facilitated glucose homeostasis in a dose-dependent manner by decreasing fasting blood glucose and total cholesterol, and improving glucose tolerance. Suppressing resistin (RETN) expression was observed in the inulin treatment group and the expression was significantly correlated with fasting blood glucose levels. The ratios of p-IRS to IRS and p-Akt to Akt in liver tissue and the ratio of p-Akt to Akt in adipose tissue increased significantly after inulin treatment. Conclusions: Our findings indicated the observed decreased glucose level may be due to insulin signaling pathway repairment due to decreased expression of RETN and enhanced phosphorylation of IRS and Akt in GDM mice.

The present study aimed to compare the differences between the humanized CD19 chimeric antigen receptor (CAR)-T cell therapy and the murine CD19 CAR-T therapy in recurrent B-acute lymphoblastic leukemia (B-ALL). A 62-year-old male patient who had B-ALL (BCR/ABL+) for 4 years was diagnosed with relapsed central nervous system leukemia (CNSL). After several courses of high dose methotrexate combined with intrathecal chemotherapy, the patient received murine CD19 CAR-T therapy and achieved complete response (CR). The patient was diagnosed with relapsed CNSL again 15 months after his murine CD19 CAR-T therapy, and was therefore enrolled in the humanized CD19 CAR-T therapy. Subsequently, the present study aimed to compare murine and humanized CD19 CAR-T cells against Nalm-6 cells in vitro and in mice. The patient initially achieved CR from his murine CD19 CAR-T therapy with Grade 1 cytokine-release syndrome (CRS) and Grade 1 CAR-T cell-related encephalopathy syndrome (CRES). The patient then achieved CR again from his humanized CD19 CAR-T therapy with Grade 1 CRS and Grade 2 CRES. Peak levels of CD19 CAR-T cells were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy 7 days after infusion in the peripheral blood, in bone marrow and in cerebrospinal fluid (CSF). The cytokine levels were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy in the peripheral blood and in CSF. The cytotoxicity to Nalm-6 cells was higher in humanized CD19 CAR-T cells than that in murine CD19 CAR-T cells in vitro. In Nalm-6 BALB/c mice, the median survival time of mice in the murine CD19 CAR-T group was 35 days, while it was 43 days in the humanized CD19 CAR-T group. In conclusion, humanized CD19 CAR-T cell therapy had a better curative effect than that of murine CD19 CAR-T therapy, and may be used as a salvage treatment for recurrent B-ALL after treatment with murine CD19 CAR-T therapy.

Ovarian cancer is one of the most fatal gynecological cancers. For most ovarian cancer patients, nutritional risk or malnutrition may accompany them for life. Regular nutritional risk screening, timely nutritional assessment and necessary nutritional treatment play an extremely important role in the process of comprehensive treatment of ovarian cancer. The nutritional status and influence of ovarian cancer patients, preoperative screening and assessment of nutritional risk, preoperative and postoperative nutritional treatment indicate that nutritional treatment of ovarian cancer is one of the key factors in the treatment of cancer. We have summarized the status and progress of nutritional support therapy for ovarian cancer. We are aimed to improve the understanding of the impact of nutritional support therapy for ovarian cancer and to guide the clinical work.

Previous study indicated that co-infusion of cord blood cells may potentially improve the outcome of haploidentical donor (HID) transplantation. In this study, we analyzed the outcomes of patients who underwent HID transplantation supported by cord blood when compared with HLA-matched unrelated donor (URD) transplantation. Starting in 2015, 40 patients with hematopoietic malignancies underwent HID transplantation and 26 patients underwent URD transplantation. Hematopoietic recovery, the incidences of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was comparable in the two groups. At two year, the relapse risk in HID group was significantly lower than in URD group (RR 4.630; 95%CI, 1.081-19.839

The short tungsten fibre reinforced Zr41.2Ti13.8Ni10.0Cu12.5Be22.5 bulk metallic glass composites with macroscopic isotropic mechanical properties were prepared by infiltration and rapid solidifica...

Mechanical reliability of metallic glass composites is an important performance affecting their engineering applications as structural materials. In this work, the reliability of shape memory bulk metallic glass composites was evaluated by Weibull analysis. The Weibull modulus of mechanical properties, especially the plastic strain was improved more than 72% by 1 cycle mechanical training at 800~900 MPa or by 10 cycles at 600 MPa. The mechanism of enhanced reliability by proper mechanical training was revealed. These proper training treatments would provide more martensite nuclei, thus reduce the randomness of martensitic transformation and shear bands initiation. This investigation provides a method for improving the mechanical reliability of bulk metallic glass composites for the first time.

Qing Li,1 Juan Mu,1 Jijun Yuan,2 Zhenxing Yang,2 Jia Wang,1 Qi Deng1 1Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, People’s Republic of China; 2Medical Department, Shanghai Genbase Biotechnology Co., Ltd, Shanghai 201203, People’s Republic of ChinaCorrespondence: Qi Deng Email kachydeng@126.comPurpose: To investigate the donor chimerism changes and curative effects associated with the use of autologous anti-CD19 chimeric antigen receptor (CAR) T cells with B-cell acute lymphoblastic leukemia (B-ALL) presenting with a low donor chimerism level and relapse after allogeneic hematopoietic stem cell transplant (allo-HSCT).Methods: Nine patients with B-ALL showing low donor chimerism level and relapse after allo-HSCT were enrolled. Patients 1– 3 received CD19 CAR-T cell therapy using cells derived from autologous peripheral blood mononuclear cells (PBMCs) (comprising a mixture of patient and original donor cells) as their donors could not provide PBMCs. Samples from the other six patients (Patients A–F) were investigated only in vitro. The changes in the degree of donor chimerism, function of the CD19 CAR-T cells and T cells in all nine patients were analyzed in vitro. The therapeutic effects and adverse events (AEs) were also evaluated in Patients 1– 3.Results: The CAR-T cells and T cells in all nine patients showed complete donor chimerism restoration following a 12-day culture period in vitro. These CD19 CAR-T cells demonstrated strong cytotoxicity towards Nalm 6 cells in vitro except in patients 3 and D. In the latter patients, the absolute numbers of all subsets, especially the CD8 + T-cell absolute numbers in peripheral blood were very low. Patients 3 and D showed relatively short durations from transplant to recurrence and received chemotherapy after relapse. In the patients receiving CD19 CAR-T cell therapy, the most commonly observed AE was grade 1 to 2 cytokine release syndrome. None of the cases showed acute graft-versus-host disease during treatment. Patients 1 and 2 achieved complete response with complete restoration of donor chimerism. Patient 3, who received the same CD19 CAR-T cell therapy, did not respond to this therapy.Conclusion: CD19 CAR-T cells derived from patients relapsed after allo-HSCT with a low level of donor chimerism were effective for salvage therapy and could restore to complete donor chimerism after 12 days’ culture in vitro.Trial Registration: Humanized CD19 CAR-T cell therapy for relapse or refractory B-cell lymphoma or acute B lymphocytic leukemia, ChiCTR1800019622, Registered 24 November 2018, http://www.chictr.org.cn/index.aspx.Keywords: chimeric antigen receptor, acute lymphoblastic leukemia, allogeneic hematopoietic stem cell transplant, relapse, donor chimerism

Ovarian cancer is a predominant gynecologic malignancy and correlated with high mortality and severe morbidity. Exosomal microRNAs (miRNAs) play crucial roles in various processes during the progression of ovarian cancer, such as cell proliferation, apoptosis, and invasion. However, the function of exosomal miR-21-5p in ovarian cancer is still unknown. Here, we found that miR-21-5p was upregulated in ovarian cancer tissues, plasma exosomes of ovarian cancer patients, and exosomes from ovarian cancer cells. MiR-21-5p was incorporated in the exosomes from the ovarian cancer cells. In addition, 5-ethynyl-2'-deoxyuridine (Edu), a marker of cancer cell proliferation, was enhanced by miR-21-5p mimic while reduced by miR-21-5p inhibitor in ovarian cancer cells. MiR-21-5p mimic could increase, but miR-21-5p inhibitor could decrease the migration and invasion of cancer cells. Ovarian cancer cell apoptosis was induced by miR-21-5p inhibitor. Moreover, miR-21-5p inhibitor could up-regulate the expression of pro-apoptotic cleaved caspase3 and Bax while downregulate the expression of anti-apoptotic Bcl2 in the cells. Exosomal miR-21-5p inhibited the expression of cyclin-dependent kinase 6 (CDK6) by targeting its 3'-untranslated region (3'-UTR) at both the mRNA and protein levels. Tumorigenicity analysis in nude mice revealed that exosomal miR-21-5p could increase tumor volume, size, and weight of ovarian cancer in vivo. Besides, miR-21-5p targeted CDK6 in tumor tissues of nude mice. In conclusion, exosomal miR-21-5p contributes to the progression of ovarian cancer by regulating CDK6. Our findings will provide novel insights into the mechanism of exosomal miR-21-5p in the development of ovarian cancer. Exosomal miR-21-5p may serve as a potential target for the therapy of ovarian cancer.

Background Ibrutinib might improve the efficacy of CD19 CAR-T cell therapy in chronic lymphocytic leukemia (CLL). We expect to study the possibility and mechanism of synergistic effect of ibrutinib and CAR-T cells in other types of lymphoma. Methods We selected the CD19 CAR-T cells of a patient who failed in this therapy and a dose of 8 mg/kg/day ibrutinib to study the synergistic effect. Subcutaneous and tail vein tumorigenic mice were established with Raji cells. The differences of the synergistic effect between these two models were compared by bioluminescence imaging (BLI) monitoring and flow cytometry (FCM). Then the expression of STAT-3 signaling pathway was assessed by western blot analysis. Results The expression of PD-L1 was 0.23±0.06% in Raji cells. In subcutaneous tumorigenic model, the luciferase signal was reduced significantly in the ibrutinib combined with CD19 CAR-T cell group. The proportion of CD19 CAR-T cells was higher in the polytherapy group than that of the CAR-T cell monotherapy group. But we didn't get analogous synergistic effect in tail vein tumorigenic model. There was no difference between the STAT-3 signaling pathway expression in residual tumor cells with or without ibrutinib. Conclusions Our result might indicate that no IL-10/STAT-3/PD-L1 pathway were involved in the synergistic effect. Then some other mechanism about tumor microenvironment might be a possible target for ibrutinib. We expect our results provide evidence for the use of ibrutinib in polytherapy to other types of B cell lymphoma.

A new benzylated alkamide, N-(3,4-dimethoxybenzyl)-9Z-oleamide (1), along with two known ones (2 and 3) were isolated from the roots of Lepidium meyenii collected from Lijiang, Yunnan Province of China. Their structures were elucidated by extensive spectroscopic analyses and the new compound further confirmed by a one-step synthesis. All the isolated alkamides were evaluated for their cytotoxicity against five human cancer cell lines. However, no significant activities were detected at concentrations up to 40 μM.

Micro-mechanical behaviors of a Cu46.5Zr46.5Al7 bulk metallic glass composite in the plastic regime were investigated by continuous in situ neutron diffraction during compression. Three stages of the plastic deformation were observed according to the work-hardening rate. The underlying natures of the work hardening, correlating with the lattice/microscopic strain evolution, are revealed for the three stages: (1) the initiation of shear bands, (2) the phase load transferring from the amorphous phase to the B2 phase and (3) the accelerated martensitic transformation and the work hardening of the polycrystalline phases promoted by the rapid propagation of the shear bands.

A luminescent Zn(II) metal-organic framework (MOF), [Zn3(L)2(bipy)(μ3-OH)2]·3H2O (1) (bipy = 4,4′-bipyridine, H2L = 9H-carbazolyl-3,6-dicarboxylic acid) was obtained by the reaction of a rigid ligand H2L and Zn(II) ions. Compound 1 possesses an interesting 3D network with [Zn9(μ3-OH)6(CO2)12] units as eighteen-connected nodes. Particularly, 1 shows highly sensitive response to nitroaromatic compounds (NACs) and Fe3+ ions through fluorescence quenching. At the same time, 1 can be easily recycled by washing with N,N'-dimethylformamide (DMF) or distilled water after sensing studies, indicating that it can be reused easily. Furthermore, the possible detection mechanisms have also been discussed.

Phase transformation behaviors can modulate the stress distribution under loading and enhance the plasticity and work hardening ability of amorphous alloy composite. Effect of pre-plastic deformation on the phase transformation kinetics and the mechanical properties of the TiZr-based amorphous alloy composite were studied systematically in the current work. The plasticity of the composites was improved by lateral pre-compression deformation and pre-tensile deformation. However, the plasticity reduced after axial pre-compression deformation. These results were attributed to the distinguish of the directions between the pre-existing shear bands formed during pre-plastic deformation and new developed shear bands during the final compression, which can favor the severe interaction of shear bands.