The increase in adipocytes induced by chemotherapeutic drugs may play a negative role in hematopoietic recovery. However, the mechanism underlying adipocyte differentiation of mesenchymal stem cells ...(MSCs) in hematopoietic stress is still unknown. Hence, the involvement of reactive oxygen species (ROS) in adipocyte differentiation under hematopoietic stress was investigated in vitro and in vivo.
The roles of cellular ROS in adipogenesis were investigated in vivo through an adipocyte hyperplasia marrow model under hematopoietic stress induced by arabinosylcytosine (Ara-C) and in vitro via adipocyte differentiation of human MSCs. ROS levels were detected using the CM-H2DCFDA probe and Mito-SOX dye. Adipogenesis was evaluated by histopathology and oil red O staining, whereas detection of mRNA levels of antioxidant enzymes and adipogenesis markers was performed using quantitative real-time polymerase chain reaction analysis.
ROS were found to play an important role in regulating adipocyte differentiation of MSCs by activating peroxisome proliferator-activated receptor gamma (PPARγ,) while the antioxidant N-acetyl-L-cysteine acts through ROS to inhibit adipocyte differentiation. The elevated ROS levels induced by Ara-C were caused by both over-generation of mitochondrial ROS and reduction of antioxidant enzymes (Cu/Zn Superoxide dismutase and catalase). Our findings suggest that a mitochondrial-targeted antioxidant could diminish adipocyte differentiation.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high‐risk AML/MDS. Allogeneic hematopoietic stem cell transplantation ...(allo‐HSCT) is the only curative option for patients suffering from high‐risk AML/MDS. However, many patients relapse after allo‐HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL‐2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft‐versus‐host disease (GVHD) and boost the graft‐versus‐leukemia (GVL) effect post‐transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low‐dose decitabine (LDEC) plus VEN to prevent relapse after allo‐HSCT for high‐risk AML/MDS patients. Twenty patients with high‐risk AML (n = 17) or high‐risk MDS (n = 3) post‐transplantation were recruited. Approximately day 100 post‐transplantation, all patients received LDEC (15 mg/m2 for 3 d) followed by VEN (200 mg) on d 1‐21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event‐free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo‐HSCT. Survival outcomes were assessed using Kaplan‐Meier analysis. The median follow‐up was 598 (149‐1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2‐y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2‐y EFS time was 525 (149‐1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo‐HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high‐risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high‐risk AML/MDS patients.
The results of the current study suggest that maintenance treatment with LDEC combined with VEN introduced nearly 3 mo after allo‐HSCT is efficacious, with an acceptable toxicity profile and impressive long‐term disease control.
Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment for patients with refractory/relapsed B-cell non-Hodgkin lymphoma (B-NHL), and combination with PD1 inhibitors may further ...improve the efficacy of anti-CD19 CAR (CD19 CAR)-T cells in the treatment of lymphomas. In a single-center study, we evaluated the safety and efficacy of a combination therapy with CD19 CAR-T cells and an anti-PD-1 antibody (nivolumab) in patients with relapsed/refractory B-NHL. A total of 11 patients with refractory/relapsed B-NHL were recruited and subsequently received CD19 CAR-T cells and nivolumab. The primary end points were safety and feasibility. The infusions were safe, and no dose-limiting toxicities occurred. Grade 1 or 2 cytokine release syndrome (CRS) was observed in 25% (3/11) and 50% (6/11) of the patients, respectively, and only one patient (1/11) experienced neurotoxicity. The objective response rate (ORR) and complete response (CR) rate were 81.81% (9/11) and 45.45% (5/11), respectively. The median follow-up time was 6 (1~15) months. The median progression-free survival (PFS) time was 6 months (1~14 months), and 3 patients continued to have a response at the time of this writing. Our study demonstrated that the combination of CD19 CAR-T cells and nivolumab was feasible and safe and mediated potent anti-lymphoma activity, which should be examined further in prospective clinical trials in refractory/relapsed B-NHL.
Unmanned aerial vehicle (UAV) photogrammetry was used to monitor crop height in a flooded paddy field. Three multi-rotor UAVs were utilized to conduct flight missions in order to capture RGB ...(RedGreenBlue) and multispectral images, and these images were analyzed using several different models to provide the best results. Two image sets taken by two UAVs, mounted with RGB cameras of the same resolution and Global Navigation Satellite System (GNSS) receivers of different accuracies, were applied to perform photogrammetry. Two methods were then proposed for creating crop height models (CHMs), one of which was denoted as the M1 method and was based on the Digital Surface Point Cloud (DSPC) and the Digital Terrain Point Cloud (DSPT). The other was denoted as the M2 method and was based on the DSPC and a bathymetric sensor. An image set taken by another UAV mounted with a multispectral camera was used for multispectral-based photogrammetry. A Normal Differential Vegetation Index (NDVI) and a Vegetation Fraction (VF) were then extracted. A new method based on multiple linear regression (MLR) combining the NDVI, the VF, and a Soil Plant Analysis Development (SPAD) value for estimating the measured height (MH) of rice was then proposed and denoted as the M3 method. The results show that the M1 method, the UAV with a GNSS receiver with a higher accuracy, obtained more reliable estimations, while the M2 method, the UAV with a GNSS receiver of moderate accuracy, was actually slightly better. The effect on the performance of CHMs created by the M1 and M2 methods is more negligible in different plots with different treatments; however, remarkably, the more uniform the distribution of vegetation over the water surface, the better the performance. The M3 method, which was created using only a SPAD value and a canopy NDVI value, showed the highest coefficient of determination (R2) for overall MH estimation, 0.838, compared with other combinations.
Using survey data to calculate composite financial literacy (CFL), existed studies do not consider the geographical difference of the means of objectively-measured financial literacy and ...subjectively-perceived financial literacy, i.e., comparative benchmark.
Taking the survey data of National Financial Capability Study (NFCS) for example, we explain why it is more reasonable to use the within-state average rather than the national average of financial literacy as the comparative benchmark to measure CFL. Then we use NFCS 2009, 2012, 2015 and 2018 dataset to comparatively analyze the difference between CFL measured with the two benchmarks.
The results of statistical analysis show that there is a great difference among the four groups of CFL measured with the two benchmarks, and 10.7% of respondents are categorized as a particular group of CFL incorrectly for all datasets. Additionally, the findings of spatial distribution analysis unveils that 36, 19, 15, and 6 states have respondents miscategorized in the four groups of CFL for 2009, 2012, 2015, and 2018 respectively, in which the highest proportion of the population miscategorized in a state is up to 49.91%. Finally, we find that several groups of CFL measured with the two benchmarks have significantly different effects on stock market participation behavior.
Using the national average as a benchmark to determine all the respondents' relative financial literacy levels for different states is not meaningful, and will lose the practical appeal to tackle the regional inequalities of financial literacy among the households. Therefore, we suggest that the within-state average of financial literacy, not the national average, should be taken as the comparative benchmark for identifying the more precise groups of CFL in survey.
This study reports the translocation of cesium-137 (137Cs) into deep soil layers, and the 137Cs transfer from soil to soybean in farmland under three tillage (no tillage, NT; rotary cultivation, RC; ...moldboard plow; MP) treatments and an undisturbed grassland (GL) at eight years after the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident on 11 March 2011 in Japan. Tillage influences the 137Cs distribution in the 0–30 cm of soil; the distribution of 137Cs in the soil was uniform under RC and MP treatments, while in the grassland, most 137Cs was concentrated on the soil surface (0–2.5 cm). The center of vertical 137Cs radioactivity concentration (the thickness of the soil from surface which containing half of the 137Cs inventory) in GL was 5.5 cm, which was shallower than that in farmland (9.5 cm in NT, 13.6 cm in RC and 15.2 cm in MP). Hence, the total translocation distance of 137Cs 8 years after FDNPP accident showed the following trend: GL (2.4 cm) < NT (7.0 cm) < RC (10.0 cm) < MP (12.3 cm). Meanwhile, a significant positive correlation was observed between 137Cs radioactivity concentration and organic carbon and nitrogen content in the soil. However, the 137Cs radioactivity concentration in soybean grains was negatively correlated with the center of vertical 137Cs radioactivity concentration but positively correlated with the ratio of exchangeable 137Cs (ExCs) and K content in the soil. The ExCs/K and 137Cs distributions in the soil were combined into a statistical model to predict the 137Cs radioactivity concentration in soybean grain. The results revealed the magnitude of the impact of 137Cs distribution on the 137Cs transfer from soil to crop. The addition of the 137Cs distribution dramatically improved the accuracy of the prediction model of 137Cs radioactivity concentration in soybean.
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•Soil 137Cs downward migration was investigated under three tillage treatments.•137Cs concentration in soybean grain was positively correlated with ExCs/K ratio.•137Cs concentration in soybean grain was affected by 137Cs distribution in soil.•A prediction model for 137Cs activity concentration in soybean was developed.
Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis. In this study, we evaluated chimeric antigen receptor (CAR) T cell therapy targeting CLL-1 in adults with R/R AML ...patients. Patients received conditioning chemotherapy with cyclophosphamide (500 mg/m.sup.2) and fludarabine (30 mg/m.sup.2) for 3 days and an infusion of a dose of 1-2 x 10.sup.6 CAR-T cells/kg. The incidence of dose-limiting toxicity was the primary endpoint. Ten patients were treated, and all developed cytokine release syndrome (CRS); 4 cases were low-grade, while the remaining 6 were considered high-grade CRS. No patient developed CAR-T cell-related encephalopathy syndrome (CRES). Severe pancytopenia occurred in all patients. Two patients died of severe infection due to chronic agranulocytosis. The complete response (CR)/CR with incomplete hematologic recovery (CRi) rate was 70% (n = 7/10). The median follow-up time was 173 days (15-488), and 6 patients were alive at the end of the last follow-up. CAR-T cells showed peak expansion within 2 weeks. Notably, CLL-1 is also highly expressed in normal granulocytes, so bridging hematopoietic stem cell transplantation (HSCT) may be a viable strategy to rescue long-term agranulocytosis due to off-target toxicity. In conclusion, this study is the first to demonstrate the positive efficacy and tolerable safety of CLL-1 CAR-T cell therapy in adult R/R AML. Keywords: Chimeric antigen receptor, Acute myeloid leukemia, C-type lectin-like molecule 1
B cell lymphoma 2 (BCL-2) family proteins play an important role in intrinsic apoptosis. Overexpression of BCL-2 proteins in acute myeloid leukemia can circumvent resistance to apoptosis and ...chemotherapy. Considering this effect, the exploration of anti-apoptotic BCL-2 inhibitors is considered to have tremendous potential for the discovery of novel pharmacological modulators in cancer. This review outlines the impact of BCL-2 family proteins on intrinsic apoptosis and the development of acute myeloid leukemia (AML). Furthermore, we will also review the new combination therapy with venetoclax that overcomes resistance to venetoclax and discuss biomarkers of treatment response identified in early-phase clinical trials.
There is increasing clinical evidence to suggest a suppressive effect on hematopoiesis in myelodysplastic syndrome patients with iron overload. However, how iron overload influences hematopoiesis in ...myelodysplastic syndrome (MDS) remains unknown. Here, the
-transduced bone marrow mononuclear cells were yielded and transplanted into lethally irradiated recipient mice together with radioprotective bone marrow cells to generate MDS mice. Eight weeks post transplantation, the recipient mice received an intraperitoneal injection of 0.2 mL iron dextran at a concentration of 25 mg/mL once every other day for a total of 8 times to establish an iron overload model. In the present study, we show that iron overload impairs the frequency and colony-forming capacity of normal hematopoietic stem and progenitor cells, especially in erythroid, in MDS mice, which is due, at least in part, to growth differentiation factor 11-induced reactive oxygen species, shortening survival of MDS mice. Given that we are the first to construct an iron overload model in MDS mice, we hope this model will be helpful for further exploring the influence and mechanism of iron overload on MDS.
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