text:
The Relationship between Nutrient Intake and Cataracts in the Older Adult Population of Korea
Regular Supplementation with Antioxidants Rescues Doxorubicin-Induced Bone Deformities and Mineralization Delay in Zebrafish
10.3390/nu14234961
Piergiorgio Bolasco
D'Ambrosio, V.
Ferraro, P. Manuel
Lombardi, G.
Friso, S.
Gambaro, G.
Open AccessReview
Unravelling the Complex Relationship between Diet and Nephrolithiasis: The Role of Nutrigenomics and Nutrigenetics
Viola D'Ambrosio
1,2,† ,
Pietro Manuel Ferraro
Gianmarco Lombardi
Simonetta Friso
Giovanni Gambaro
Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
U.O.C. Nephrology, Department of Medical and Surgical Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy
Division of Nephrology, Department of Medicine, University of Verona, 37126 Verona, Italy
Unit of Internal Medicine, Department of Medicine, University of Verona, 37126 Verona, Italy
Nutrients 2022, 14(23), 4961; https://doi.org/10.3390/nu14234961
(This article belongs to the Special Issue Eating Habits and Chronic Kidney Disease: Epidemiological and Interventional Aspects)
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Nephrolithiasis is an increasingly prevalent condition, especially in high income countries, and is associated with high morbidity. Extraordinary progress in genetics made the identification of genetic forms of nephrolithiasis possible. These genetic diseases are usually rare and do not account for the most common forms of nephrolithiasis that are the result of several factors such as environment, dietary habits, and predisposing genes. This knowledge has shaped what we classify as nephrolithiasis, a condition that is now recognized as systemic. How and to what extent all these factors interact with one another and end in kidney stone formation, growth, and recurrence is not completely understood. Two new research fields have recently been trying to give some answers: nutrigenomics and nutrigenetics. These fields have the aim of understanding the intricate diet/genome interface that influences gene expression regulation mainly through epigenetic mechanisms and results in specific medical conditions such as cancer, metabolic syndrome, and cardiovascular diseases. Epigenetics seems to play a crucial role and could represent the link between environmental factors, that we are constantly exposed to, and risk factors for nephrolithiasis. In this systematic review, we summarize all the available evidence of proven or hypothesized epigenetic mechanisms related to nephrolithiasis.
kidney stones; diet; nutrigenomics; epigenomics
Nephrolithiasis is a common condition whose prevalence has been increasing in recent decades [1]. Calcium-containing kidney stones are the most common type and account for almost 75% of the cases [2]. This condition is generally referred to as idiopathic stone disease and is different from the much rarer secondary calcium nephrolithiasis (caused by monogenic disorders, hyperparathyroidism, and other endocrine disorders, such as malabsorption). This review specifically addresses idiopathic kidney stones, which are hereinafter referred to as kidney stones or nephrolithiasis. The increasing prevalence and studies on the heritability of kidney stones have paved the way for our understanding that nephrolithiasis results from a complex interaction of predisposing genes and environmental factors [3,4]. This hypothesis has been reinforced by evidence of the association between highly prevalent diseases, such as diabetes and metabolic syndrome, or lifestyle and dietary habits, and kidney stones [5,6,7,8,9]. Diet plays a major role in the incidence of nephrolithiasis. Over the last few decades, several dietary patterns have been associated with an increased risk of nephrolithiasis. In particular, the Western-style diet (i.e., a diet high in fat, calories, and animal protein, and low in fibre and plant-based proteins) has been blamed for the increased incidence of kidney stones in Japan [8]. Although not fully understood, the underlying causes of this association have been investigated, linking lithogenic dietary patterns with risk factors for nephrolithiasis, such as reduced urinary excretion of citrate and magnesium, increased excretion of calcium, oxalate and sodium, and acidic urinary pH [10,11,12]. The paradigm to explain the relationship between nutrients and nephrolithiasis is mechanistic; nutritional modifications have a direct and immediate impact on urine composition: higher sodium intake leads to higher natriuresis and to higher urinary excretion of calcium, higher oxalate intake (after balancing in the gut with the calcium intake) leads to increased oxaluria, and higher animal protein/sulphated amino acid intake leads to a bodily acidogenic tide compensated by more acidic urine. The beneficial effect on the development of kidney stones of dietary patterns, such as the Dietary Approach to Stop Hypertension (DASH) diet [12] or the Mediterranean diet [13,14], is explained in the mechanistic way of the previous paradigm [15]. In fact, both diets are characterised by a high intake of fruits and vegetables (a diet rich in alkali) and a reduced intake of animal protein (a diet poor in acids) and sodium. However, there are nutrition-dependent conditions that are associated with the risk of developing nephrolithiasis, such as insulin resistance, diabetes, obesity, and metabolic syndrome, and whose association cannot be entirely mechanistically explained [13].
A large body of evidence now supports the idea that nephrolithiasis is one of the manifestations of systemic conditions, which include bone and cardiovascular (CV) diseases [14,16,17]. While mechanistic explanations might be possible for the association between metabolic bone disease and kidney stones, the mechanisms of the association with CV morbidities are not straightforward [13].
Several studies have demonstrated that bone remodelling and atherosclerotic processes are epigenetically regulated [18]. Whether and to what extent the pathogenesis of nephrolithiasis and its systemic nature are mediated by epigenetic mechanisms remains unknown. Many environmental factors interact with genes through epigenetic mechanisms in human diseases, and nutrition is one of these factors [19]. Several studies have addressed different dietary components that can modify epigenetic processes, thereby modulating gene expression and metabolic effects [20].
Nutrigenomics is the science that studies the influences of micro- and macronutrients and dietary patterns on gene expression; nutrigenetics studies the role of genetic polymorphisms (e.g., single nucleotide polymorphisms; SNPs) on the relationship between dietary patterns and phenotypes. In this systematic review, we aim to summarise recent evidence on the role of nutrigenomics in nephrolithiasis, with a focus on potential epigenetic mechanisms.
In this narrative review, we searched the available literature about nutrigenomics, nutrigenetics, epigenetics, and nephrolithiasis and its risk factors/correlates. We selected papers from PubMed using the following search: ("epigen*"[Title/Abstract] or nutriepigen*[Title/Abstract]) and ("nutri*"[Title/Abstract] or "diet*"[Title/Abstract]). This first search was then coupled with risk factors/correlates of nephrolithiasis and (nephrolithiasis[Title/Abstract] or "kidney stones"[Title/Abstract] or nephrolithiasis[mesh]); and calcium[Title/Abstract]; and phosphorus[Title/Abstract]; and magnesium[Title/Abstract]; and acid-base[Title/Abstract]; and supersaturat*[Title/Abstract]; and vitamin D[Title/Abstract].
All the papers were included irrespective of the language, type of article, or year of publication. We included papers that reported at least one of the following:
For any given nutrient/dietary pattern, an epigenetic mechanism on either kidney stone formation or risk factors/correlates of nephrolithiasis
For a nutrient/dietary pattern already known to be associated with kidney stones or risk factors/correlates of nephrolithiasis, an epigenetic mechanism in general (not necessarily related to kidney stone formation)
A total of 120 references were read in full and their main findings are summarised in this review.
3. Epigenetics in Nephrolithiasis
The term 'epigenetics' literally means 'above the genome' and is defined as any process that alters gene expression without altering the DNA sequence. Epigenetic phenomena are stable and heritable and are of fundamental importance in regulating gene expression. To date, several epigenetic mechanisms have been identified in eukaryotic cells, among which DNA methylation (usually associated with gene silencing when the cytosine-guanine dinucleotide sequence-rich regions [CpG islands] of gene promoters are methylated), histone modifications (which allow the switch from euchromatin to heterochromatin and vice versa and therefore regulate gene expression; this includes histone acetylation, methylation, phosphorylation, and ubiquitination), noncoding RNA (ncRNA)-associated gene silencing (ncRNAs include microRNAs [miRNAs], short interfering RNAs [siRNAs], and long noncoding RNAs [lncRNAs]). Given the ability to regulate gene expression, epigenetic modifications may affect multiple cellular and metabolic pathways and have been considered in the pathophysiology of many diseases, especially environment-associated diseases. It is therefore not surprising that epigenetics represents a link between medical conditions and nutrition, an environmental factor to which we are constantly exposed [21]. Lifestyle, environmental factors, and diet have been proven to affect and regulate the genome via epigenetic modulations, making it clear that highly prevalent diseases, such as CV diseases, diabetes, and metabolic syndrome, are the result of intricate biological mechanisms that interact with one another [22,23,24]. Nephrolithiasis is among the diseases with increasing prevalence, especially in high-income countries. Although nephrolithiasis is a complex multisystemic condition that depends on both genetic predisposition and environmental factors, many aspects of this disease, especially in idiopathic stone formers, are not completely understood. Unresolved issues, such as intra- and interindividual variability or the recurrence of kidney stones in the absence of specific triggers, suggest that there are other factors involved in its pathogenesis [25]. Among these potential factors, epigenetic modifications may unravel the link between genetic predisposition and environmental factors that are associated with nephrolithiasis. Recently, Khatami et al. demonstrated epigenetic differences between recurrent kidney stone formers and healthy subjects [26]. More specifically, their aim was to quantitatively assess promoter methylation in three genes that are frequently identified in recurrent kidney stone formers and whose expression patterns are controlled by promoter methylation: vitamin D receptor (VDR), calcium-sensing receptor (CaSR), and claudin 14 (CLDN14). Promoter methylation of the three genes was significantly different between recurrent stone formers and controls when methylation status was classified as unmethylated (<9%), methylated (9–29%), or highly/hypermethylated (>29%). However, when methylation status was classified only into unmethylated (<9%) and methylated (≥9%), a statistically significant difference was observed only for the VDR promoter and the distal promoter region of the CLDN14 gene, leading to the hypothesis that epigenetic changes of these two genes' expression patterns may be of fundamental importance in recurrent kidney stone formation. Both VDR and CLDN14 regulate the urinary excretion of calcium. VDR is expressed by many cell types in the kidney; however, it is highly expressed in proximal and distal tubule cells, where it regulates the expression of genes, such as calbindins and CaSR. High levels of VDR upregulate calbindins and CaSR expression, leading to high urine calcium excretion and a consequent increased risk of stone formation [27]. Claudins play a major role in kidney tubular handling of calcium. They are transmembrane proteins of the epithelial tight junctions that control the transport of calcium and other divalent ions through the epithelium. Data from Khatami et al. suggested that promoter hypermethylation may cause decreased expression of CLDN14, an interesting finding as mutations in the genes encoding for some claudins may cause high urine calcium excretion [28,29,30,31]. Moreover, CLDN14 inhibits claudin 16 (CLDN16) and 19 (CLDN19), which are expressed in the tight junctions of the thick ascending limb of the loop of Henle, and whose function is paracellular reabsorption of Ca2+ and Mg2+ via a pathway mediated by CaSR and other intracellular intermediate factors [32].
4. Nutrigenomics
Nutritional genomics or nutrigenomics is the science that studies the role of nutrients or dietary patterns in gene expression. Nutriepigenomics is therefore the branch of nutrigenomics that studies the epigenetic modifications on gene expression exerted by nutrients and food compounds (Figure 1).
Numerous nutrients involved in epigenetic changes have been identified, comprising methyl donors, amino acids, vitamins, minerals, polyphenols, other phytochemicals, and fatty acids (FAs) [33].
In the following sections, we report the available evidence on nutrigenomics and nephrolithiasis with a focus on epigenetic mechanisms. The relationships between food compounds, dietary patterns, and risk factors/correlates for kidney stone formation and potential underlying epigenetic mechanisms are summarised in Table 1.
5. Food Compounds
5.1. Acetic Acid (Vinegar)
In a Chinese epidemiological study, the daily intake of vinegar was shown to be associated with a reduced risk of nephrolithiasis [26]. Zhu et al. demonstrated that the administration of vinegar in rat models of calcium oxalate (CaOx) nephrolithiasis reduced urine calcium and increased citrate excretion, thereby reducing the risk of CaOx aggregation and stone formation [34]. The authors demonstrated both in vitro and in vivo that vinegar and acetic acid (the main component of vinegar) act via an acetate-enhanced epigenetic regulatory mechanism by which acetate increases histone H3 acetylation in renal tubular cells and stimulates the expression of miRNAs that suppress the expression of NaDC1 and CLDN14 by enhancing expression of microRNAs -130a-3p, -148b-3p and -374b-5p by increasing H3K9 and H3K27 acetylation at their promoter regions [34].
NaDC1 is a sodium/dicarboxylate cotransporter encoded by the SLC13A2 gene, which is mainly expressed in the proximal tubule and whose function is to reabsorb freely filtered citrate and other Krebs cycle intermediates (e.g., succinate) [38]. Reduced activity of NaDC1 leads to decreased reabsorption of citrate from the tubular lumen, and thus reduces the risk of nephrolithiasis. Furthermore, as previously described, CLDN14 is a tight junction protein that regulates paracellular calcium handling in the thick ascending limb of the loop of Henle. Its downregulation leads to increased reabsorption of Ca2+ mediated by CLDN16/19 and a subsequent reduction in calcium urinary excretion. The benefits of vinegar on CaOx kidney stone formation have been recently confirmed by Liu et al. in a CaOx nephrolithiasis rat model [35]. The working hypothesis was that vinegar decreases CaOx crystal formation and adhesion to tubular epithelial cells by regulating gut microbiota and tubular epithelial cell tight junctions. Disruption of the gut microbiota has been associated with CaOx formation through increased absorption and decreased secretion of oxalate in the gut [39,40,41,42,43]; this eventually leads to increased urinary oxalate excretion, supersaturation, and CaOx crystal formation. The disruption of tight junctions induced by CaOx leads to the apoptosis of tubular epithelial cells, increasing the exposure on the luminal surface of crystal-binding molecules, such as hyaluronan, and promoting crystal adhesion to tubular cells [44,45]. Of note, Liu et al. found that dietary administration of vinegar reduced urinary oxalate excretion, CaOx crystal deposition in the kidney, and increased serum acetate (one of the main components of vinegar) concentration [35]. Furthermore, they found that serum acetate increased the expression of occludins in tubular epithelial cell tight junctions both at the messenger RNA (mRNA) and the protein level. The underlying mechanisms have not been fully elucidated; however, one can speculate that, similar to the effects reported by Zhu et al. [25], the effect of vinegar on occludins might be due to epigenetic modifications at a tubular level, as described in other pathological conditions [46,47].
5.2. Amino Acids—L-Arginine
Among the results reported by Liu Yu et al., in gut microbiota, a metabolic pathway involved in arginine synthesis was found to be increased in the vinegar group compared with the control group [35]. Clinical or biochemical manifestations of the increased metabolic pathway were not described; however, the effect of dietary supplementation of L-arginine has been previously described in a CaOx stone former and a uninephrectomised rat model [36]. Dietary L-arginine supplementation significantly decreased urinary calcium and increased citrate excretion; interestingly, it also increased urinary sodium and albumin excretion, two well-known risk factors for kidney damage. Urinary oxalate excretion was not evaluated; however, L-arginine-treated rats showed less CaOx crystal deposition in the kidney compared with controls. Additional evidence of the potential benefit of L-arginine dietary supplementation on CaOx stone formation was reported by Pragasam et al., who demonstrated the role of L-arginine in reducing oxalate excretion and oxidative stress-induced kidney injury, thereby reducing the risk of kidney stone formation in a hyperoxaluric rat model [48]. L-arginine is an amino acid found mainly in animal protein (dairy, fish, and poultry) and nuts (walnuts, hazelnuts, pecans, peanuts, almonds, and cashews). Since dietary L-arginine acts via epigenetic mechanisms in other conditions and metabolic pathways [49,50], it is tempting to hypothesise the role of epigenetic mechanisms behind the effects of L-arginine on nephrolithiasis.
5.3. Fructose
Fructose is a macronutrient of interest in nephrolithiasis. A diet high in fructose, which can be mainly found in processed food and carbonated beverages, is strongly associated with an increased incidence of nephrolithiasis [37,51]. High fructose intake has previously been associated with high urinary calcium and oxalate excretion in a magnesium-depleted mouse model [52,53] and in healthy individuals [54,55]. Fructose intake also increases insulin resistance, which in turn is associated with a low urinary pH [56] (a risk factor for uric acid kidney stones). The exact mechanisms by which fructose modifies urine composition are still not completely understood and a specific epigenetic mechanism exerted by fructose in nephrolithiasis or risk factors for kidney stone formation have not been described. However, from available data, we know that fructose acts via epigenetic mechanisms (ncRNA and DNA methylation) in other conditions [57,58,59], such as nonalcoholic fatty liver disease (NAFLD) [60,61,62]. Therefore, we can speculate that fructose might act via epigenetic mechanisms to regulate the expression of genes that encode crucial transporters of anti- and prolithogenic urinary molecules.
5.4. Sodium Chloride
Sodium chloride is a widely used food compound in our diet. In Western countries, sodium chloride serves as an additional compound to improve the taste of food and is used also as a preservative. This is the reason why diets largely based on processed food, such as the Western diet, are generally high in sodium chloride. High dietary salt intake has been associated with several medical conditions, such as hypertension [63], CV disease [64], and nephrolithiasis [65,66]. The mechanisms underlying these associations have been extensively studied over the last two decades, and the results have highlighted a strong relationship between high dietary sodium chloride intake, increased urinary excretion of sodium, and high urinary calcium excretion [10,67]. Several studies reported a direct correlation between increased dietary sodium chloride intake and high urinary calcium excretion and vice versa (reduced salt intake and decreased urinary calcium excretion) [68,69,70]. Furthermore, the reduction in calciuria caused by the reduced intake of salt might lead, through a homeostatic mechanism, to a reduction in the absorption of calcium in the more proximal portions of the intestine, leaving a greater proportion of it more available at the distal level to form greater quantities of nonabsorbable calcium oxalate [71]. Regarding the underlying physiological mechanisms, Yatabe et al. conducted a study on murine models and found that a high sodium chloride diet was associated with decreased expression of claudin 2 (CLDN2) in the proximal tubule [72]. Interestingly, they also demonstrated increased expression of proteins involved in transcellular calcium reabsorption in the distal convoluted tubule: transient receptor potential cation channel subfamily V member 5 (TRPV5; an apical calcium transporter), calbindin-D28k (an intracellular calcium-binding protein), and sodium-calcium exchanger 1 (NCX1; a basolateral sodium-calcium exchanger). These changes did not seem to compensate for the CLDN2-mediated decrease in calcium reabsorption in the proximal tubule. The mechanisms behind this shift in protein expression in response to sodium load remain unclear; however, it would be of interest to investigate the possible role of epigenetic mechanisms. Amara et al. demonstrated epigenetic alterations and a predisposition to cardiac dysfunction in uninephrectomised rats exposed to a high sodium chloride diet, although a cause-effect mechanism has not yet been elucidated [73].
5.5. Vitamin D
In the topic of nutrigenomics in nephrolithiasis, vitamin D has received much of the focus. In the previous section, we reported how epigenetic changes in vitamin D receptor (VDR) were associated with an increased risk of nephrolithiasis [18,19]. Endogenous and dietary vitamin D act via their active metabolite, 1α,25-dihydroxyvitamin D3 (1.25 (OH)2-vitamin D), and regulate the genome, epigenome, and transcriptome involved in calcium homeostasis and other physiological or pathological pathways, such as innate and adaptive immune response, osteoporosis, sarcopenia, and cancer [74]. The ability of vitamin D to regulate genome expression has been investigated as a possible cause of interindividual variability in response to exogenous supplementation. The same could be applied to high urinary calcium excretion and the risk of kidney stone formation. Due to the known effect of vitamin D on increasing the intestinal absorption of calcium and phosphorus, its association with nephrolithiasis has been of interest both in research and in clinical practice; however, prospective interventional studies are scarce. In addition to nephrolithiasis, vitamin D is crucial in bone metabolism. Several studies [75] have demonstrated the link between the genome and environment in the development of osteoporosis and vitamin D, and its receptor VDR may act as a mediator. Other studies, both in animal models and in humans, found an association between vitamin D deficiency during pregnancy and the risk of medical conditions in offspring, such as inflammation and adiposity [76], allergies [77], ageing [78], and osteoporosis [79] via epigenetic modifications. In a review by Snegarova et al., hypovitaminosis D was associated with an increased incidence of obesity, insulin resistance, diabetes, and osteoporosis, all conditions that are associated with nephrolithiasis [80]. The vitamin D pathway is tightly regulated by epigenetic mechanisms and seems to also regulate epigenetic modifications. It is therefore interesting to speculate an underlying epigenetic mechanism regulating a possible prolithogenic response to endogenous and exogenous vitamin D. However, direct data to corroborate or refute this hypothesis are currently unavailable.
5.6. Calcium
Calcium plays a crucial role in nephrolithiasis. From a biochemical perspective, high urinary excretion of calcium is one of the main risk factors for nephrolithiasis, and CaOx and calcium phosphate are the most common components of kidney stones. The role of dietary calcium has long been debated. Although it was previously believed that a low calcium diet would reduce the risk of kidney stones, it is now widely accepted that the opposite is true; in fact, a diet containing 1000–1200 mg/day of calcium reduces the risk of kidney stone formation by reducing the intestinal absorption of oxalate [81,82]. Moreover, it has been reported that when patients were advised to reduce their dietary intake of milk and dairy, they tended to increase their animal protein intake [83]. It is currently unknown whether dietary calcium per se induces epigenetic changes that would predispose to nephrolithiasis; however, there are reports in the literature of epigenetic mechanisms induced by dietary calcium [84,85,86]. In a paper published by Takaya et al., a low-calcium diet in mice during pregnancy was associated with insulin resistance and reduced insulin secretion in offspring via a heritable epigenetic mechanism [87]. In humans, insulin resistance plays a role in uric acid nephrolithiasis [88]. Therefore, it would be interesting to investigate whether a link exists between dietary calcium, insulin resistance, and uric acid nephrolithiasis in vivo via epigenetic mechanisms. The interaction between DNA polymorphisms and dietary calcium and its impact on the risk of calcium nephrolithiasis is discussed in the 'nutrigenetics' section.
5.7. Magnesium
Magnesium is an abundant element in our body, although its free circulating concentration makes up only 1% of the total body magnesium; the rest is in combination with calcium and phosphate in bone and soft tissue [89]. It is because of this affinity for calcium and phosphate, two players in kidney stone formation, that magnesium has drawn attention as a potential kidney stone inhibitor. In recent decades, several in vivo and in vitro studies have demonstrated the ability of magnesium to reduce the risk of nephrolithiasis. Magnesium supplementation in kidney stone formers increases magnesium and citrate excretion [90] and decreases oxalate excretion [91]; this could represent an underlying mechanism for a reduction in the incidence of new kidney stone events [68]. Curhan et al. demonstrated an inverse association between urinary magnesium and nephrolithiasis. However, clinical evidence that supports the beneficial effects of magnesium supplementation alone in stone formers is scarce [92,93]. From a physiological point of view, urinary magnesium acts as an inhibitor of crystal formation; it competitively binds oxalate, forming magnesium oxalate, which is more soluble than CaOx [90]. Whether or not magnesium influences the risk of kidney stone formation via epigenetic modifications has not yet been evaluated to our knowledge. However, a subclinical magnesium deficit may stimulate intracellular inflammatory pathways via possible epigenetic mechanisms, leading to chronic inflammation-related diseases, such as type 2 diabetes, metabolic syndrome, osteoporosis, and CV disease [94,95]. These conditions are all associated with an increased incidence of nephrolithiasis. In an animal model of magnesium deficiency-induced disease, inflammatory and apoptosis response-related genes were modulated by epigenetic mechanisms [96]. Therefore, it would be interesting to explore whether magnesium deficiency or low magnesium urinary excretion, in addition to other lifestyle and environmental factors, could cause prolithogenic epigenetic modifications.
5.8. Phosphate
Phosphate is an essential molecule for cellular metabolism and bone health. Up to 80–85% of body phosphate is present in the bone as salt, and the remaining 15–20% circulates in the serum as free ion or protein-bound phosphate. Phosphate concentration ultimately depends on dietary intake, gastrointestinal absorption, and urinary excretion; it shifts between the intracellular and the extracellular fluid and is tightly regulated by hormones, such as PTH, FGF23, and vitamin D [97]. Phosphate is freely filtered by the glomerulus and is mainly reabsorbed by the proximal tubule via transcellular Na+-driven transport. Tubular phosphate handling has been of interest in nephrolithiasis. Increased tubular phosphate leak increases the risk of urinary supersaturation with calcium phosphate and lowers plasma phosphate concentration. This causes an increased conversion of 1.25 (OH)2-vitamin D and the enhanced intestinal absorption of calcium and phosphate by the gut, resulting in high urinary calcium excretion [98,99,100]. In addition to the vitamin D-mediated effects, urinary phosphate leak affects other prolithogenic urinary parameters, such as uric acid, oxalate, citrate, the incidence and recurrence of nephrolithiasis, and bone demineralisation [98]. To our knowledge, the role of phosphate intake in nephrolithiasis has not yet been evaluated. It must be noted that all foods contain phosphate; however, it is the type and bioavailability of the phosphate that regulates intestinal absorption. Processed food is high in inorganic phosphate, which has the highest bioavailability. Animal and plant-based proteins are both high in organic phosphate; however, phosphate from animal proteins has higher bioavailability [101]. The Western diet provides a high phosphate load. Given the link between urinary phosphate and nephrolithiasis [98], and the link between a Western diet and nephrolithiasis [10], it would be interesting to explore whether and how dietary phosphate intake is associated with prolithogenic risk factors and whether this link is mediated by epigenetic mechanisms. Dietary phosphate intake has been associated with altered miRNA expression in neck squamous cell carcinoma [102], indicating that this element is potentially able to activate epigenetic pathways.
5.9. Dietary Acid-Base
One of the main functions of the kidney is to maintain acid-base balance and serum pH in the physiological range (7.35–7.45). Many factors have been demonstrated to affect this equilibrium; among them, diet plays an important role. Previous studies comparing high acid-load diets (e.g., the Western diet) to alkalinising diets (e.g., vegan or vegetarian diets) have demonstrated beneficial effects on general health outcomes, and more specifically kidney outcomes [4]. A high dietary acid load can imbalance acid-base homeostasis, leading to physiological responses in the kidneys and bone to buffer acidity. These responses include increased reabsorption of citrate by the renal proximal tubule and increased reabsorption of bone by osteoclasts to release calcium salts that buffer serum acids at the expense of increased excretion of calcium in the urine. Diet-induced acidosis stimulates osteoclast activity in bone reabsorption through receptor activation of the NF-κB ligand (RANKL) pathway [103]. Low urine citrate, high urine calcium, and acidic urine are risk factors for kidney stone formation, and the association between diets with an increased acid load and nephrolithiasis has been extensively studied. Whether other mechanisms, such as epigenetic modifications, play a role in this relationship has not been evaluated. However, dietary acid load, even when transient, may upregulate biological pathways, such as the cortisol pathway, as demonstrated by Espino et al. [104], or insulin growth factor 1 (IGF-1) [105]; however, the data in the literature is controversial.
6. Dietary Patterns
Western Diet
After analysing the association between single-food compounds or elements and nutrigenomics, it is natural to question whether dietary patterns might predispose to certain clinical conditions via epigenetic mechanisms. Dietary patterns and habits have been of key interest in nephrolithiasis, especially in high-income countries where food processing is associated with highly prevalent diseases, including hypertension, CV disease, obesity, insulin resistance, and diabetes. As previously mentioned, the Western diet involves high animal protein intake, low fruit and vegetable intake, and sweetened beverages [51]. Several studies have been conducted comparing different dietary patterns on the risk of nephrolithiasis [106,107]. It is currently accepted that plant-based diets are high in potassium, magnesium, and alkalinising agents, such as citrate, and thus act as a protective factor against nephrolithiasis. These diets include the vegan or vegetarian diet, the DASH diet [108], and the Mediterranean diet [109]. Of particular interest is the role of potassium in kidney stone formation. Previous studies have demonstrated a strong inverse relationship between dietary potassium and the incidence of nephrolithiasis; however, the relationship was even stronger when the dietary animal protein to potassium ratio was considered [110]. This underlies the importance of a potassium source and accompanying anion (chloride vs. citrate), with a net beneficial effect of potassium citrate that can be mainly found in fruits and vegetables, even with regard to urinary excretion of calcium [111]. Although a protective effect of urinary potassium excretion has been demonstrated for the progression of CKD [112] and hypertension [113], whether this is true for kidney stone formation and whether this could be mediated by epigenetic mechanisms has yet to be consistently proven.
Regarding dietary patterns and epigenetic mechanisms, Choi et al. conducted a study in murine models and demonstrated that the Western diet reduced DNA methylation [114]. Reductions in DNA methylation have been observed in other physiological processes, such as ageing. This study demonstrated that dietary patterns could indeed induce epigenetic modifications, and it would be interesting to explore a possible epigenetic link between different types of diet and nephrolithiasis.
7. Nutrition-Induced Epigenetic Modifications as Determinants of the Multisystemic Nature of Nephrolithiasis and the Possible Role of Fatty Acids
Epigenetic modifications may influence many cellular and metabolic pathways relevant to the expression of carriers at the level of the tubular and intestinal epithelium, the bone in the interface between osteoclasts and osteoblasts [18], and in the vessel wall. Epigenetic modifications regulate the expression of several genes in different tissues and have an impact on the pathophysiology of many diseases, especially the ones that are associated with the environment [115,116]. Some cellular and metabolic pathways are shared by different tissues (e.g., Wnt cascade, NF-κB cascade, and macrophage colony-stimulating factor). Therefore, epigenetic modifications induced by certain environmental conditions, namely nutrition, may simultaneously affect the biology of different tissues and organs. To our knowledge, the systemic impact (i.e., the simultaneous effect on different organs/tissues) of nutrigenetics has never been investigated apart from studies on the epigenetic regulation of fetal development and growth and the long-term pathological effects in adulthood of mother's conditions during pregnancy [117]. We speculate that this approach might be fruitful to explain the systemic nature of nephrolithiasis. In this respect, it is possible to revisit and partly reinterpret previous data on the association of nephrolithiasis with a derangement of FAs.
FAs may also be an interesting player in nutrigenomics. FAs, such as α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), modify DNA methylation sites in several genes associated with CV morbidities [118]. Interestingly, n − 3 polyunsaturated FAs (i.e., EPA, DHA) have been associated with the prevention of CV disease, metabolic alterations (i.e., lipid metabolism disturbances), and other chronic diseases (obesity, type 2 diabetes mellitus, and NAFLD) [118]. Abnormal FA 6-desaturase activity has been reported in nephrolithiasis and is responsible for the significantly higher content of arachidonic acid in lipoproteins and erythrocyte membrane phospholipids, lower content of linoleic acid, and a higher arachidonic/linoleic acid ratio compared with healthy subjects [119]. FA 6-desaturase, the rate-limiting enzyme in the biosynthetic pathway of highly unsaturated FAs, is modulated by nutritional factors, specifically protein and glucose intake, and dietary lipid composition [120]. Therefore, we may propose a scenario in which nutritional factors, by modulating the composition of FAs in plasma and cell membrane phospholipids, namely the n − 6/n − 3 ratio, can exert epigenetic effects on several genes and metabolic pathways relevant to the pathogenesis of nephrolithiasis, atherosclerosis, CV disease, and bone. The experimental manipulation of FA 6-desaturase activity and/or nutritional supplementation with n − 3 FA (fish oil) that altered plasma and cell membrane phospholipid composition was associated with changes in biomarkers of bone turnover [121,122,123].
A deeper understanding of the pathophysiological mechanisms underlying nephrolithiasis is of crucial importance in the diagnosis, treatment, and prevention of this increasingly prevalent condition. Retrospective and prospective association studies made it clear that nephrolithiasis is a systemic condition, and several factors, such as the environment, dietary habits, and predisposing genes, all play a role in its development.
Although it is possible to speculate that epigenetic mechanisms might also play a role in the formation of noncalcium-containing stone types, especially those that are sensitive to urinary pH such as uric acid, cystine, or calcium phosphate, no evidence is available in the literature. Nutrigenomics may represent a crucial tool for pursuing personalised treatment, and unravelling underlying epigenetic mechanisms may lead to the discovery of therapeutic targets and the development of nutraceutical drugs with an impact on stone formation and its systemic manifestations.
Conceptualization, G.G. and P.M.F.; methodology, G.G. and P.M.F.; writing—original draft preparation, V.D. and P.M.F.; writing—review and editing, all authors; supervision, G.G. and P.M.F. All authors have read and agreed to the published version of the manuscript.
P.M.F. received consultant fees and grant support from Allena Pharmaceuticals, Alnylam, AstraZeneca, BioHealth Italia, and Vifor Fresenius. V.D. received consultant fees from Allena Pharmaceuticals. The other authors declare no conflicts of interest.
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Figure 1. Schematic representation of the link between nutrients, genes, and risk factors for nephrolithiasis.
Table 1. Schematic summary of the relationship between food compounds and pro or antilithogenic urinary phenotypes mediated by proved or hypothesized epigenetic mechanisms.
Epigenetic Mechanism
Acetic acid (vinegar) [34] ncRNA-mediated gene silencing (miRNA) by promoting expression of microRNAs -130a-3p, -148b-3p, and -374b-5p by increasing H3K9, H3K27 acetylation at their promoter regions Reduced urinary calcium
Increased urinary citrate
Acetic acid (vinegar) [35] unknown Reduced urinary oxalate
Reduced CaOx crystals adhesion
Reduced plasma acetate -> increased occludins in tight junctions -> reduced CaOx stone formation
L-arginine [36] unknown Reduced urinary calcium
Fructose [37] unknown Increased urinary calcium
Increased urinary oxalate
D'Ambrosio, V.; Ferraro, P.M.; Lombardi, G.; Friso, S.; Gambaro, G. Unravelling the Complex Relationship between Diet and Nephrolithiasis: The Role of Nutrigenomics and Nutrigenetics. Nutrients 2022, 14, 4961. https://doi.org/10.3390/nu14234961
D'Ambrosio V, Ferraro PM, Lombardi G, Friso S, Gambaro G. Unravelling the Complex Relationship between Diet and Nephrolithiasis: The Role of Nutrigenomics and Nutrigenetics. Nutrients. 2022; 14(23):4961. https://doi.org/10.3390/nu14234961
D'Ambrosio, Viola, Pietro Manuel Ferraro, Gianmarco Lombardi, Simonetta Friso, and Giovanni Gambaro. 2022. "Unravelling the Complex Relationship between Diet and Nephrolithiasis: The Role of Nutrigenomics and Nutrigenetics" Nutrients 14, no. 23: 4961. https://doi.org/10.3390/nu14234961
Nutrients, EISSN 2072-6643, Published by MDPI


text:
The Jazz Review, Vol. 3, No. 9 (Nov.1960)
This PDF is a full-text searchable reproduction of the entire issue of this publication with all images, including advertisements.
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redpajama_set_name: RedPajamaCommonCrawl


text:
2.1.1 - Upgraded to `get-pixels@3.3.0` via @BS-Harou in #9

2.1.0 - Added `quality` support for JPEGs

2.0.1 - Upgraded to `save-pixels@2.3.0` to resolve `pngjs2` deprecation warning. Fixes #6

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1.3.4 - Added `specVersion` support and `spritesmith-engine` keyword

1.3.3 - Updated documentation to be a little cleaner and link to `spritesmith-engine-spec`

1.3.2 - Upgraded to `spritesmith-engine-test@3.0.0` to clean up technical debt

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1.1.2 - Moved from deprecated `licenses` key to `license` in `package.json`

1.1.1 - Fixed example in README via @tmcw in #3

1.1.0 - Added support for custom background. Fixes twolfson/gulp.spritesmith#33

1.0.0 - Initial fork from `pngsmith@0.1.3`

redpajama_set_name: RedPajamaGithub


In a recent IATA study, they say that returns on capital invested in airlines are still far below what investors would normally expect to earn. Investors can make much more money investing elsewhere. IATA's director general, Tony Tyler, said: "Unless we find ways to improve returns for our investors it may prove difficult to attract the $4-5 trillion of capital we need to serve the expansion in connectivity over the next two decades, the vast majority of which will support the growth of developing economies." IATA says during 2004-2011 period, returns on capital invested in the airline industry worldwide averaged 4.1% but that is nowhere near the average cost of capital of 7.5% which represents the return on capital that investors would expect. "On average industry returns were just sufficient for the industry to service its debt, with nothing left to reward equity investors for risking their capital." Tony Tyler said: "Airlines . . . face a hyper fragmented industry structure owing to government policies that discourage cross-border consolidation. There is plenty of room for some fresh thinking." Tony Tyler also said that net profits per airline passenger worldwide were just $2.56 in 2012. So little profit – for so much environmental damage and so much CO2.
Airlines will struggle to pay for the next generation of more fuel-efficient passenger jets unless governments and carriers take steps to improve industry profitability, the sector's representative body warned on Monday.
The International Air Transport Association used a report about the sector's weak earnings record to urge governments to take a more relaxed view on global mergers because consolidation is seen as a key driver of profits.
More consolidation; ever larger multinational companies; ever more chance to avoid tax due to be paid to the UK or other national government…..
Geneva – The International Air Transport Association (IATA) called for new thinking on the relationships between partners in the air transport value chain in order to attract the $4-5 trillion that will be needed over the next 20 years to meet the growing demand for aviation-enabled connectivity.
The call came in an IATA study supported by analysis from McKinsey & Company, "Profitability and the Air Transport Value Chain", which shows that returns on capital invested in airlines have improved in recent years, but are still far below what investors would normally expect to earn.
During the 2004-2011 period, returns on capital invested in the airline industry worldwide averaged 4.1%. This is an improvement on the average of 3.8% generated in the previous business cycle over 1996-2004. However, this is nowhere near the average cost of capital of 7.5% which represents the return on capital that investors would expect to earn by investing in assets of similar risk outside the airline industry. While some airlines have consistently created value for equity investors, these are few in number. On average industry returns were just sufficient for the industry to service its debt, with nothing left to reward equity investors for risking their capital.
The study showed that over the past 40 years virtually all industries have generated higher returns on invested capital (ROIC) than the airline industry. Moreover, airlines are the least profitable segment of the air transport value chain while other segments consistently generate good returns for their investors. The biggest cost for airlines today is fuel and companies in this sector benefited from an estimated $16-48 billion of their annual net profits generated by air transport. The most profitable part of the rest of the value chain is in distribution, with the computer reservation systems businesses of the three global distribution system companies generating an average ROIC of 20%, followed by freight forwarders with an ROIC of 15%.
However, high profits and inefficient costs in the value chain are only part of the explanation for persistently poor airline profitability. In fact over the past 40 years the airline industry has more than halved the cost of air transport in real terms, owing to better fuel efficiency, asset utilization and input productivity. Yet these efficiency gains have ended up in lower air transport yields rather than improved investor returns. That has created tremendous value for customers and the wider economy, but has left equity investors in the airline industry unrewarded. The study shows this aspect of the airlines' performance lies more in the industry's highly fragmented and unconsolidated structure and the nature of competition, rather than in the supply chain, although distribution is a key part of the puzzle.
"More effective partnerships are required among stakeholders in the air transport industry. Efficiency gains are a win-win for all concerned. We have seen that with the adoption of 100% e-ticketing and the introduction of global self-service standards. Not only did partners in the industry benefit, but consumers gained great value through more efficient and convenient processes. This study points to the active collaboration needed to find even more such solutions," said Tyler.
An agenda for governments is also outlined in the study. "Smart regulation is needed from governments around the world in order to maximize the economic benefits of connectivity—jobs and growth. Unfortunately, high taxation and poorly designed regulation in many jurisdictions make it difficult for airlines to develop connectivity. On top of the cost issues, airlines also face a hyper fragmented industry structure owing to government policies that discourage cross-border consolidation. There is plenty of room for some fresh thinking on all accounts," said Tyler.
Posted: Wednesday, July 3rd, 2013. Filed in General News, Recent News.


Androgen-deprivation therapy effect on benign prostatic tissue.
Compared with conservative management, primary androgen-deprivation therapy is not associated with improved survival in the majority of men aged 66 years or older with clinically localized prostate cancer.  Neoadjuvant hormonal therapy before radical prostatectomy has not been shown to be effective.
Grading of hormonal treatment effects (regression grading) to predict clinical outcome has been attempted but has yielded variable results. This is not routinely performed, and special studies on prostatic carcinoma with treatment effect are not currently done.
Endocrine therapy for prostate cancer is viewed as palliative and not curative, although most patients do experience an objective response. Eventually, all patients with metastatic disease treated with hormonal therapy develop hormone-independent (hormone-refractory or hormone-resistant) prostate cancer, with a rising prostate-specific antigen (PSA) level or other evidence of progression in the presence of androgen blockade.
Androgen-deprivation therapy effects may be seen in prostatic tissue from needle biopsy, transurethral resection of the prostate (TURP), and radical prostatectomy. These effects can also be found in tissue samples of metastatic prostatic carcinoma.
When evaluating the effects of androgen-deprivation therapy on prostatic tissue, also consider the possibility of benign conditions that may mimic carcinoma following such therapy, such as benign atrophy and histiocytic infiltration.
The gross findings and microscopic effects of hormonal therapy on prostatic tissue and prostate cancer are briefly reviewed in this section.
Androgen-deprivation therapy effect on a nodule in benign prostatic hypertrophy.
There is a decrease in the tumor volume and number of malignant glands in adenocarcinoma. In a small percentage of patients treated with neoadjuvant hormonal therapy before radical prostatectomy, no residual tumor is identified. A decrease in size of the adenocarcinoma glands is characteristic, with small and atrophic glands being detected. Loss or collapse of luminal spaces is typical.
A particularly insidious pattern of growth that can be difficult to recognize as malignant is the presence of widely scattered single tumor cells embedded in a wide expanse of stroma. A branching pattern and mucinous spaces and clefts (so-called pseudomyxoma ovarii-like pattern) may be seen. Cytologically, the carcinoma cells classically show nuclear pyknosis, hyperchromasia, inconspicuous nucleoli, cytoplasmic clearing, and cytoplasmic vacuolization. These changes can impart a histiocytoid appearance to the tumor cells. The stroma may be inflamed and edematous, fibrotic, hyalinized, and sclerotic. There is no change in high–molecular-weight cytokeratin expression in basal cells, so this marker still has diagnostic value in difficult-to-diagnose cases following hormonal therapy.
Hormonal therapy has been associated, in rare cases, with the emergence (or selection and progression) of prostatic carcinoma variants, including small cell carcinoma, sarcomatoid carcinoma, and squamous cell carcinoma. Images of hormonal therapy effects on prostate cancer are provided below.
Androgen-deprivation therapy effect on prostatic carcinoma.
Androgen-deprivation therapy effect on prostatic carcinoma: mucin pools without residual carcinoma cells.
Androgen-deprivation therapy effect on prostatic carcinoma: subtle, single-cell infiltrate.
Diagnostic recognition of carcinoma cells with hormonal treatment effects that are outside the prostate and in metastatic sites may be difficult (see the image below). Immunohistochemical stains can be of utility in these settings, and they can facilitate a more accurate stage assignment.
Androgen-deprivation therapy effect on metastatic prostatic carcinoma in bone marrow.
Immunohistochemical stains for basal cells and alpha-methylacyl-coenzyme A (CoA) racemase (AMACR) can be helpful in the diagnosis of prostatic carcinoma after hormonal treatment. [16, 17, 18] There is a reduction in AMACR immunoreactivity following hormonal therapy, such that 45% to 71% of cases are AMACR positive. [16, 18] In these post–hormonal therapy, AMACR-negative cases, basal cell stains assume great importance.
In radical prostatectomy cases with neoadjuvant hormonal treatment, detection of single-cell carcinoma infiltrates (see the image below) and distinction of carcinoma cells with treatment effect from inflammatory cells such as histiocytes and lymphocytes may be facilitated by the use of pan-cytokeratin, prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSAP), and prostate-specific membrane antigen (PSMA) immunostains. [11, 19] PSA and PSAP expression may be reduced after hormonal therapy, whereas cytokeratin expression is unaltered.
Cytokeratin immunostain, with detection of single-cell carcinoma infiltrate, following hormonal therapy.
Unlike breast carcinoma in which immunostains for estrogen and progesterone receptors are useful in predicting response to hormonal therapy, androgen-receptor immunohistochemistry has no value in predicting response to hormonal therapy for patients with untreated prostatic adenocarcinoma.
Nelson JB. Hormone therapy for prostate cancer. Wein AJ, Kavoussi LR, Novick AC, et al, eds. Campbell-Walsh Urology. 9th ed. Philadelphia, Pa: Saunders-Elsevier; 2007. 3082-3100.
Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003 Jul 17. 349(3):215-24. [Medline]. [Full Text].
Armas OA, Aprikian AG, Melamed J, et al. Clinical and pathobiological effects of neoadjuvant total androgen ablation therapy on clinically localized prostatic adenocarcinoma. Am J Surg Pathol. 1994 Oct. 18(10):979-91. [Medline].
Cher ML, Bova GS, Moore DH, et al. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res. 1996 Jul 1. 56(13):3091-102. [Medline]. [Full Text].
Best CJ, Gillespie JW, Yi Y, et al. Molecular alterations in primary prostate cancer after androgen ablation therapy. Clin Cancer Res. 2005 Oct 1. 11(19 pt 1):6823-34. [Medline]. [Full Text].
Petraki CD, Sfikas CP. Histopathological changes induced by therapies in the benign prostate and prostate adenocarcinoma. Histol Histopathol. 2007 Jan. 22(1):107-18. [Medline].
Wilcox C, Kautto A, Steigler A, et al. Androgen deprivation therapy for prostate cancer does not increase cardiovascular mortality in the long term. Oncology. 2012. 82(1):56-8. [Medline].
Sevilla C, Maliski SL, Kwan L, et al. Long-term quality of life in disadvantaged men with prostate cancer on androgen-deprivation therapy. Prostate Cancer Prostatic Dis. 2012 Jan 31. [Medline].
Walker LM, Tran S, Wassersug RJ, et al. Patients and partners lack knowledge of androgen deprivation therapy side effects. Urol Oncol. 2012 Jan 25. [Medline].
Reuter VE. Pathological changes in benign and malignant prostatic tissue following androgen deprivation therapy. Urology. 1997 Mar. 49(3A suppl):16-22. [Medline].
Bostwick DG, Meiers I. Diagnosis of prostatic carcinoma after therapy. Arch Pathol Lab Med. 2007 Mar. 131(3):360-71. [Medline]. [Full Text].
Civantos F, Marcial MA, Banks ER, et al. Pathology of androgen deprivation therapy in prostate carcinoma. A comparative study of 173 patients. Cancer. 1995 Apr 1. 75(7):1634-41. [Medline].
Montironi R, Magi-Galluzzi C, Muzzonigro G, Prete E, Polito M, Fabris G. Effects of combination endocrine treatment on normal prostate, prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. J Clin Pathol. 1994 Oct. 47(10):906-13. [Medline]. [Full Text].
Rubin MA, Allory Y, Molinie V, et al. Effects of long-term finasteride treatment on prostate cancer morphology and clinical outcome. Urology. 2005 Nov. 66(5):930-4. [Medline].
Lucia MS, Epstein JI, Goodman PJ, et al. Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial. J Natl Cancer Inst. 2007 Sep 19. 99(18):1375-83. [Medline]. [Full Text].
Suzue K, Montag AG, Tretiakova M, Yang XJ, Sahoo S. Altered expression of alpha-methylacyl-coenzyme A racemase in prostatic adenocarcinoma following hormone therapy. Am J Clin Pathol. 2005 Apr. 123(4):553-61. [Medline].
Tang X, Serizawa A, Tokunaga M, et al. Variation of alpha-methylacyl-CoA racemase expression in prostate adenocarcinoma cases receiving hormonal therapy. Hum Pathol. 2006 Sep. 37(9):1186-92. [Medline].
Sung MT, Jiang Z, Montironi R, MacLennan GT, Mazzucchelli R, Cheng L. Alpha-methylacyl-CoA racemase (P504S)/34betaE12/p63 triple cocktail stain in prostatic adenocarcinoma after hormonal therapy. Hum Pathol. 2007 Feb. 38(2):332-41. [Medline].
Kusumi T, Koie T, Tanaka M, et al. Immunohistochemical detection of carcinoma in radical prostatectomy specimens following hormone therapy. Pathol Int. 2008 Nov. 58(11):687-94. [Medline]. [Full Text].
Wissing MD, De Morrée ES, Dezentjé VO, Buijs JT, De Krijger RR, Smit VT, et al. Nuclear Eg5 (kinesin spindle protein) expression predicts docetaxel response and prostate cancer aggressiveness. Oncotarget. 2014 Sep 15. 5(17):7357-67. [Medline]. [Full Text].
Huang KC, Alshalalfa M, Hegazy SA, Dolph M, Donnelly B, Bismar TA. The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy. Cancer Biol Ther. 2014 Sep. 15(9):1120-8. [Medline]. [Full Text].
Marques RB, Aghai A, de Ridder CM, Stuurman D, Hoeben S, Boer A, et al. High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models. Eur Urol. 2014 Sep 11. [Medline].


text:
R A/O I
Vagal Group — Exciter
The breeze of delicate synths and non-defined music is what I was searching for these past few months. No need to say that we are all experiencing a really weird and scary time, but it's also interesting how this situation has affected me in music and moreover in the research process: time froze and allowed me to get lost in the Internet maze.
One day, I stumbled upon "𝙈𝙪𝙨𝙞𝙘𝙖𝙡 𝙙𝙚𝙡 𝘼𝙢𝙗𝙞𝙖𝙣𝙩𝙚" from Vagal Group and I remember being quite amazed by what I just heard. It sounded so light, soft and intense at the same time. I tried to get deeper in the artist's work and found some really interesting material.
Vagal is a contraction of both the first and last name of Valerio Gallo, and "Group" must be a joke because Valerio did it all by himself. Well as I started to become obsessed with his work, one thing led to another, and I was chatting with Valerio about another experimental project he worked on 4 years before called "𝙀𝙭𝙘𝙞𝙩𝙚𝙧". Valerio said this project was a kind of "art commission", launched by the Italian national television.
They needed tons and tons of music material to illustrate different TV contents for advertising and documentaries, things like that. It reminded me how much TV and music were bound to each other, and how you can easily find really nice musical projects that were initially made for TV (jingles, OST, etc...)
Never underestimate the power of TV!
At that time, the raise of MIDI protocol was just at its beginning, placing the computer as a key instrument in the process of creation and experimentation. Valerio told me this period was kind of hybrid to him, some of the instruments he used were able to be controlled with this new protocol, some weren't, which lead him to improvise and experiment new ways of making music. The way in which Valerio used the Yamaha DX7 helped to create an imaginary musical landscape, each track of this LP refers to a place, or a state. This project is built in order to take you on a pleasant trip across the "𝙍𝙚𝙙 𝙎𝙚𝙖" or even to get lost in "𝙈𝙪𝙨𝙚𝙪𝙢𝙨" .
Us Contact  


How Likely Are You To Be Stopped And Searched?
Londonist How Likely Are You To Be Stopped And Searched?
Double-take caption in the Times today reads: "More whites than Asians stopped by antisuicide bomber police." According to this article, Scotland Yard released figures yesterday on the ethnic composition of its stop-and-search figures: of the 32,000 people stopped between April and August of this year under the Terrorism Act, 17,348 were white, compared to 6,755 Asians and 4,287 blacks. Of course this evidence does not extricate the Police from the witch hunt charge: given the discrepancy in size between London's Asian and white community (earlier statistics revealed Asians represent 12% of the community, compared with a white population of 63%), Asian people are still 2.1 times more likely to be stopped than white people. Nor does it say much of other controversial 'counter-terrorism' tactics such as the request for university employees to spy on 'Asian-looking' and Muslim students.
Indeed, the Terrorist Act, which legitimises police to stop and search whomever at will, providing they are in an area deemed a potential terrorist target (City of Westminster ranks number one, as do railway stations, airports and most popular buildings), has attracted much wrath from the population at large, who cite the Act as ineffective and a source of alienation amongst London's Muslim population. Ire has also increased with numbers – the amount of searches over the past five months outstrips the total conducted since the Act's nascence back in 2000.
Londonist feels none the wiser despite this recent information, although we would place a wager on who would be the most likely victim of a stop-and-search warrant.


The Archie Hartwell Nash Memorial Scholarship is available to students at Middle Tennessee State University. You must be at least a sophomore and have a minimum GPA of 2.0 to be eligible for this award. This award is available to students who work a minimum of 20 hours a week while attending school.


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Cannes Classics
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Director: Jafar Panahi
Filmmaker Jafar Panahi and actress Behnaz Jafari travel to the rural northwest of Iran after receiving a plea for help from a girl whose family has forbid her from studying acting in Tehran. Amusing... More
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The Image Book
The legendary Jean-Luc Godard adds to his influential, iconoclastic legacy with this provocative collage film essay, a vast ontological inquiry into the history of the moving image and a commentary o... More
Director: Emmanuel Gras
Featuring stunning cinematography, Makala (Swahili for "charcoal") is a powerful testament to one man's commitment to his family, and his endurance in working to provide them with a brighter future. More
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Charlotte Rampling: The Look
Director: Angelina Maccarone
THE LOOK features Charlotte Rampling in a series of reflective conversations with artists, friends, and one-time collaborators such as novelist Paul Auster and photographers Peter Lindbergh and... More
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Sweet Bean
Director: Naomi Kawase
Country: France, Germany, Japan
A lonely baker has his life (and business) reinvigorated when he hires an elderly woman with an uncanny culinary skill and a mysterious communion with nature, in this graceful, quietly moving drama... More
Mountains May Depart
Director: Jia Zhangke
Country: China, France, Japan
Mainland master Jia Zhangke scales new heights with Mountains May Depart. At once an intimate drama and a decades-spanning epic that leaps from the recent past to the present to the speculative... More
The Measure of a Man
Director: Stéphane Brizé
Vincent Lindon (Mademoiselle Chambon) gives his Cannes Film Festival-winning performance as unemployed everyman Thierry, who must submit to a series of humiliating ordeals in his search for work.... More
Director: Lina Wertmüller
NEW 2K RESTORATION! Set against the backdrop of the beautiful Mediterranean, Swept Away is Lina Wertmuller's most famous and controversial film about sex, love and politics. On an elegant yacht... More
Goodbye to Language
Winner of the Jury Prize at the 2014 Cannes Film Festival, Goodbye to Language is a triumphant masterpiece from Jean-Luc Godard. More
Salaam Bombay
Director: Mira Nair
From director Mira Nair (Monsoon Wedding), Salaam Bombay! is a ""brilliantly achieved, stunning and powerful"" (Los Angeles Times) film that ""burst onto the Indian cinema scene with the force of a... More
The Scent of Green Papaya
Director: Tran Anh Hung
Country: France, Vietnam
An Academy Award nominee for Best Foreign Language Film and winner of the Camera D'Or at the Cannes Films Festival, THE SCENT OF GREEN PAPAYA is set in 1951 Saigon, where 10 year old Mui (Lu Man San)... More
Barton Fink (Special Edition)
Directors: Joel Coen, Ethan Coen
Country: U.S.
John Turturro shines in the lead role as Barton Fink, the Coen Brothers' hilarious satire set in 1940s Hollywood. Barton Fink is a Broadway playwright who reluctantly relocates to Hollywood to write... More
Director: Andrey Zvyagintsev
Directors: Etgar Keret, Shira Geffen
Director: Kim Ki-Duk
Acclaimed South Korean filmmaker Kim Ki-duk returns with his 14th film as a director, a tender romantic drama centering on the unusual relationship between a condemned prisoner and a married female... More
Director: Julie Bertuccelli
Director: Sergey Dvortsevoy
Love & Anarchy
An epic tragicomedy from director Lina Wertmuller (Seven Beauties), LOVE AND ANARCHY plumbs the depths of fascist Italy from the perspective of a simple farm boy sent to kill Mussolini. More
Graceful, enigmatic, and often frightening, DOGTOOTH is an ingenious dark comedy that won the Prix Un Certain Regard at the 2009 Cannes Film Festival, propelling Yorgos Lanthimos to the forefront of... More
Director: Lee Chang-dong
A sixty-something woman, faced with a crippling medical diagnosis and the discovery of a heinous family crime, finds strength and purpose when she enrolls in a poetry class. Lee Chang-dong's follow-u... More
This is Not a Film
Directors: Jafar Panahi, Mojtaba Mirtahmasb
This clandestine documentary, shot partially on an iPhone and smuggled into France in a cake for a last-minute submission to Cannes, depicts the day-to-day life of acclaimed director Jafar Panahi... More
Director: David Lynch
After breaking parole for self defensive manslaughter, Sailor Ripley (Nicholas Cage) and his girlfriend Lula Fortune (Laura Dern) head down the highway for California. Lula's mother sends out a... More
Winter Sleep
Director: Nuri Bilge Ceylan
A retired actor has inherited a small hotel where he is ensconced with his recently divorced sister, his much younger and growingly discontented wife. A seemingly trivial incident sets in motion a... More
Director: Lisandro Alonso
A man employed on a massive cargo ship requests shore leave to visit his sickly mother, who lives in a remote logging town in Tierra del Fuego. He depends on booze and the unkindness of strangers t... More