Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. ...Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs.
Abstract Background Intraventricular fluid dynamics can be assessed clinically using imaging. The contribution of vortex structures to left ventricular (LV) diastolic function has never been ...quantified in vivo. Objectives This study sought to understand the impact of intraventricular flow patterns on filling and to assess whether impaired fluid dynamics may be a source of diastolic dysfunction. Methods Two-dimensional flow velocity fields from color Doppler echocardiographic sequences were obtained in 20 patients with nonischemic dilated cardiomyopathy (NIDCM), 20 patients with hypertrophic cardiomyopathy (HCM), and 20 control healthy volunteers. Using a flow decomposition method, we isolated the rotational velocity generated by the vortex ring from the surrounding flow in the left ventricle. Results The vortex was responsible for entering 13 ± 6% of filling volume in the control group and 19 ± 8% in the NIDCM group (p = 0.004), but only 5 ± 5% in the HCM group (p < 0.0001 vs. controls). Favorable vortical effects on intraventricular pressure gradients were observed in the control and NIDCM groups but not in HCM patients. Differences in chamber sphericity explained variations in the vortex contribution to filling between groups (p < 0.005). Conclusions The diastolic vortex is responsible for entering a significant fraction of LV filling volume at no energetic or pressure cost. Thus, intraventricular fluid mechanics are an important determinant of global chamber LV operative stiffness. Reduced stiffness in NIDCM is partially related to enhanced vorticity. Conversely, impaired vortex generation is an unreported mechanism of diastolic dysfunction in HCM and probably other causes of concentric remodeling.
Tannins are phenolic compounds with considerable abundance in nature. They have attracted significant attention lately owing to their huge variety of potential applications. Accordingly, the ...tannin-related activity in terms of research has undergone a great boost, especially as green feedstock for materials in several fields. Nevertheless, the extraction process remains as the main bottleneck for their valorization, due to their heterogeneous nature. In the present review, a comprehensive study of the main types of tannins extraction techniques was carried out based on the works from the last 20 years. The literature review was carried through analysis of an initial sample of works followed by snowballing process, obtaining the main extraction parameters of each method. Thereby, the different tannins extraction methods were assessed and their major strengths and weaknesses elucidated. Moreover, a direct comparison between the different techniques was done, leading to the main prospectives for the efficient and clean tannins extraction and production.
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•The great potential of tannins is hindered by their extraction process.•A literature review was carried out assessing the main tannins extraction methods.•Novel extraction techniques represented a greener option for tannins production.•Combination of novel techniques is an interesting option for industrial scale up.
Anthracycline-induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed.
The purpose of this study was to identify early doxorubicin-induced cardiotoxicity by ...serial multiparametric cardiac magnetic resonance (CMR) and its pathological correlates in a large animal model.
Twenty pigs were included. Of these, 5 received 5 biweekly intracoronary doxorubicin doses (0.45 mg/kg/injection) and were followed until sacrifice at 16 weeks. Another 5 pigs received 3 biweekly doxorubicin doses and were followed to 16 weeks. A third group was sacrificed after the third dose. All groups underwent weekly CMR examinations including anatomical and T2 and T1 mapping (including extracellular volume ECV quantification). A control group was sacrificed after the initial CMR.
The earliest doxorubicin-cardiotoxicity CMR parameter was T2 relaxation-time prolongation at week 6 (2 weeks after the third dose). T1 mapping, ECV, and left ventricular (LV) motion were unaffected. At this early time point, isolated T2 prolongation correlated with intracardiomyocyte edema secondary to vacuolization without extracellular space expansion. Subsequent development of T1 mapping and ECV abnormalities coincided with LV motion defects: LV ejection fraction declined from week 10 (2 weeks after the fifth and final doxorubicin dose). Stopping doxorubicin therapy upon detection of T2 prolongation halted progression to LV motion deterioration and resolved intracardiomyocyte vacuolization, demonstrating that early T2 prolongation occurs at a reversible disease stage.
T2 mapping during treatment identifies intracardiomyocyte edema generation as the earliest marker of anthracycline-induced cardiotoxicity, in the absence of T1 mapping, ECV, or LV motion defects. The occurrence of these changes at a reversible disease stage shows the clinical potential of this CMR marker for tailored anthracycline therapy.
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Physical exercise is beneficial to reduce the risk of several conditions associated with advanced age, but to our knowledge, no previous study has examined the association of long-term exercise ...interventions (≥ 1 year) with the occurrence of dropouts due to health issues and mortality, or the effectiveness of physical exercise versus usual primary care interventions on health-related outcomes in older adults (≥ 65 years old).
To analyze the safety and effectiveness of long-term exercise interventions in older adults.
We conducted a systematic review with meta-analysis examining the association of long-term exercise interventions (≥ 1 year) with dropouts from the corresponding study due to health issues and mortality (primary endpoint), and the effects of these interventions on health-related outcomes (falls and fall-associated injuries, fractures, physical function, quality of life, and cognition) (secondary endpoints).
Ninety-three RCTs and six secondary studies met the inclusion criteria and were included in the analyses (n = 28,523 participants, mean age 74.2 years). No differences were found between the exercise and control groups for the risk of dropouts due to health issues (RR = 1.05, 95% CI 0.95-1.17) or mortality (RR = 0.93, 95% CI 0.83-1.04), although a lower mortality risk was observed in the former group when separately analyzing clinical populations (RR = 0.67, 95% CI 0.48-0.95). Exercise significantly reduced the number of falls and fall-associated injuries, and improved physical function and cognition. These results seemed independent of participants' baseline characteristics (age, physical function, and cognitive status) and exercise frequency.
Long-term exercise training does not overall influence the risk of dropouts due to health issues or mortality in older adults, and results in a reduced mortality risk in clinical populations. Moreover, exercise reduces the number of falls and fall-associated injuries, and improves physical function and cognition in this population.
•Exercise increases plasma BDNF levels in individuals with neurodegenerative disorders.•Effects were consistent for different exercise type, weekly volume, and intervention length.•These findings ...support the benefits of exercise against neurodegenerative disorders.
Neurodegenerative disorders are associated with reduced levels of brain-derived neurotrophic factor (BDNF). We aimed to assess the effect of exercise interventions on plasma BDNF levels in individuals with neurodegenerative disorders. Eighteen randomized controlled trials (RCT) assessing the effects of exercise interventions versus no exercise on plasma BDNF levels in individuals with neurodegenerative disorders (i.e., multiple sclerosis, Parkinson’s disease, mild cognitive impairment MCI and Alzheimer’s disease) were included. Overall, exercise interventions induced a significant increase in plasma BDNF levels (SMD=2.22, 95% CI=1.33–3.12, p<0.001; 18 studies), which was separately confirmed for multiple sclerosis (SMD= 2.40, 95% CI= 1.30–3.50, p<0.001; 10 studies) and Parkinson's disease (SMD= 10.00, 95% CI= 2.48–17.51, p=0.009; 3 studies), with a non-significant trend also observed for MCI (SMD= 1.07, 95% CI= -0.14–2.28, p=0.080; 4 studies). BDNF levels significantly increased regardless of exercise type (p<0.001, p=0.003 and p=0.020 for combined, aerobic and resistance exercise, respectively), weekly exercise volume (p<0.001 for both ≥150 and <150 min/week) and intervention length (p<0.001 for both interventions of ≥12 and <12 weeks). In conclusion, physical exercise interventions increase plasma BDNF levels in individuals with neurodegenerative disorders.
PROSPERO registration number: CRD42020199459.
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•The valorization of waste biomass from almond agriculture activities was achieved.•A novel multistep organosolv process of almond shells was carried out.•An extensive mass balance ...was done, providing a full understanding of the process.•Pulps with high cellulose content remained after each extraction cycle.•Highly pure (≈90%) and reactive lignins were obtained after each stage.
Almond shells are waste biomass generated in agro-industrial activities, which represent a resource that can be further valorized upon treatment. The purpose of this work was to assess new value-added products obtained through a novel multi-stage delignification process of almond shells. A comprehensive chemical characterization of the raw materials and products involved in each stage of the process was carried out. Moreover, an extensive mass balance was developed, providing a full understanding of the extraction process. The pulps produced did not display a significant cellulose loss and hence they could be exploited as cellulose-rich materials. On the other hand, the obtained lignins presented high purity values (≈90%) and a high reactivity, and their structures became more condensed and homogeneous after each extraction cycle. These features would allow their utilization as feedstock of renewable materials such bio-sourced phenolic resins.
Carbohydrate availability affects fat metabolism during exercise; however, the effects of complete muscle glycogen unavailability on maximal fat oxidation (MFO) rate remain unknown. Our purpose was ...to examine the MFO rate in patients with McArdle disease, comprising an inherited condition caused by complete blockade of muscle glycogen metabolism, compared to healthy controls. Nine patients (three women, aged 36 ± 12 years) and 12 healthy controls (four women, aged 40 ± 13 years) were studied. Several molecular markers of lipid transport/metabolism were also determined in skeletal muscle (gastrocnemius) and white adipose tissue of McArdle (Pygm p.50R*/p.50R*) and wild‐type male mice. Peak oxygen uptake (V̇O2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}$), MFO rate, the exercise intensity eliciting MFO rate (FATmax) and the MFO rate‐associated workload were determined by indirect calorimetry during an incremental cycle‐ergometer test. Despite having a much lower V̇O2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}$ (24.7 ± 4 vs. 42.5 ± 11.4 mL kg−1 min−1, respectively; P < 0.0001), patients showed considerably higher values for the MFO rate (0.53 ± 0.12 vs. 0.33 ± 0.10 g min−1, P = 0.001), and for the FATmax (94.4 ± 7.2 vs. 41.3 ± 9.1 % of V̇O2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}$, P < 0.0001) and MFO rate‐associated workload (1.33 ± 0.35 vs. 0.81 ± 0.54 W kg−1, P = 0.020) than controls. No between‐group differences were found overall in molecular markers of lipid transport/metabolism in mice. In summary, patients with McArdle disease show an exceptionally high MFO rate, which they attained at near‐maximal exercise capacity. Pending more mechanistic explanations, these findings support the influence of glycogen availability on MFO rate and suggest that these patients develop a unique fat oxidation capacity, possibly as an adaptation to compensate for the inherited blockade in glycogen metabolism, and point to MFO rate as a potential limiting factor of exercise tolerance in this disease.
Key points
Physically active McArdle patients show an exceptional fat oxidation capacity.
Maximal fat oxidation rate occurs near‐maximal exercise capacity in these patients.
McArdle patients’ exercise tolerance might rely on maximal fat oxidation rate capacity.
Hyperpnoea might cloud substrate oxidation measurements in some patients.
An animal model revealed overall no higher molecular markers of lipid transport/metabolism.
figure legend McArdle disease is caused by inherited blockade of glycogen breakdown in skeletal muscle fibres, with subsequent intolerance to most exercise tasks, as well as a substantial impairment of peak aerobic capacity. The present study indicates that the exercise capacity of these patients is mainly sustained by fat oxidation, with active patients showing an exceptional maximal fat oxidation rate (comparable to athletes) during endurance exercise, possibly as an adaptation to muscle glycogen unavailability. On the other hand, data in the (untrained) mouse model of the disease revealed overall no major differences at baseline in molecular markers of lipid transport/metabolism compared to wild‐type mice.
Two organosolv lignins from different origins, namely, almond shells and maritime pine, were modified by using a nanoclay and nanosilicate. Prior to modification, they were activated via glyoxalation ...to enhance the reactivity of the lignins and thus ease the introduction of the nanoparticles into their structure. The lignins were characterized by several techniques (Fourier transformed infrared, high-performance size exclusion chromatography, 1H NMR, X-ray diffraction, and thermogravimetric analysis) before and after modification to elucidate the main chemical and structural changes. The reaction with glyoxal proved to increase the amount of hydroxyl groups and methylene bridges. This tendency was more pronounced, as the percentage of glyoxal was incremented. On the other side, the addition of the nanoclay and nanosilicate particles improved the thermal stability of the lignins compared to that of the original unmodified ones. This trend was more evident for the lignin derived from maritime pine, which displayed better results regarding the thermal stability, indicating a more effective combination of the nanoparticles in the lignin structure during the modification process.
The synthesis and unique tunable optical properties of core/crown nanoplatelets having an inverted Type‐I heterostructure are presented. Here, colloidal 2D CdS/CdSe heteronanoplatelets are grown with ...thickness of four monolayers using seed‐mediated method. In this work, it is shown that the emission peak of the resulting CdS/CdSe heteronanoplatelets can be continuously spectrally tuned between the peak emission wavelengths of the core only CdS nanoplatelets (421 nm) and CdSe nanoplatelets (515 nm) having the same vertical thickness. In these inverted Type‐I nanoplatelets, the unique continuous tunable emission is enabled by adjusting the lateral width of the CdSe crown, having a narrower bandgap, around the core CdS nanoplatelet, having a wider bandgap, as a result of the controlled lateral quantum confinement in the crown region additional to the pure vertical confinement. As a proof‐of‐concept demonstration, a white light generation is shown by using color conversion with these CdS/CdSe heteronanoplatelets having finely tuned thin crowns, resulting in a color rendering index of 80. The robust control of the electronic structure in such inverted Type‐I heteronanoplatelets achieved by tailoring the lateral extent of the crown coating around the core template presents a new enabling pathway for bandgap engineering in solution‐processed quantum wells.
Continuously tunable photoluminescence in a model platform of inverted core/crown nanoplatelets is demonstrated with a tunability range of 90 nm. The unique continuous tunable emission is achieved by controlling the lateral width of the CdSe crown around the seed CdS nanoplatelet template because of the finely tuned lateral quantum confinement in the crown region additional to the pure vertical confinement.
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