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Doxorubicin (DOX) is a chemotherapeutic agent frequently used for the treatment of a variety of tumor types, such as breast cancer. Despite the long history of DOX, the mechanistic details of its cytotoxic action remain controversial. Rather than one key mechanism of cytotoxic action, DOX is characterized by multiple mechanisms, such as (1) DNA intercalation and adduct formation, (2) topoisomerase II (TopII) poisoning, (3) the generation of free radicals and oxidative stress, and (4) membrane damage through altered sphingolipid metabolism. Many past reviews of DOX cytotoxicity are based on supraclinical concentrations, and several have addressed the concentration dependence of these mechanisms. In addition, most reviews lack a focus on the time dependence of these processes. We aim to update the concentration and time-dependent trends of DOX mechanisms at representative clinical concentrations. Furthermore, attention is placed on DOX behavior in breast cancer cells due to the frequent use of DOX to treat this disease. This review provides insight into the mechanistic pathway(s) of DOX at levels found within patients and establishes the magnitude of effect for each mechanism.

In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy. The most common subjective adverse effects included fatigue, nausea, and vomiting, which were typically low grade and self-limiting. Our a-priori hypothesis was that maintenance olaparib would not negatively affect health-related quality of life (HRQOL) and additionally that the prolongation of progression-free survival with olaparib would be underpinned by additional patient-centred benefits. In SOLO2, 196 patients were randomly assigned to olaparib tablets (300 mg twice daily) and 99 to placebo. Randomisation was stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6–12 vs >12 months). The prespecified primary HRQOL analysis evaluated the change from baseline in the Trial Outcome Index (TOI) score during the first 12 months of the study. To be assessable, patients had to have an evaluable score at baseline and at least one evaluable follow-up form. Secondary planned quality-of-life (QOL) analyses included the duration of good quality of life (defined as time without significant symptoms of toxicity [TWiST] and quality-adjusted progression-free survival [QAPFS]). Efficacy and QOL outcomes were analysed in all randomly assigned patients (the full analysis set), and safety outcomes were analysed in all randomly assigned patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01874353, and is closed to new participants. The adjusted average mean change from baseline over the first 12 months in TOI was −2·90 (95% CI −4·13 to −1·67) with olaparib and −2·87 (–4·64 to −1·10) with placebo (estimated difference −0·03; 95% CI −2·19 to 2·13; p=0·98). Mean QAPFS (13·96 [SD 10·96] vs 7·28 [5·22] months; difference 6·68, 95% CI 4·98–8·54) and mean duration of TWiST (15·03 [SD 12·79] vs 7·70 [6·42] months; difference 7·33, 95% CI 4·70–8·96) were significantly longer with olaparib than with placebo. Olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo. There were clinically meaningful patient-centred benefits in both TWiST and QAPFS despite the adverse effects associated with olaparib. These patient-centred endpoints support the improvement in progression-free survival, the primary endpoint in SOLO2, and should be included in future trials of maintenance therapies. AstraZeneca.

Soilless cultivation represent a valid opportunity for the agricultural production sector, especially in areas characterized by severe soil degradation and limited water availability. Furthermore, this agronomic practice embodies a favorable response toward an environment-friendly agriculture and a promising tool in the vision of a general challenge in terms of food security. This review aims therefore at unraveling limitations and opportunities of hydroponic solutions used in soilless cropping systems focusing on the plant mineral nutrition process. In particular, this review provides information (1) on the processes and mechanisms occurring in the hydroponic solutions that ensure an adequate nutrient concentration and thus an optimal nutrient acquisition without leading to nutritional disorders influencing ultimately also crop quality (e.g., solubilization/precipitation of nutrients/elements in the hydroponic solution, substrate specificity in the nutrient uptake process, nutrient competition/antagonism and interactions among nutrients); (2) on new emerging technologies that might improve the management of soilless cropping systems such as the use of nanoparticles and beneficial microorganism like plant growth-promoting rhizobacteria (PGPRs); (3) on tools (multi-element sensors and interpretation algorithms based on machine learning logics to analyze such data) that might be exploited in a smart agriculture approach to monitor the availability of nutrients/elements in the hydroponic solution and to modify its composition in . These aspects are discussed considering what has been recently demonstrated at the scientific level and applied in the industrial context.

Progranulin has been recognized as an adipokine related to obesity, insulin resistance and type 2 diabetes mellitus (T2DM). There are scarce data regarding progranulin and kidney disease, but there are some data linking diabetic kidney disease (DKD) and increased progranulin levels. We aimed to better describe the relationship between serum and urinary progranulin levels and DKD in T2DM. This is a case-control study including four groups of subjects: 1) Advanced DKD cases: T2DM patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2; 2) Albuminuric DKD cases: T2DM patients with urinary albumin excretion (UAE) ≥30 mg/g creatinine and eGFR ≥60 mL/min/1.73m2; 3) Diabetic controls: T2DM patients with UAE <30 mg/g creatinine and eGFR ≥60 mL/min/1.73m2; and 4) Non-diabetic controls: individuals without T2DM. Progranulin was determined by enzyme-linked immunosorbent assay. One hundred and fourteen patients were included (23 advanced DKD cases, 25 albuminuric DKD cases, 40 diabetic controls and 26 non-diabetic controls). Serum progranulin was increased in advanced DKD compared to other groups [70.84 (59.04-83.16) vs. albuminuric cases 57.16 (42.24-67.38), diabetic controls 57.28 (42.08-70.47) and non-diabetic controls 44.54 (41.44-53.32) ng/mL; p<0.001]. Urinary progranulin was decreased in advanced DKD cases compared to albuminuric cases [10.62 (6.30-16.08) vs. 20.94 (12.35-30.22); diabetic controls 14.06 (9.88-20.82) and non-diabetic controls 13.51 (7.94-24.36) ng/mL; p = 0.017]. There was a positive correlation between serum progranulin and body mass index (r = 0.27; p = 0.004), waist circumference (r = 0.25; p = 0.007); body fat percentage (r = 0.20; p = 0.042), high-sensitive C reactive protein (r = 0.35; p<0.001) and interleukin-6 (r = 0.37; p<0.001) and a negative correlation with eGFR (r = -0.22; p = 0.023). Urinary progranulin was positively associated with albuminuria (r = 0.25; p = 0.010). In conclusion, progranulin is affected by a decrease in eGFR, being at a higher concentration in serum and lower in urine of DKD patients with T2DM and eGFR <60 mL/min/1.73m2. It is also associated with markers of obesity and inflammation.

Zonulin is a protein associated with the tight junction complex opening at the intestinal epithelium, previously linked to obesity, cardiovascular diseases, type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). However, its role in CKD has not been totally elucidated. This study aimed to evaluate zonulin levels in subjects with diabetic kidney disease (DKD). This case-control study included two cases groups: 1) Advanced DKD cases: T2DM patients with estimated glomerular filtration rate (eGFR) <60ml/min/1.73m 2 ; 2) Albuminuric T2DM cases: diabetic patients with urinary albumin excretion (UAE) >30mg/g creatinine, but with eGFR>60ml/min/1.73m 2 . Two control groups were also included: 1) T2DM controls: patients with T2DM without impaired kidney function; 2) Non-T2DM controls: subjects without T2DM and normal renal function. Serum levels of zonulin were measured by ELISA. Eighty-six individuals were included. Zonulin levels was different among study groups (P = 0.003). T2DM controls presented higher zonulin levels than non-T2DM controls [(131.35 (83.0–170.5) vs. 87.25 (54.7–111.8), P = 0.018] and advanced DKD cases [63.72 (45.03–106.0); P = 0.007]. Zonulin showed a positive correlation with eGFR (r = 0.222; P = 0.040), total cholesterol (r = 0.299; P = 0.034), LDL (r = 0.258; P = 0.021), and negative with albuminuria (r = -0.243; P = 0.024) and body fat (r = -0.271; P = 0.014). In the multivariate logistic regression analyses, zonulin levels were independently associated to renal outcomes [OR 0.99 (0.98–0.99, P = 0.012)] after 5-year inclusion. In conclusion, increased zonulin levels in patients with TD2M without renal disease suggest an impaired intestinal permeability. Moreover, its association with renal outcomes could indicate its use as a disease monitoring marker. However, the mechanisms behind this association should be better understood.

Progranulin (PGRN) is secreted by adipose tissue and has been linked to obesity, insulin resistance and type 2 diabetes mellitus. There is evidence that a high fat diet increases PGRN expression in rodent adipose tissue. In humans, the relationship between diet composition and concentration of PGRN is still unknown. To investigate the association between dietary intake and serum PGRN levels. This is an exploratory cross-sectional study including 85 subjects. Demographic, clinical, laboratory and anthropometric data were collected. Serum PGRN was determined by enzyme-linked immunosorbent assay after overnight fasting. Dietary intake was assessed by food frequency questionnaire validated for Brazilian southern population. Focused principal component analyses (FPCA) was used to verify the association of dietary components and food groups with PGRN levels. Sensitivity analyses were performed including only subjects with reporting according to the Goldberg and Black cut-offs of energy intake-energy expenditure ratio between 0.76 and 1.24. The median PGRN was 51.96 (42.18 to 68.30) ng/mL. Analyzing all sample, the FPCA showed no association of serum PGRN with total energy, protein, carbohydrate, fat and its types, fiber intake and dietary glycemic index; but a significant and positive association between solid fats and PGRN levels (p<0.05). Including only subjects with reporting according cut-off of energy intake-energy expenditure ratio between 0.76 and 1.24, FCPA showed significant and positive association of serum PGRN with saturated fatty acids and solid fats intake (p<0.05). In this subgroup, PGRN correlated with saturated fatty acids (r = 0.341; p = 0.031). Solid fats intake was independently associated to serum PGRN (beta = 0.294; p = 0.004) in multivariate model. The dietary intake of solid fats, mainly represented by saturated fatty acids, is associated to serum PGRN concentration in human subjects.

Renal transplantation is the best modality of renal replacement therapy for patients with end-stage renal disease. However, it is associated with weight gain and metabolic abnormalities, which adversely impact transplant outcomes. The objective of this study was to identify the risk factors of one-year weight gain after renal transplantation. A retrospective cohort study was conducted with 374 patients that underwent kidney transplantation between January 2006 and July 2013. Clinical and laboratory variables were collected from electronic records, and the outcome of interest was weight gain during the first year after renal transplantation. The data were reported as mean ± standard deviation, median (interquartile range) or number of subjects (%). The association between variables were assessed via chi-square test and ANOVA. For analysis of risk factors related to the outcomes of interest, multivariable logistic regression models were used. There were 181 (48.4%) female patients, 334 (89.3%) with white ethnicity and the mean age was 44.4 ± 12.8 years. The mean BMI pre-transplant was 24.7 ± 4.1 kg/m2, and 35 (9.9%) patients were classified as obese; 119 (33.6%) as overweight; 187 (52.8%) as normal weight; and 13 (3.7%) as malnourished. After one year of follow-up, the mean BMI was 26.2 ± 5.0 kg/m2, and 61 (17.3%) patients were classified as obese; 133 (37.8%) as overweight; 148 (42.0%) as normal weight; and 10 (2.8%) as malnourished. Weight gain was observed in 72.7% patients, and the average increase was 7.12 ± 5.9 kg. The female gender, lower pre-transplant body weight, lower number of hospitalizations, and a kidney received from a living donor were associated with weight gain by more than 5% in the first year post-transplant. Female gender and lower pre-transplant body weight were independently associated with weight gain by more than 5% in the first year after kidney transplantation; lower rates of hospitalization and donation from living donors were also risk factors for this outcome.

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Aquaponics (AP) is a semi-closed system of food production that combines aquaculture and hydroponics and represents a new agricultural system integrating producers and consumers. The aim of this study was to test the effect of stocking densities (APL, 2.5 kg m-3; APH, 4.6 kg m-3) on water quality, growth performance of the European Carp (Cyprinus carpio L.), and yield of leafy vegetables (catalogna, lettuce, and Swiss Chard) in a low-technology AP pilot system compared to a hydroponic cultivation. The AP daily consumption of water due to evapotranspiration was not different among treatments with an average value of 8.2 L d-1, equal to 1.37% of the total water content of the system. Dissolved oxygen was significantly (p < 0.05) different among treatments with the lowest median value recorded with the highest stocking density of fish (5.6 mg L-1) and the highest median value in the hydroponic control (8.7 mg L-1). Marketable yield of the vegetables was significantly different among treatments with the highest production in the hydroponic control for catalogna (1.2 kg m-2) and in the APL treatment for Swiss Chard (5.3 kg m-2). The yield of lettuce did not differ significantly between hydroponic control and APL system (4.0 kg m-2 on average). The lowest production of vegetables was obtained in the APH system. The final weight (515 g vs. 413 g for APL and APH, respectively), specific growth rate (0.79% d-1 vs. 0.68% d-1), and feed conversion (1.55 vs. 1.86) of European Carp decreased when stocking density increased, whereas total yield of biomass was higher in the APH system (4.45 kg m-3 vs. 6.88 kg m-3). A low mortality (3% on average) was observed in both AP treatments. Overall, the results showed that a low initial stocking density at 2.5 kg m-3 improved the production of European Carp and of leafy vegetables by maintaining a better water quality in the tested AP system.

Aquaponics (AP), the integrated multi-trophic fish and plants production in quasi-closed recirculating system, is one of the newest sustainable food production systems. The hydroponic component of the AP directly influences water quality (in turn influencing fish growth and health), and water consumption (through evapotranspiration) of the entire system. In order to assess the role of the design and the management of the hydroponic component on the overall performance, and water consumption of the aquaponics, 122 papers published from 1979 to 2017 were reviewed. Although no unequivocal results were found, the nutrient film technique appears in several aspects less efficient than medium-based or floating raft hydroponics. The best system performance in terms of fish and plant growth, and the highest nutrient removal from water was achieved at water flow between 0.8 L min–1 and 8.0 L min–1. Data on water consumption of aquaponics are scarce, and no correlation between the ratio of hydroponic unit surface/fish tank volume and the system water loss was found. However, daily water loss was positively correlated with the hydroponic surface/fish tank volume ratio if the same experimental conditions and/or systems were compared. The plant species grown in hydroponics influenced the daily water loss in aquaponics, whereas no effect was exerted by the water flow (reciprocating flood/drain cycle or constant flow) or type (medium-based, floating or nutrient film technique) of hydroponics.