AKR1C enzymes sustain therapy resistance in paediatric T-ALL

BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (TALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy

Assessment of soy phytoestrogens' effects on bone turnover indicators in menopausal women with osteopenia in Iran: a before and after clinical trial

BACKGROUND: Osteoporosis is the gradual declining in bone mass with age, leading to increased bone fragility and fractures. Fractures in hip and spine are known to be the most important complication of the disease which leads in the annual mortality rate of 20% and serious morbidity rate of 50%. Menopause is one of the most common risk factors of osteoporosis. After menopause, sex hormone deficiency is associated with increased remodeling rate and negative bone balance, leading to accelerated bone loss and micro-architectural defects, resulting into increased bone fragility. Compounds with estrogen-like biological activity similar to "Isoflavones" present in plants especially soy, may reduce bone loss in postmenopausal women as they are similar in structure to estrogens. This research, therefore, was carried out to study the effects of Iranian soy protein on biochemical indicators of bone metabolism in osteopenic menopausal women. MATERIALS AND METHODS: This clinical trial of before-after type was carried out on 15 women 45–64 years of age. Subjects were given 35 g soy protein per day for 12 weeks. Blood and urine sampling, anthropometric measurement and 48-h-dietary recalls were carried out at zero, 6 and 12 weeks. Food consumption data were analyzed using Food Proccessor Software. For the study of bone metabolism indicators and changes in anthropometric data as well as dietary intake, and repeated analyses were employed. RESULTS: Comparison of weight, BMI, physical activity, energy intake and other intervening nutrients did not reveal any significant changes during different stages of the study. Soy protein consumption resulted in a significant reduction in the urinary deoxypyridinoline and increasing of total alkaline phosphatase (p < 0.05), although the alterations in osteocalcin, c-telopeptide, IGFBP3 and type I collagen telopeptide were not significant. CONCLUSION: In view of beneficial effect of soy protein on bone metabolism indicators, inclusion of this relatively inexpensive food in the daily diet of menopausal women, will probably delay bone resorption, thereby preventing osteoporosis

Vertical distribution of root biomass and soil carbon stocks in forage cropping systems

Background and aims: Forage cropping systems may differentially affect the vertical distribution of roots and soil organic C stock (C-OM). In annual crops sequences (ACS) and perennial pastures (PP), we assessed the association between root biomass, C-OM, C in mineral-associated organic matter (C-MAOM), and C in particulate organic matter (C-POM) and its vertical distribution. Methods Root biomass, C-OM, C-MAOM and C-POM were measured in a Petrocalcic Argiudol at five soil depths up to 100 cm during two years in the south-eastern Pampas of Argentina. The field experiment comprised 28 plots including five perennial pastures and two annual crop sequences. Associations between variables were assessed by regression analysis and non-linear models. Results Overall, ACS and PP had similar cumulative root biomass. Both, root biomass and soil C stocks exponentially decreased with soil depth. Soil C stocks associated to root biomass tended to stabilize over a threshold value of root biomass for C-MAOM and C-OM. C-POM tended to stabilize over a threshold value only in treatments that included tall fescue. Conclusions Our results highlights the key role of roots to improve soil C stocks through the design of forage crop rotations that include crops able to increase root inputs to the soil, such as tall fescue.</p

Modelling inter-annual veriation in dry matter yield and precipitation use efficiency of prennial pastures and annual forge crops sequences

In livestock systems of the Argentinean Pampas, its forage production stability relies on the integration of two landcovers, annual forage crop sequences and perennial pastures. Despite the key role that these forage cropping systems have on current milk and beef production, it is unclear how year-by-year variability of precipitation affect forage dry matter (DM) yield and precipitation use efficiency (PUE, i.e. the quotient between forage DM yield and precipitation). The aims of this study were to analyze the impact (i) of year-by-year precipitation variability on DM yield and PUE of oats-maize (Avena sativa L. - Zea mays L.) double-crop and alfalfa (Medicago sativa L.) and (ii) of cumulative precipitation during the critical period of maize on DM yield and PUE of oats-maize double-crop. We used a modelling approach to estimate DM yield and PUE of oats-maize (sequence) and alfalfa in five locations of the Argentinean Pampas, which differed in annual precipitation (AP) and variability of it. Coefficient of variation (CV) was used as the main statistical variable to compare the variability of AP (CVAP), DM yield (CVDM), and PUE (CVPUE). Mean DM yield of both landcovers was higher in locations with high AP (>800 mm) than with low AP (DM than sequence. In contrast, sequence showed lower and higher CVDM than CVAP, depending on location. Moreover, changes in DM yield due to variations of AP were higher in sequence than in alfalfa. On the other hand, mean PUE was higher for sequence (2.2 g DM m−2 mm−1) than that of alfalfa (1.6 g DM m−2 mm−1). The CVPUE between locations, i.e. an index that reflects the spatial variability, ranged from 20 for the sequence to 68% for alfalfa, whereas CVPUE between years, i.e. an index that reflects the temporal variability, ranged from 16 to 31 % for both landcovers. Precipitation use efficiency tended to be similar across locations in years with low AP (800 mm). Our results provided valuable knowledge for decision making in livestock systems of this region through the development of spatial and temporal models between DM yield and AP. In a broader sense, they also showed that shifts from perennial to seasonal forage covers increased yields but also its inter-annual variability, posing a risk for farmers

Forage yield, water- and solar radiation-productivities of perennial pastures and annual crops sequences in the south-eastern Pampas of Argentina

Livestock production systems of Argentina show an ongoing process of change in the composition of their forage base, with a gradual increase in the proportion of their area assigned to forage crop sequences (FCS) −in particular that involving successive winter and summer annual forage crops–, at the expense of the area assigned to perennial pastures (PP). However, there are several concerns regarding the efficient use of available environmental resources due to differences in the extent of the establishment periods and due to the occurrence of fallow periods in FCS, as well as regarding the species involved in these systems. Therefore, the main objective of this study was to evaluate the water (WP) and solar radiation productivity (RP) of PP [pure stands of alfalfa (Medicago sativa L.), fertilized and unfertilized stands of tall fescue (Festuca arundinacea Schreb.), and fertilized and unfertilized mixed stands of alfalfa/tall fescue] and FCS [including a summer alternative and oats (Avena sativa L.); the summer alternative was either maize (Zea mays L.) or intercropped maize/soybean (Glycine max L.)] through the analysis of their components, i.e. water (WC) and radiation capture (RC), and their water (WUE) and radiation use efficiency (RUE). Resource capture (WC and RC) was defined as the ratio between captured (evapotranspiration and intercepted solar radiation) and annual available resource (rainfall and incident solar radiation). Resource use efficiency (WUE and RUE) was computed as the dry matter (DM) yield per unit of captured resource. A field experiment was conducted during two consecutive years under rainfed conditions and under non-limiting nitrogen availability in the south-eastern Pampas of Argentina. Perennial pastures were evaluated during both their initial establishment year (Y1) and when already fully established (Y2). Annual-based forage DM yield ranged between 13.0 and 32.4 Mg ha−1 in Y1 and between 5.1 and 23.5 Mg ha−1 in Y2. Differences in resource capture between PP and FCS were directly associated with the crop establishment and fallow periods depending on the nature of the considered resource. The highest WP (2.75–3.64 g DM m−2 mm−1) and RP (0.93–1.42 g DM MJ−1) were reached by FCS, which did not differ (P > 0.05) from that of fully established fertilized PP. Our results demonstrate that resource productivity in FCS is not necessarily higher than for PP, once PP are fully established

Modelling stover and grain yields, and subsurface artificial drainage from long-term corn rotations using APSIM

The Agricultural Production Systems Simulator (APSIM) is a key tool to identify agricultural management practices seeking to simultaneously optimize agronomic productivity and input use efficiencies. The aims of this study were to validate APSIM for prediction of stover and grain yield of corn in four contrasting soils with varied N fertilizer applications (156 to 269 kg N ha-1) and to predict timing and volume from artificial subsurface drains in continuous corn and corn-soybean rotations in a silty clay loam soil at West Lafayette, IN. The APSIM validation was carried-out using a long-term dataset of corn stover and grain yields from the North Central Region of IN. The CCC (Concordance Correlation Coefficient) and SB (Simulation Bias) were used to statistically evaluate the model performance. The CCC integrates precision through Pearson’s correlation coefficient and accuracy by bias, and SB indicates the bias of the simulation from the measurement. The model demonstrated very good (CCC=0.96; SB=0%) and satisfactory (CCC=0.85; SB=2%) ability to simulate stover and grain yield, respectively. Grain yield was better predicted in continuous corn (CCC=0.73-0.91; SB=19-21%) than in corn-soybean rotations (CCC=0.56-0.63; SB=17-18%), while stover yield was well predicted in both crop rotations (CCC=0.85-0.98; SB=1-17%). The model demonstrated acceptable ability to simulate annual subsurface drainage in both rotations (CCC=0.63-0.75; SB=2-37%) with accuracy being lower in the continuous corn system than in corn-soybean rotation system (CCC=0.61-0.63; SB=9-12%). Daily subsurface drainage events were well predicted by APSIM during late spring and summer when crop water use was high, but under-predicted during fall, winter and early spring when evapotranspiration was low. Occasional flow events occurring in summer when soils were not saturated were not predicted by APSIM and may represent preferential flow paths currently not represented in the model. APSIM is a promising tool for simulating yield and water losses for corn-based cropping systems in north central Indiana US