Oxaliplatin was the first platinum drug with proven activity against colorectal tumors, becoming a standard in the management of this malignancy. It is also considered for the treatment of pancreatic ...and gastric cancers. However, a major reason for treatment failure still is the existence of tumor intrinsic or acquired resistance. Consequently, it is important to understand the molecular mechanisms underlying the appearance of this phenomenon to find ways of circumventing it and to improve and optimize treatments. This review will be focused on recent discoveries about oxaliplatin tumor-related resistance mechanisms, including alterations in transport, detoxification, DNA damage response and repair, cell death (apoptotic and nonapoptotic), and epigenetic mechanisms.
Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and ...are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.
In human cancers, transforming growth factor‐β1 (TGF‐β1) plays a dual role by acting as both a tumor suppressor and a promoter of tumor metastasis. Although TGF‐β1 contributes to the metabolic ...reprogramming of cancer cells and tumor‐associated stromal cells, little is known of the molecular mechanisms connecting this cytokine with enhanced glycolysis. PFKFB3 is a homodymeric bifunctional enzyme, belonging to the family of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatases, that controls the conversion of fructose‐6‐phosphate (Fru‐6‐P) to fructose‐2,6‐bisphosphate (Fru‐2,6‐P2). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating phosphofructokinase‐1, a rate‐limiting enzyme in glycolysis. The PFKFB3 gene is involved in cell proliferation via its role in carbohydrate metabolism. Here, we studied the mechanisms connecting TGF‐β1, glucose metabolism, and PFKFB3 in glioblastoma cell lines. We demonstrate that TGF‐β1 upregulates PFKFB3 mRNA and protein expression resulting in an increase in fructose 2,6‐bisphosphate concentration, glucose uptake, glycolytic flux and lactate production. Moreover, these increases in PFKFB3 mRNA and protein expression and Fru‐2,6‐P2 concentration were reduced when the Smad3, p38 mitogen‐activated protein kinase (MAPK), and phosphoinositide 3‐kinase (PI3K)/Akt signaling pathways were inhibited. We demonstrate that inhibition of PFKFB3 activity with 3PO or siRNA‐mediated knockdown of PFKFB3 significantly eliminated the capacity of the T98G cells to form colonies by TGF‐β1, one of the hallmarks of transformation. Taken together, these results show that TGF‐β1 induces PFKFB3 expression through activation of the p38 MAPK and PI3K/Akt signaling pathways that complement and converge with early activation of Smad signaling. This suggests that PFKFB3 induction by TGF‐β1 can be one of the main mechanisms mediating the reprogramming of glioma cells.
Transforming growth factor‐β1 (TGF‐β1) upregulates PFKFB3 expression resulting in an increase in fructose 2,6‐bisphosphate (Fru‐2,6‐P2) concentration, glucose uptake, glycolytic flux, and lactate production through the activation of the Smad, p38 mitogen‐activated protein kinase, and phosphoinositide 3‐kinase/Akt signaling pathways in glioblastoma cells. PFKFB3 inhibition decreases Fru‐2,6‐P2 levels and impairs colony formation by TGF‐β1, indicating that PFKFB3 induction is one of the main mechanisms mediating the reprogramming of glioma cells.
This paper uses a model of intergenerational accounting to simulate the intergenerational distribution of oil wealth in Venezuela. Venezuelan oil production does not seem to follow an optimal ...extraction path. Nevertheless, this is true if we do not consider what the government does with the resources received from the oil sector. We explored the interaction of oil policy and fiscal policy using such intergenerational accounting model. We argue that the way in which tax revenues (both, those coming from oil and those who do not) are used today can affect voters preferences on how they will be used tomorrow. These interactions could explain certain outcomes. In particular, the model could explain why the sector was open for investment in 1991 and then “re-nationalized” in 2001. Results suggest that when fiscal policy could leave an important burden to future generations, voters seem to favor a more tax-oriented oil policy, leaving the oil in the subsoil.
Intensive groundwater development is a common circumstance in semiarid and arid areas. Often abstraction exceeds recharge, thus continuously depleting reserves. There is groundwater mining when the ...recovery of aquifer reserves needs more than 50years. The MASE project has been carried out to compile what is known about Spain and specifically about the south-eastern Iberian Peninsula and the Canary Islands. The objective was the synthetic analysis of available data on the hydrological, economic, managerial, social, and ethical aspects of groundwater mining. Since the mid-20th century, intensive use of groundwater in south-eastern Spain allowed extending and securing the areas with traditional surface water irrigation of cash crops and their extension to former dry lands, taking advantage of good soils and climate. This fostered a huge economic and social development. Intensive agriculture is a main activity, although tourism plays currently an increasing economic role in the coasts. Many aquifers are relatively high yielding small carbonate units where the total groundwater level drawdown may currently exceed 300m. Groundwater storage depletion is estimated about 15km3. This volume is close to the total contribution of the Tagus-Segura water transfer, but without large investments paid for with public funds. Seawater desalination complements urban supply and part of cash crop cultivation. Reclaimed urban waste water is used for irrigation. Groundwater mining produces benefits but associated to sometimes serious economic, administrative, legal and environmental problems. The use of an exhaustible vital resource raises ethical concerns. It cannot continue under the current legal conditions. A progressive change of water use paradigm is the way out, but this is not in the mind of most water managers and politicians. The positive and negative results observed in south-eastern Spain may help to analyse other areas under similar hydrogeological conditions in a less advanced stage of water use evolution.
Display omitted
•Intensive use and mining of groundwater allow social development.•Groundwater mining is not sustainable, but is a valuable transient water resource.•Groundwater mining in south-eastern Spain is estimated to be 15km3.•Groundwater mining is not compatible with the European Water Framework Directive.•The intensive and mining uses of groundwater involve ethical and moral problems.
The aim of this study was to analyze the differences in body composition and physical fitness according to the weight status (normoweight, overweight and obese) and the level of adherence to the ...Mediterranean diet (MD; low, medium or high), in physically active children and adolescents. Furthermore, this study also analyzed the relationship between body composition and physical fitness with Body Mass Index (BMI), fat mass and the level of adherence to the MD. In total, 1676 participants aged 6-17 from different municipal sports schools participated in this cross-sectional study. Data on adherence to the MD (a KIDMED questionnaire), anthropometric measurements, body composition and physical fitness parameters (the 20-m shuttle run test and muscular strength) were collected. A total of 43.5% of the sample were presented as overweight and obese, and only 35.7% had high or optimal adherence to the MD. The results revealed that a normoweight status was associated with greater cardiorespiratory fitness (
< 0.05; ES: 0.50 to 0.67) and lower-body muscular strength (
< 0.05; ES: 0.58 to 1.10). The overweight group showed more significant results than the other groups in handgrip strength (
< 0.01). Greater adherence to the MD in this population indicated better physical fitness, but only in boys. It is concluded that normoweight status and optimal adherence to the MD in children and adolescents are associated with health benefits, which are significant in the body composition and the effect on physical fitness.
Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, ...with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy. The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them.
To evaluate whether the addition of hydrochlorothiazide (HCTZ) to intravenous furosemide is a safe and effective strategy for improving diuretic response in acute heart failure (AHF).
A prospective, ...double-blind, placebo-controlled trial, including patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The coprimary endpoints were changes in body weight and patient-reported dyspnoea 72 h after randomization. Secondary outcomes included metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. Safety outcomes (changes in renal function and/or electrolytes) were also assessed. Two hundred and thirty patients (48 women, 83 years) were randomized. Patients assigned to HCTZ were more likely to lose weight at 72 h than those assigned to placebo 2.3 vs. 1.5 kg; adjusted estimated difference (notionally 95 confidence interval) 1.14 (1.84 to 0.42); P 0.002, but there were no significant differences in patient-reported dyspnoea (area under the curve for visual analogue scale: 960 vs. 720; P 0.497). These results were similar 96 h after randomization. Patients allocated to HCTZ showed greater 24 h diuresis (1775 vs. 1400 mL; P 0.05) and weight loss for each 40 mg of furosemide (at 72 and at 96 h) (P 0.001). Patients assigned to HCTZ more frequently presented impaired renal function (increase in creatinine 26.5 moL/L or decrease in eGFR 50; 46.5 vs. 17.2; P 0.001), but hypokalaemia and hypokalaemia were similar between groups. There were no differences in mortality or rehospitalizations.
The addition of HCTZ to loop diuretic therapy improved diuretic response in patients with AHF.
The aim of this study is to analyse the relationship between sport modalities practiced, physical fitness, body composition, and healthy habits in an active young population, using a statistical ...model for prediction. A total of 2255 (1528 boys and 727 girls) children and adolescents aged 6–17 years old who were involved in extracurricular sports from rural areas of Spain participated. Physical fitness was assessed through validated field test and, body composition was determinated using bioelectrical impedance analysis. Adherence to the Mediterranean diet was assessed by KIDMED questionnaire. The general sport variable was significant in VO2max when comparing the invasion and combat modalities to the reference level (court/net). The sex and age variables revealed significant differences in all physical fitness and body composition parameters. Health parameters, such as hours of additional practice, adherence to the Mediterranean diet, and previous experience, showed significant differences. The study concludes that the sport modality variables of training, sex, age, and maturational period have an impact on body composition and fitness parameters in this population. Therefore, by focusing on factors associated with lower values in health indicators, we can prevent health problems during adulthood, such as cardiorespiratory deficits.
The pathways of melanization and sclerotization of the cuticle in insects are carried out by the action of laccases on dopamine and related compounds. In this work, the laccase action of Trametes ...versicolor (TvL) on catecholamines and related compounds has been kinetically characterized. Among them, dopamine, l-dopa, l-epinephrine, l-norepinephrine, dl-isoprenaline, l-isoprenaline, dl-α-methyldopa, l-α-methyldopa and l-dopa methylester. A chronometric method has been used, which is based on measuring the lag period necessary to consume a small amount of ascorbic acid, added to the reaction medium.
The use of TvL has allowed docking studies of these molecules to be carried out at the active site of this enzyme. The hydrogen bridge interaction between the hydroxyl oxygen at C-4 with His-458, and with the acid group of Asp-206, would make it possible to transfer the electron to the T1 Cu-(II) copper centre of the enzyme. Furthermore, Phe-265 would facilitate the adaptation of the substrate to the enzyme through Π-Π interactions.
To kinetically characterize these compounds, we need to take into consideration that, excluding l-dopa, l-α-methyldopa and dl-α-methyldopa, all compounds are in hydrochloride form. Because of this, first we need to kinetically characterize the inhibition by chloride and, after that, calculate the kinetic parameters KM and VmaxS.
From the kinetic data obtained, it appears that the best substrate is dopamine. The presence of an isopropyl group bound to nitrogen (isoprenaline) makes it especially difficult to catalyse. The formation of the ester (l-dopa methyl ester) practically does not affect catalysis. The addition of a methyl group (α-methyl dopa) increases the rate but decreases the affinity for catalysis. l-Epinephrine and l-norepinephrine have an affinity similar to isoprenaline, but faster catalysis, probably due to the greater nucleophilic power of their phenolic hydroxyl.
•A chronometric method has been applied to characterize the action of laccase on catecholamines and related compounds.•From lag-phase experimental recordings, steady-state rates have been determined.•Non-linear regression of steady-state rates gave us the kinetic parameters Vmax and KM for each substrate.•Laccase inhibition by chloride has been characterized.
PDF
