Takotsubo cardiomyopathy (TCM) is characterized by apical ballooning with basal preservation in the absence of obstructive coronary artery disease (CAD) that can otherwise explain wall motion abnormalities. However, there is increasing evidence that acute coronary syndromes (ACSs) may coexist with TCM. This report describes a 61-year-old man with a previous medical history of hypertension, diabetes mellitus, and hyperlipidemia, who presented with acute chest pain and associated shortness of breath. He was diagnosed with a non-ST segment myocardial infarction. Echocardiography revealed impaired systolic function with evidence of apical and periapical ballooning of the left ventricle, characteristic of TCM. Coronary angiography revealed evidence of significant luminal stenosis of the right coronary artery (RCA), necessitating intervention with a drug-eluting stent. This patient demonstrated wall motion abnormalities characteristic of TCM beyond the territory of the affected coronary artery suggesting that CAD and TCM can coexist. Apical ballooning with basal preservation in the absence of coronary artery obstruction is the hallmark of the most common variant of Takotsubo cardiomyopathy (TCM). Although the clinical presentation of TCM is similar to that of acute coronary syndrome (ACS), TCM is associated with a better prognosis, with reversal of left ventricular dysfunction occurring within weeks to months . CurrentA 61-year-old man with a previous medical history of hypertension, diabetes mellitus, and hyperlipidemia presented with acute pressure-like chest pain and shortness of breath. Physical examination revealed a heart rate of 71 beats per minute (bpm), a blood pressure of 144/71 mmHg, and an oxygen saturation of 96%. On cardiopulmonary examination, he had a normal S1 and S2 with no appreciable murmur, rub, or gallop and with clear lung fields bilaterally. Peripheral pulsations were 2+ and symmetric, and there was no evidence of lower extremity edema. His family history was notable for hypertension, diabetes, and myocardial infarction in his mother. The patient denied any tobacco, ethanol, or illicit drug use.Blood tests showed elevated concentrations of troponin I  and brain-type natriuretic peptide . His complete blood count and chemistry panel were otherwise unremarkable. An electrocardiogram (EKG) revealed a first-degree heart block and intra-ventricular conduction delay, with a QRS of 136 milli-seconds and pathological Q waves in the inferior leads , the TIMI flow was reduced to II. Along with the presence of Q waves in the inferior leads, these factors suggested possible ruptured plaque and lysis. Stenting resulted in the complete resolution of stenosis, with TIMI flow increasing from II to III following stent deployment.The Mayo Clinic criteria defined the elements needed to diagnose TCM. These criteria include the absence of occlusive CAD or acute plaque rupture on angiography, the presence of a reversible or transient wall motion abnormality not limited to a single vascular territory, and EKG changes in the absence of pheochromocytoma, myocarditis, or intracranial bleeding. These and other criteria, including the Johns Hopkins criteria, have emphasized the absence of acute CAD that can explain the wall motion abnormalities observed in patients with TCM, such as LAD abnormalities that can explain classic apical regional wall motion abnormalities . As thesDespite evidence suggesting that incidental nonacute CAD occurs in a significant percentage of patients with TCM, it is not yet clear whether ACSs can trigger or are associated with TCM, especially in patients with wall motion abnormalities extending beyond the culprit vessel and in those with systolic dysfunction being disproportionately reduced compared with the degree of vascular insult. For example, a report describing an 88-year-old woman with an occluded diagonal branch, acute plaque rupture, and echocardiographic findings of apical akinesia extending beyond the occluded vascular territory suggested that this form of ACS may have triggered TCM through somatic stress . AnotherPost-ischemic myocardial stunning can also present with regional wall motion abnormalities similar to TCM, suggesting that TCM may actually be a form of stunning . BecauseThe behavior of the remote noninfarcted myocardium in patients with myocardial infarction is a complex process. The remote myocardium may become hyperkinetic and contractile during and after acute myocardial infarction, possibly due to increased catecholamine levels . In contIn conclusion, findings in our patient and in similar patients showed no causal relationship between ACS and TCM. However, ACS, like any other physical illness, may trigger TCM. Further aspects of the pathogenesis of this reversible condition and the possible association between ACS and TCM have not yet been determined.


Association between hyperhomocysteinemia and stroke has been well documented in the literature. However, there are limited reports revealing stroke events in the pediatric population affected by hyperhomocysteinemia. Herein, we present a case which shows genetically inherited hyperhomocysteinemia leading to a stroke event in a 14-year-old child. The patient presented to the outpatient clinic with dizziness and nonprojectile vomiting since the previous day without any history of weakness in the extremities or unconsciousness. The preliminary neurologic examination showed positive right-sided cerebellar signs like ataxia on physical examination and the final diagnostic workup confirmed acute non-hemorrhagic bilateral cerebellar and medullary infarction with hyperhomocysteinemia. We discuss the case presentation, diagnostic workup, and management strategies. It is being hypothesized that homocysteine is highly reactive amino acid and potentiates oxidation of very low-density lipoprotein which is toxic to endothelial cells and can cause arterial and venous thrombosis . ConsistA 14-year-old male patient presented to the outpatient clinic with dizziness since the previous day without any history of loss of consciousness, weakness in the extremities or seizure episode. He also complained of non-bloody, nonbilious, and projectile vomiting with a negative history of abdominal pain and diarrhea. In the past, he had identical complaints of dizziness one and half months back after falling off his bicycle. His parents had a nonconsanguineous marriage. There was a positive family history with his father suffering premature cardiovascular death at the age of 35 years.On presentation to the clinic, he was in a hemodynamically stable state. Neurological evaluation was normal without any complaints of weakness, positive Babinski sign, or sensory involvement. He was admitted on the floor for thorough evaluation for his vertigo. Local causes of vertigo were ruled out on initial evaluation by an ear, nose, and throat consultation. Ophthalmology evaluation was done to rule out causes of raised intracranial tension, which showed no evidence of papilloedema on indirect ophthalmoscopy. The patient was reviewed anthropometrically which showed an increased arm length more than height.The patient suddenly became drowsy along with complaints of right-sided weakness and continuous hiccups with high fever spikes, thus he was shifted to pediatric intensive care unit and his neurological assessment showed upper motor neuron facial nerve palsy as evident from right-sided hemiparesis.The magnetic resonance imaging showed bilateral cerebellar non-hemorrhagic infarcts. Later, the patient deteriorated and developed respiratory distress along with pooling of secretions, hoarseness of voice, and deviation of uvula to the right side with an absent gag reflex, thus, suggesting a medullary component with ninth and tenth nerve involvement.Other examinations including complete blood count, coagulation profile, 2D (transthoracic) echocardiogram, and electrocardiogram were found to be normal and helped us to rule out arrhythmias for syncope workup. The antinuclear antibody assessment was negative and helped to rule out any autoimmune disorder. Magnetic resonance angiography showed a vascular loop of the anterior inferior cerebellar artery around the seventh cranial nerve on the right side. Furthermore, he had elevated homocysteine levels (18.54 micromoles/liter). Thus, he was diagnosed with acute non-hemorrhagic bilateral cerebellar and medullary infarction with homocysteinemia after a careful assessment and exclusion of all relevant differential diagnoses.The patient was given supportive treatment while admitted to the pediatric intensive care unit. He was treated by oral antispasmodics for spasms and anti-emetics for vomiting. For homocysteinemia, he was managed with oral pyridoxine, folic acid, and aspirin. On follow-up visits, the patient was doing well.Elevated levels of homocysteine (>15 micromoles/liter) is considered a major risk factor for non-hemorrhagic stroke . HomocysThe etiologies of hyperhomocysteinaemia are multifactorial. Non-genetic determinant etiology includes dietary deficiency whereas genetic determinants include enzyme defects such as classical homocystinuria due to deficiency of cystathionine beta-synthase. It can also occur due to a defect in methylcobalamin formation leading to the triad of megaloblastic anemia, homocystinuria, and hypoketonemia .This case highlights the fact that when a young patient presents with an incident stroke event along with other supportive systemic findings with or without a family history, homocysteinemia should form a major differential diagnosis to expedite the diagnostic screening and further timely management strategies -6. TableA young pediatric patient with stroke-like features should be immediately evaluated for thrombotic disorders like protein C deficiency and hyperhomocysteinaemia in addition to any metabolic derangements. Cerebellar infarcts typically present with complaints of vertigo in this age group.


Tumors driven by mutant KRAS are among the most aggressive and refractory to treatment. Unfortunately, despite the efforts, targeting alterations of this GTPase, either directly or by acting on the downstream signaling cascades, has been, so far, largely unsuccessful. However, recently, novel therapeutic opportunities are emerging based on the effect that this oncogenic lesion exerts in rewiring the cancer cell metabolism. Cancer cells that become dependent on KRAS-driven metabolic adaptations are sensitive to the inhibition of these metabolic routes, revealing novel therapeutic windows of intervention. In general, mutant KRAS fosters tumor growth by shifting cancer cell metabolism toward anabolic pathways. Depending on the tumor, KRAS-driven metabolic rewiring occurs by up-regulating rate-limiting enzymes involved in amino acid, fatty acid, or nucleotide biosynthesis, and by stimulating scavenging pathways such as macropinocytosis and autophagy, which, in turn, provide building blocks to the anabolic routes, also maintaining the energy levels and the cell redox potential . This re KRAS mutations can promote all the key aspects of cancer cell metabolism. It elevates glucose, glutamine and fatty acids uptake and consumption to sustain biosynthetic pathways and the cell redox potential. All these functions are regulated by a number of events, here summarized in three major points, that cooperate with mutant Kras in metabolic reprogramming and specify metabolic adaptation in different tumor types.KRAS mutations in metabolic adaptation can differ in distinct tumor types depending on the tissue of origin. This has been revealed by comparing the metabolic adaptations of non-small cell lung carcinoma (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) driven by Kras mutations and Trp53 deletion in mice. These two cancer types, despite sharing the same genetic alteration, use branched-chain amino acids differently. While NSCLCs incorporate free branched-chain amino acids into tissue protein and use them as nitrogen source, uptake of these amino acids and expression of key enzymes responsible for their catabolism are decreased in PDACs ((i) Similarly to other oncogenic lesions , the eff(ii) Cancer cells carrying mutant Kras crosstalk with the microenvironment, exchanging cytokines, growth factors, and metabolites to improve metabolic adaptation and overcome low nutrients availability –6.KRAS mutations in sustaining specific metabolic adaptations ((iii) Finally, a number of concomitant genetic alterations have been shown to cooperate with ptations –10.In this framework, the purpose of this review is to discuss the most recent findings on the interplay between Kras and metabolism focusing on metabolic dependencies of mutant Kras-driven lung and pancreatic cancers that could be attractive as therapeutic targets.KRAS mutations are an early event being detectable in the initial lesions known as pancreatic intraepithelial neoplasias (PanIN), which can progress in infiltrating ductal carcinomas through the acquisition of additional genetic alterations , abrogation of KrasG12D expression causes tumor regression that is accompanied by severe reduction of the expression of GLUT1 and rate-limiting glycolytic enzymes, and of the amount of glycolytic intermediates as revealed by both metabolomics and transcriptomic studies , a target of p53 transcriptional repression, has been found to join forces with mutant Kras to elevate glycolysis. PON2 increases glucose uptake by binding to GLUT1 thus preventing interaction of the latter with the inhibitory protein STOM , a condition that reproduces the stepwise human development of pancreatic cancer, increases the number of PanIN lesions, but impairs the progression of PanIN to PDAC, prolonging mice survival  promotes survival under metabolic stress conditions by directing intracellular components to lysosomes via the formation of vesicles known as autophagosomes . Even ifsurvival . Moreovenografts . In addiNotably, two recent studies have shown that autophagy inhibition synergizes with pharmacological targeting of the KRAS downstream effectors MEK1/2 or ERK, preventing growth of KRAS-driven pancreatic adenocarcinomas , 44. TheG12D expression, not only affects tumor growth, but also reduces the desmoplastic stroma, which is typical of this type of cancer  in the respiratory epithelium (Acsl3 and Acsl4) are significantly down regulated in tumors undergoing KrasG12D extinction and Acsl3 seems to contribute the most to the oncogenic phenotype both in vitro and in vivo , KRAS mutations are associated to a gain of function mutation on the gene GNAS (GNASR201C) which encodes Gαs, the stimulatory subunit of heterotrimeric G proteins (GNAS mediates G-protein-coupled receptor (GPCR)-stimulated cAMP signaling, and its mutation has been identified in different tumor types   . Proteomrewiring .G12D-driven lung cancer during glucose starvation (KRAS mutations on metabolic reprogramming are also strongly influenced by the availability of nutrients which can be heterogeneously distributed within the tumor and change over time. There is a lot more to be learned, there are still big research gaps in the field that need to be addressed in future studies. Moreover the interplay with other pathways, such as PPARγ and WNT/β-catenin, involved in metabolic enzymes changes in other cancers (Studies on the role of mutant Kras in rewiring cancer cell metabolism are blooming and the approaches to exploit Kras-driven metabolic vulnerabilities that stem from these findings hold promises, at least in pre-clinical settings, as we summarized in arvation , and on arvation , reveal  cancers , 54 shouEP and LL wrote the manuscript. EP and EM performed the staining showed in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The liver is strategically positioned to drain the intra-abdominal organs through the portal vein. As such, the liver is constantly challenged with foreign food antigens, bacterial products that require a high degree of tolerance and restraint. In chronic liver disease, when hepatocyte damage occurs, this tolerant state is often lost resulting in local and systemic inflammation and fibrosis development, which may be detrimental to the host. It is well-established that macrophages, as highly diverse immune cells, play a central role in both the initiation as well as restoration of inflammation and fibrogenesis. Macrophages can be either embryonically seeded in organs where they are maintained through self-renewal  or derivWeston et al. provide a comprehensive overview regarding the role for myeloid-derived cells during acute and chronic hepatic injury. More specifically, they describe how tissue-resident Kupffer cells, infiltrating monocytes/macrophages, dendritic cells, and neutrophils act in concert to initiate an inflammatory response but also to regenerate tissue following injury. Finally, they touch upon the idea that strategies targeting liver macrophages would require precision medicine to specifically target pathogenic subsets only.In this Research Topic, Trebicka et al. demonstrated that the extent of systemic immune inflammation in acute decompensated cirrhotics correlates with a higher risk of disease progression toward ACLF or death of the patient. Another study by Alvarez-Silva et al. demonstrated that the levels of inflammatory cytokines and microbial richness are significantly higher in ascites fluid compared to plasma samples from patients with decompensated cirrhosis. However, the authors could not find any correlation between the bacterial DNA abundance and/or richness and the extent of systemic inflammation in these patients.Patients with acute decompensated cirrhosis and acute-on-chronic liver failure (ACLF), display evidence of hepatic and systemic inflammation but paradoxically also features of immunosuppression, rendering them highly susceptible to infections. Within this Research Topic, a clinical investigation by Irvine et al. and Martin-Mateos et al. review the respective innate immune dysfuntions observed in cirrhosis and ACLF, within this Research Topic. Furthermore, Irvine et al. propose mechanisms that improve susceptibility to infections, while Martin-Mateos et al. highlights mechanisms targeting the gut, -high-grade systemic inflammation and reverting immune paralysis as therapeutic opportunities to improve clinical outcome of these patients. Also within this Research Topic, Triantafyllou et al. provide an overview of the role of monocytes/macrophages in driving systemic immunosuppression and hepatic inflammation thereby contributing to the pathophysiology of acute decompensated cirrhosis as well as ACLF. Additionally the authors describe the opportunities and challenges of therapeutic strategies aiming at reverting Kupffer cell activation, hampering monocyte recruitment to the liver or manipulating macrophage polarization to interfere in disease progression. Along the same line of investigation, Riva and Mehta provide evidence for epigenetic mechanisms, and the role of checkpoint receptors in regulating monocyte function. In combination with recent advances in the field whereby metabolic rewiring can influence immunological functions  release and defective bactericidal activity within neutrophils during cirrhosis. Importantly, they report some studies that suggest that defective neutrophil functions, at least in vitro, could be rescued by TLR7/8 agonists.Finally, Mouhadeb et al., may shed some light on this aspect by demonstrating that disruption of COMMD10, a protein with yet unknown function, unleashes the inflammatory capacity of circulating Ly6Chi monocytes, resulting in intestinal barrier dysfunction and elevated bacterial translocation to the mouse liver. It would be intriguing to verify whether similar mechanisms set the stage for pathogenic bacterial translocation during cirrhosis development.Patients with advanced stages of cirrhosis often exhibit a dysfunctional intestinal barrier, whereby luminal bacteria and their products translocate into the circulation and reach the liver via the portal vein (gut-liver axis). Very exciting recent research elucidate for the first time the mechanisms of intestinal barrier breach during cirrhosis . NeverthHundertmark et al. provide a comprehensive overview of the functional and phenotypic versatility of myeloid cells as well as the microenvironmental signals that trigger their activation during NAFLD progression. Additionally, they point out the existence of an orchestrated interplay between myeloid cells in different compartments, such as circulation, gut, adipose tissue, and the liver. Extending along the same line of investigation, Vonghia et al. review current data on experimental NAFLD treatment strategies whereby myeloid-derived cells constitute the targeted population.Non-alcoholic fatty liver disease (NAFLD) is hallmarked by chronic low-grade inflammation and lipid accumulation in the liver as well as in extra-hepatic sites such as adipose tissue. Furthermore, a complex inter-organ crosstalk fuels the onset and progression of hepatic injury and fibrosis development. Within this disease setting, it is well-established that myeloid-derived cells play a prominent role in regulating inflammation and metabolism. In this Research Topic, Liao et al. demonstrated that palmitate-induced hepatocyte stress resulted in the release of extracellular vesicles enriched in the lipotoxic molecule, sphingosine 1-phosphate (S1P). These extracellular vesicles promoted macrophage chemotaxis through interaction with the S1P1 receptor on the surface of the macrophages. Although awaiting further in vivo confirmation, the authors suggest this to be a novel signaling axis for macrophage recruitment during NAFLD, where hepatic lipotoxicity prevails.In another manuscript within this Research Topic, Stahl et al. review macrophage deficits in mitochondrial function,—decline in autophagy and altered proinflammatory function, are discussed as possible mechanisms that may be relevant during age-related liver diseases.The process of aging is closely associated with a number of degenerative modifications in the liver, where hepatic structure and cell function tend to decline. In this Research Topic, Sun et al. implicate that MAPK-activated protein kinase 2 (MK2) contribute to hepatic I/R since its ablation protects against hepatic I/R injury in a murine model. This result implicates MK2 as a potential novel therapeutic target for I/R injury.Hepatic ischemia/reperfusion (I/R) is an important cause of liver damage occurring during hepatic resection and liver transplantation. Neutrophils have been shown to be one of the cellular players contributing towards tissue injury, however the molecular mechanisms involved have not been completely defined. Within this Research Topic, Emerging evidence demonstrated that myeloid-derived cells play a key role in the initiation, and progression of liver disease. This Research Topic provides multiple examples of how different myeloid cell subsets but also neutrophils can contribute to the inflammatory processes that underlie the clinical manifestations of various liver diseases. Such a compilation of relevant information may uncover new therapeutic targets and ultimately lead to improved outcomes in patients with advanced liver disease.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Fetal metabolic programming caused by the adverse intrauterine environment can induce metabolic syndrome in adult offspring. Adverse intrauterine environment introduces fetal long-term relatively irreversible changes in organs and metabolism, and thus causes fetal metabolic programming leading metabolic syndrome in adult offspring. Fetal metabolic programming of obesity and insulin resistance plays a key role in this process. The mechanism of fetal metabolic programming is still not very clear. It is suggested that epigenetic programming, also induced by the adverse intrauterine environment, is a critical underlying mechanism of fetal metabolic programming. Fetal epigenetic programming affects gene expression changes and cellular function through epigenetic modifications without DNA nucleotide sequence changes. Epigenetic modifications can be relatively stably retained and transmitted through mitosis and generations, and thereby induce the development of metabolic syndrome in adult offspring. This manuscript provides an overview of the critical role of epigenetic programming in fetal metabolic programming. Metabolic syndrome is well-known as a syndrome involved in obesity, insulin resistance, impaired glucose tolerance/diabetes, disturbance of lipid metabolism, and cardiovascular complications. Metabolic syndrome includes at least three typical phenotypes as follow: 1) elevated abdominal obesity, (2) elevated fasting glucose, (3) elevated blood pressure, (4) elevated fasting triglycerides (TG), (5) reduced high-density lipoprotein cholesterol (HDL-C)  . This thAlthough fetal metabolic programming is a relatively new concept, there have been various supporting evidence. It is proposed that the adverse intrauterine environment can cause intrauterine growth retardation (IGR), small for gestational age (SGA) and further metabolic syndrome risk in adult offspring. The intrauterine environment of malnutrition or nutrition deficiency can induce such fetal abnormal growth which is associated with metabolic syndrome in adult offspring . On the Adverse intrauterine environment could introduce fetal long-term relatively irreversible changes in organs and metabolism, and thus may cause fetal metabolic programming of obesity and insulin resistance, leading metabolic syndrome in adult offspring.Offspring obesity in adults can be caused by intrauterine malnutrition exposure. This concept was first proposed in a study that the male offspring's obesity rate in adult was significantly associated with severe malnutrition in pregnant women in 40s Holland famine in the last century . SimilarOn the other hand, maternal over-nutrition or obesity is also highly correlated with offspring obesity –21. It iIn the animal model studies, factors causing the prevalence of obesity in offspring can be elaborately studied by gestational interventions such as diet, drugs, surgery, and others. Animal model studies also offer an opportunity to disclose the detailed mechanism of fetal development programming.In agreement with human studies, it was reported that offspring obesity could be induced by maternal malnutrition or over-nutrition during pregnancy, in studies in mice, rats, sheep, and non-human primates. Offspring obesity has been reported to be related to the significant expression changes of genes involved in abnormal metabolism, such as mitochondrial dysfunction  and signRodent animal experiments have reported that fetal developmental programming caused by adverse intrauterine environment could induce hyperphagia leading offspring obesity in adults. Additional studies reported that the factors causing this offspring hyperphagia included hypothalamic programming of leptin resistance, increased neuropeptide Y and decreased proopiomelanocortin –30. It wThe concept of fetal/neonatal hyperinsulinemia in pregnant women with gestational diabetes mellitus has been proposed a long time ago . IntrautIt is suggested that neonatal hyperinsulinemia may not only be a transient phenomenon caused by neonatal hyperglycemia but also reflect fetal or neonatal insulin resistance which would induce metabolic syndrome in adults. For one thing, fetal/neonatal hyperinsulinemia can be introduced by maternal obesity, higher weight gain, a high-fat diet or other factors –36. For Fetal or neonatal insulin resistance was newly reported to be induced by gestational diabetes –41. OtheIt has been reported by animal experiments that various maternal interventions could introduce hyperinsulinemia or insulin resistance in offspring.Earlier studies proposed that fetal/neonatal hyperinsulinemia might be directly caused by fetal/neonatal simultaneous hyperglycemia. However, it was reported in some animal experiments that hyperinsulinemia can also be introduced without hyperglycemia in offspring. For example, fetal/neonatal hyperinsulinemia was reported to be induced by maternal hyperinsulinemia .Further related animal experiments suggested that not only fetal/neonatal hyperinsulinemia but also fetal/neonatal insulin resistance can be induced by various maternal gestational interventions. It was reported that insulin resistance in offspring can be induced by gestational interventions such as high-fat diets –48, highSome adverse intrauterine environment also induces decreased number and/or function of pancreatic beta cells leading decreased glucose-stimulated insulin secretion and further abnormal glucose tolerance in adult offspring. For example, in animal experiments, the decreased number of pancreatic beta cells, introduced by maternal low-protein diet exposure, is caused by reduced activity of the mTOR signaling pathway . BesidesIt was recently reported that there was transgenerational programming of hyperinsulinemia, insulin resistance or glucose tolerance in various studies , 66, 67.The critical mechanism underlying fetal metabolic programming induced by adverse intrauterine environment is still not very clear, while fetal metabolic programming has been reported to be contributed by changes in the developmental trajectories of tissues, stem cell numbers, neural circuits, and so on. Epigenetic programming, also induced by the adverse intrauterine environment, was reported to play an important role in the differentiation and development of embryonic, tissue, and stem cells –76. CoulEpigenetics is the inheritance of variation in gene expression without changes in the DNA nucleotide sequence. Epigenetic modification can be relatively stably transmitted in the process of cell proliferation. The known mechanisms include DNA methylation, histone modification, genomic imprinting, chromatin remodeling, non-coding RNA, and so on. Such mechanism regulates gene expression at levels of pre-transcription (heterochromatinization), transcription  and post-transcription (protein translation).DNA methylation and histone modification are known as key epigenetic regulation factors underlying the regulation of chromatin structure and gene transcription. DNA methylation adds methyl on 5-cytosine by DNA methyltransferase (Dnmt) at cis-acting element including promoter, enhancer, regulatory regions and sequence, response element, and so on. DNA methylation on such regions can cause DNA conformational changes, which may affect the binding of trans-acting factor and thereby regulate genes expression. Histone modification is known as the “histone code” including histone methylation, acetylation, phosphorylation, adenylation, ubiquitination, and so on. Histone modifications affect the structure and function of chromatin and thereby regulate the expression of the located genes.Genomic imprinting, a parent-of-origin-specific silencing manner of certain gene alleles, is established (“imprinted”) in the germline (sperm or egg cells) mainly through marks of DNA methylation and histone modification. Non-coding RNA can be divided into long chain non-coding RNA (lncRNA) and short chain non-coding RNA (sncRNA), including miRNA, siRNA, piRNA, dsRNA, Xist RNA, Tsix RNA, telomere RNA, and so on. Micro RNA (miRNA) is the main executor of RNA interference effect on gene expression. LncRNA plays an important role in cell differentiation and individual development by multiple methods. It is involved in X chromosome silencing, genomic imprinting, chromatin modification, activation or inhibition of transcription, transportation in nuclear, and other unknown functions.The concept of epigenetic programming was proposed as the potential key role of epigenetic modification in fetal metabolic programming , 78. EpiEpigenetic programming of obesity was reported in human studies to be involved in abnormal fetal growth, adipocytokines, and other obesity-associated genes.Global genome-wide epigenetic changes in offspring were reported to be associated with offspring obesity or an adverse intrauterine environment. Firstly, gestational diabetes induced genome-wide methylation changes in neonatal cord blood –82, adipThe insulin-like growth factor 2 (IGF2) and H19 genes are imprinted genes. Hypomethylation of the IGF2 gene and hypermethylation of H19 gene are associated with significantly higher expression of IGF2 (lower transcribed of H19), which induce neonatal adiposity through growth promoting effects. Such methylation changes of IGF2 and H19 in umbilical cord blood and placenta were reported to be associated with macrosomia exposed to GDM induced intrauterine hyperglycemia . Lower DLeptin could increase adipose tissue lipolysisl and hepatic β-oxidation of fatty acids, and inhibit hyperphagia. Hypermethylation and lower expression of the letpin gene in placenta and cord blood were reported to be associated with maternal impaired glucose tolerance (IGT) , GDM 10, or obesIt was reported that abnormal birth weight was associated with cord blood or placental DNA methylation changes in energy homeostasis genes  and LINEin vitro models disclosed more details of epigenetic programming of obesity in various tissues, which was involved in DNA or histone-modifying enzyme, abnormal fetal growth, hyperphagia, energy balance regulation, adipocyte differentiation/maturity, adipocytokines, hepatic metabolism, microRNA, and so on.Animal models and in vitro maturation (IVM) oocytes were reported to be changed by High-glucose concentrations  in mice . More inprimates . The proprimates .Similar to human studies, the methylation changes in the imprinted gene IGF2/H19 was reported being an important factor involved in abnormal birth weight in various animal models –122. DecEpigenetic programming of hyperphagia in offspring plays a role in the fetal programming of obesity. Leptin inhibits hyperphagia and stimulates energy expenditure through interactions with neuronal pathways in the hypothalamus. Leptin is higher in obese subjects. It was also reported that higher expression of the leptin gene, associated with higher histone or DNA methylation, was reported to be induced by maternal high-fat diet exposure  and to bEpigenetic changes in the mouse adiponectin gene promoters were also reported to be associated with offspring obesity induced by paternal high-fat diet exposure . Lower aMaternal periconceptional undernutrition induced decreased DNA methylation and increased histone acetylation was reported in pro-opiomelanocortin (POMC)  and the Epigenetic programming plays a role in adipocyte differentiation and maturity leading offspring obesity. DNA (cytosine-5) methyltransferase 3a (Dnmt3a) in 3T3-L1 preadipocytes was reported to be transcriptionally upregulated by Activator protein 2alpha  through directly binding to its proximal promoter region, leading to increased promoter methylation of adipogenic genes which were required for granting preadipocyte the ability to differentiate . Also, iA high-fat diet during pregnancy was reported to induce neonatal gender-specific hepatic fat accumulation by increased Phosphoenolpyruvate carboxykinase (PEPCK) expression and histone modification . These aChanges of microRNA was reported to be induced by the adverse intrauterine environment and associated with offspring obesity . For exaEpigenetic programming of insulin resistance in human studies was reported to be involved in the epigenetic modifying enzyme, inflammatory/proinflammatory factors, insulin associated signaling, energy balance regulation, and microRNA.Global genome-wide epigenetic changes were reported to be associated with insulin resistance. DNA methylation levels in neonatal blood were reported to be associated with insulin sensitivity in early childhood . In wholChanges of histone deacetylase 3 (HDAC3) in peripheral blood mononuclear cells is reported to be strongly related to insulin resistance and related proinflammatory mediators in patients with type 2 diabetes , 146.Higher DNA methylation changes in neonatal adiponectin gene were reported in gestational diabetes group , 106. ItIn white adipose tissue in insulin-resistant obese women, significantly differentially methylated sites were reported in IR-associated genes in pathways related to integrin cell surface interactions and insulin signaling pathway . In adulExpression of IR associated microRNA-15a and microRNA-15b was reported to be increased in skeletal muscle from adult offspring of women with diabetes in pregnancy . CirculaEpigenetic programming of insulin resistance was disclosed in more details involved in DNA or histone-modifying enzyme, adipocytokines, insulin associated signaling, lipid metabolism, microRNA, and so on.in utero  was reported to be a novel epigenetic mediator of insulin resistance  in vivo . In cultEpigenetic changes in the adiponectin gene play an important role in mediating insulin resistance. It was reported that insulin resistance was mediated by obesity-induced DNA hypermethylation of the adiponectin gene . It was in utero, associated with impaired insulin signaling  gene . Increasignaling . In a neignaling . In miceignaling . Hepaticin utero . Pathwayin vitro induced changes of DNA methylation, trimethylated histone H3-Lys27, and expression in genes involving glucose disposal and lipolysis pathway  . In thisIncreased miRNA-199a-3p and miRNA-342 were reported to cause the decrease of the mTOR signaling pathway, and thereby reduce the number of beta cells and insulin secretion , 178. LoTransgenerational epigenetic programming was considered a critical underlying mechanism of transgenerational inheritance caused by environmental interventions , 181–183The concept of transgenerational epigenetic programming is proposed as epigenetic programming in germ cells. Twice genome-wide demethylation and further remethylation happen, respectively, during the development of germ cell and preimplantation embryo . The timTransgenerational epigenetic programming has been reported to be involved in a variety of phenotypes, including diabetes , 66, insMore and more researches supported the concept of transgenerational epigenetic programming of metabolic syndrome , 192. ItSignificant differential methylation changes in the promoter region of H19 were reported in a multigenerational model of intrauterine growth restriction (IUGR) .Fetal epigenetic programming is a concept that the intrauterine environment induced fetal epigenetic modification and associated gene expression activity is relatively stably transmitted after birth until adults, and thereby decide the physiological phenotype in adult from fetal development. Strong evidence in this review indicates that fetal epigenetic programming could be a critical underlying mechanism of fetal metabolic programming, which induces the circle of metabolic syndrome across generations.Epigenetic modification involved in fetal metabolic programming of metabolic syndrome has been discussed above and demonstrated in There are still some unknowns and challenges in fetal epigenetic programming. Firstly, the molecular mechanism and regulation of epigenetic programming have not been fully disclosed. More key points and details are still required to be discovered. Secondly, results of related experiments sometimes could be disturbed by extra environmental disturbances not designed in experiments. Thirdly, epigenetic programming easily happens in susceptible “windows.” However, the threshold value of the adverse intrauterine environment is still not very clear in different types of diseases. Fourthly the size of epigenetic modifications is generally small in the whole epigenome. It may be caused by notable epigenetic modifications in fewer selectively targeted genes along with tiny epigenetic modifications in most non-targeted genes. The mechanism underlying the selective modifications is still needed to research. Beside of the selective epigenetic modifications around targeted gene region, the effects of more epigenetic modifications in other regions have not been well disclosed with their biological significance. Lastly, more importantly, there still are some limitations in the causality between epigenetic modifications and metabolic syndrome. There are a great deal of evidences of causality between epigenetic modifications and metabolic syndrome contributed by prospective clinical studies, animal and cell experiments in which the phenotypes of metabolic syndrome changed through the inhibition of DNA or histone modifying enzymes, and Chromatin immunoprecipitation assays identifying sequence-specific DNA binding protein which help to selectively modificate DNA or histone in a single gene's particular sequence. However, no molecular techniques have been invented to give direct logical evidence proving that metabolic syndrome could be induced or blocked by adding or erasing the epigenetic selectively modification in a particular sequence of a single gene. Here lies the most valuable breakthrough in epigenetic studies in future.In spite of such unknowns, limitations, and challenges, the study of epigenetic programming in fetal metabolic programming has been developing rapidly, accompanied with more and more supporting evidence. It will not be surprising if future breakthroughs come soon in this field.ZZ and XL conceived and initiated this study. ZZ contributed to writing of the manuscript. FC participated in conception and writing of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Drosophila melanogaster is a highly effective model to identify localized mRNAs and has helped identify roles for this process by regulating various cell activities. The majority of the well-characterized functional roles for localizing mRNAs to sub-regions of the cytoplasm have come from the Drosophila oocyte and early syncytial embryo. At present, relatively few functional roles have been established for mRNA localization within the relatively smaller, differentiated somatic cell lineages characteristic of later development, beginning with the cellular blastoderm, and the multiple cell lineages that make up the gastrulating embryo, larva, and adult. This review is divided into three parts—the first outlines past evidence for cytoplasmic mRNA localization affecting aspects of cellular activity post-blastoderm development in Drosophila. The majority of these known examples come from highly polarized cell lineages such as differentiating neurons. The second part considers the present state of affairs where we now know that many, if not most mRNAs are localized to discrete cytoplasmic regions in one or more somatic cell lineages of cellularized embryos, larvae or adults. Assuming that the phenomenon of cytoplasmic mRNA localization represents an underlying functional activity, and correlation with the encoded proteins suggests that mRNA localization is involved in far more than neuronal differentiation. Thus, it seems highly likely that past-identified examples represent only a small fraction of localization-based mRNA regulation in somatic cells. The last part highlights recent technological advances that now provide an opportunity for probing the role of mRNA localization in Drosophila, moving beyond cataloging the diversity of localized mRNAs to a similar understanding of how localization affects mRNA activity.Multiple mechanisms tightly regulate mRNAs during their transcription, translation, and degradation. Of these, the physical localization of mRNAs to specific cytoplasmic regions is relatively easy to detect; however, linking localization to functional regulatory roles has been more difficult to establish. Historically,  Drosophila melanogaster. Among these, the phenomenon of directed cytoplasmic restriction of mRNA localization is commonly observed and has been studied during oogenesis and in the early embryo. However, the underlying roles for this process, beyond the formation of the cellularized-blastoderm, remains poorly understood.Following transcription, mRNAs are regulated at multiple points during their lifetime. This begins in the nucleus where mRNAs undergo selective pre-mRNA splicing, base modification, sequence editing, and directed transport from the nucleus  techniques for Drosophila where anti-sense probes (either DNA or RNA) hybridize to mRNA targets in fixed cells or tissues  for Drosophila tissues expanded the utility of ISH allowing visualization and three-dimensional spatial reconstruction of mRNA localization within the cell by confocal microscopy , that helps establish body polarity, although there are many other known roles in the early embryo and germ cells,  are conserved in metazoans, reviewed in Heraud-Farlow and Kiebler , or Heat Shock Protein 83 (Hsp83), are expressed during later development or conserved in organisms without a syncytial embryo  are neural stem cells that delaminate stereotypically from the ventral nerve cord during later (stage 9) embryonic development  mRNA encodes the Drosophila Par-3 homolog and is localized to an apical cytoplasmic crescent in embryonic NBs, reviewed in Homem and Knoblich (prospero (pros) mRNA encoding a transcription factor that defines GMC identity is asymmetrically localized, initially at the apical cortex and then to the basal cell cortex during NB cell division . Stau binds the pros mRNA 3′UTR directly. Binding of Stau is required for the basal localization of pros mRNA, but not Pros protein  is required for Insc localization  mRNA localization in the oocyte is required for localized translation of the Oskar protein which is then required to maintain osk mRNA localization  have been identified  mRNA (encoding the fly Profilin homolog) which localizes to growing γ neurites  are required for germline development and establishing abdominal polarity in the early embryo  is a highly specialized region where motor neurons synapse to specific muscle targets  are not. In Msp300 mutants, there is a loss of localization of par-6 and magi but not dlg1. This is due to defective transport of the par-6 and magi mRNAs as opposed to a defect in export from the nucleus or stability of the mRNA transcripts  that surround the developing oocyte  is directed to the region just under the apical plasma membrane, within the cytoplasm of ectodermal cells, in stage 4–6 embryos. This mRNA localization is required for the production of an active Wg signaling protein , fatty acid binding protein (fabp), scheggia (sea), High mobility group protein D (HmgD), and schnurri (shn)  and the Dresden Ovary Table (DOT) database (http://tomancak-srv1.mpi-cbg.de/DOT/main.html) ,  , larva and adults. To define the scope of mRNA localization during later development, commonalities of the proteins encoded by localized mRNAs were identified. To disambiguate differences in gene names reported by different screens, mRNA lists were validated using the “ID converter” function of FlyBase  mRNA is localized apically in stage 2–10 follicle cells   mRNA is restricted to the cortex of embryo epithelia, and similar cortical enrichment is seen in follicle cells, somatic cells and border cells (stage 9–10) , encoding a protein involved in muscle contraction, oogenesis, and regulation of osk mRNA localization   encoding Drosophila Spectraplakin, both mRNAs localized basally in Stage 6–9 embryo ectodermal cells  and α-actinin (Actn)  genes encode proteins involved in peroxisome biogenesis, a process that includes vesicles budding the ER that fuse and mature by importing peroxisome enzymes (Pex1 and Pex5) or peroxisome fission (Pex11) and are conserved in Drosophila . In yeast, the Puf5 RNA binding protein, related to Drosophila Pum is required for Pex14 localization to the peroxisome  as well as mRNAs encoding homologs to several peroxisomal localized enzymes including Hmgcs1, Acaa1a/b, Hsd14b4, Paox, Nudt7, Acox, Baat, and Acsl5 as peroxisome associated  embryos  oocytes , or a perinuclear pattern which would encompass centrosomes . However, some of these mRNAs  as well as others, localized to cytoplasmic foci . The annotation of cytoplasmic foci could encompass centrosomes but could equally encompass other destinations including regulatory RNPs. Notably, the stages or tissues where these were annotated varies considerably  have been developed. These would not suffer from the effect of recruiting additional protein complexes to an mRNA    include reflected LSM (R-LSM) . ExM effectively makes cells/tissues larger via treatment with polymer hydrogels  microscopy. These techniques have now been adapted to Drosophila , there are 913 known RNA binding proteins encoded by the Drosophila, especially during later development, is at an exciting crossroad. The wealth of data from traditional FISH-based screens provides a valuable resource outlining the full scope of localized mRNAs, encoding proteins involved in multiple cellular processes, and the possibility that these processes may be linked to localized transcripts in other organisms. The advent of contemporary smFISH techniques, including those that can also locally detect translational states, provide viable avenues to correlate existing phenomenological observation to the functional roles. Recent improvements in both microscope resolution available for fluorescent imaging, as well as the advent of workflows for robust and practical three-dimensional electron-microscope imaging (Xu et al., Drosophila development to what is undoubtedly an equally broad spectrum of functional consequences of the proteins they encode.The study of mRNA localization in All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mosquitoes use chemical cues to modulate important behaviors such as feeding, mating, and egg laying. The primary chemosensory organs comprising the paired antennae, maxillary palps and labial palps are adorned with porous sensilla that house primary sensory neurons. Dendrites of these neurons provide an interface between the chemical environment and higher order neuronal processing. Diverse proteins located on outer membranes interact with chemicals, ions, and soluble proteins outside the cell and within the lumen of sensilla. Here, we review the repertoire of chemosensory receptors and other membrane proteins involved in transduction and discuss the outlook for their functional characterization. We also provide a brief overview of select ion channels, their role in mammalian taste, and potential involvement in mosquito taste. These chemosensory proteins represent targets for the disruption of harmful biting behavior and disease transmission by mosquito vectors. Mosquitoes are able to sense and track hosts over long distances, sometimes up to 70 m away , a feat 2), along with human skin and sweat odorants such as ammonia, lactic acid and other carboxylic acids , of the lumen originate from support cells near the cell body of ORNs and GRNs , ionotropic receptors (IRs), and gustatory receptors (GRs) . The expn family , dating n family , perhapsn family , each faTable 1), likely reflecting the unique requirements of each species’ ecological niche. Insect ORs are sensitive to compounds like esters, alcohols, and ketones, while IRs respond to various amines and acids  the requirement of GRs for normal responses to a variety of tastants in D. melanogaster . In the absence of CO2, ORco mutants did not respond to human-scented materials as is the case for wildtype controls , IR41c/IR25a/IR76b (most sensitive to pyrrolidine and 3-pyrroline), and IR75k/IR8a (most sensitive to carboxylic acids of eight or nine carbons). Many other IR genes are expressed in mosquito chemosensory tissues (Table 1); thus, IR deorphanization represents a crucial step toward exploring all potential receptors as targets for altering harmful host-seeking and feeding behaviors.Tuning profiles of individual IRs in mosquitoes is limited to two studies and a handful of individual genes . A studytylamine . Pitts eosophila . Differecurrents . Three IIon channels serve as the molecular basis for membrane excitability by allowing inward or outward flow of ions across a cell membrane to enable signal transduction and the alteration of other cellular processes. Ligand-gated ion channels represent the primary ion channel type in the insect chemosensory system functioning as a “receptor.” ORs, GRs, and IRs act through synaptic signaling on electrically excitable cells by converting chemical signals  to an electrical signal. Upon binding of the signal molecule(s) several actions may allow flow of cations and/or anions that stimulate neuronal transmission, downstream signaling, and other physiological processes: the ion channel protein itself may open due to a conformational shift, associated ion channels may be activated in conjunction with ligand-binding receptor activation or intracellular modulators of channel activity may initiate transmembrane ion flow indirectly.Figure 2; D. melanogaster and A. gambiae) and Lepidopteran (Bombyx mori) OR complexes expressed in Xenopus oocytes and cultured human cells suggests G-protein-coupled pathways are dispensable for OR activation in insects (D. melanogaster OR complexes showed that G-protein modulating compounds or genetic disruption of G-proteins significantly affected OR activation dynamics in cultured human cells (in vivo (Stimulus-specific ORs (ssORs) in insects are trafficked to dendritic membranes by co-receptor ORco , a membr insects . Howeveran cells  and in v . Evidence suggests IRs assemble as heterotetramers comprising two ssIR and two IRco subunits (Co-receptor IRs (IRcos), such as  (ssIRs) . IRcos asubunits . Additiosubunits . It is uD. melanogaster GR43b and B. mori GR9 act as fructose-sensitive non-selective ionotropic channels when expressed in Xenopus oocytes or cultured human cells , their ligands, phylogenetic analyses, and modulation of these receptors to obtain a desirable phenotype . Recently, studies have defined the properties of GRNs and have elegantly shown functionally different classes of GRNs expressing unique combinations of receptor genes . SpecifiFigure 2) and can be divided into six subfamilies based on their sequence homology: TRPC , TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin)  channels belong to the group of non-voltage gated, cation-permeable ion channels  and are ankyrin) . TRP chaTRPA channels are a conserved subfamily of cation channels that are expressed in vertebrates and invertebrates, and appear to perform similar physiological functions. In vertebrates, the calcium permeable cation channel, TRPA1, is expressed in nociceptive neurons and functions to detect noxious or pungent chemicals, such as environmental irritants . The majD. melanogaster are encoded by painless, the fly homolog to mammalian TRPA1/ANKTM1 ion channel protein. Like GRs, painless is expressed in GRNs of the labellum, pharynx, legs and wings, and are specifically involved in the rejection of allyl and benzyl isothiocyanate, the pungent taste and insecticidal component of wasabi  and painless. The functional dependency of these two genes is not fully understood, but we speculate that the co-expression of these two receptors, and potentially others, enables a multimodal response neuron that can detect and integrate taste modalities that result in different behavior  in Xenopus oocytes indicated that the channel transduces temperature sensation, and channel expression is on the distal antennal sensory structures  demonstrated that both proteins are functional, as each responded to the electrophilic compounds, allyl isothiocyanate and cinnamaldehyde, as well as heat. Their similar intrinsic fluorescence properties and related quenching of tryptophan, when activated by allyl isothiocyanate or heat, led the researchers to conclude that conformational change in the lipid bilayer occurs independently and outside of the N-terminal domain , N-methyl maleimide (NMM), and cinnamaldehyde (CA), and found that addition of these chemicals to food dramatically inhibited the natural proboscis extension response (PER); the inhibitory effect was considered gustatory, not olfactory, because avoidance of these non-volatiles required ingestion. This study found the responses to reactive electrophiles depend on the cation channel TRPA1 as TRPA1 mutants showed no reduction in PER when offered food containing AITC, NMM, or CA. Promoter-knockdown experiments established peripheral sensory neurons as the site of action for dTRPA1 in gustation. TEVC recordings on A. gambiae demonstrate that reactive electrophiles activate mammalian TRPA1s; mutations in TRPA1 decreased electrophile sensitivity.D. melanogaster for which citronellal activated a GPCR coupled to TRPA1 channels, A. gambiae TRPA1 was directly activated by citronellal (A. gambiae isoform TRPA1(B) did not respond robustly to citronellal   . Togethees (LPS) .in vitro by the bitter tastant camphor and is expressed in the dendrites of D. melanogaster GRNs  gene family, functionally assemble as a heterotrimeric or homotrimeric proteins , a member of the degenerin (DEG)/ENaC superfamily of ion channels encoded by the pickpocket  and Pickpocket19 (ppk19), are expressed in the taste-sensing terminal organ of larvae and in the taste bristles of the labella, legs, and wing margins of adult flies  was absent in the A. gambiae genome which suggests mosquitoes may use a different ppk gene product to detect salt.Analysis of the pk genes . ImportaD. melanogaster gene ppk28 encodes a DEG/ENaC channel that is osmo-sensitive and is expressed in the taste bristles, but not in taste pegs, which was correlated back to a water-sensing neuron through imaging of an enhancer-trap Gal4 line  molecules  channels, which serve as metabolic sensors in a variety of mammalian cell types, were co-expressed in taste cells with sugar transporters and glucose sensor proteins  channels in arthropod gustatory systems. However, previous work suggests that mammalian taste cells possess several types of Cl− channels that play a key role in signal transduction of taste cells (− channels contribute to the membrane potential and electrical excitability but are not involved in the initiation of action potentials (− channel for acid transduction in sour taste by contributing to acidification of intracellular organelles (+ by serving as an electrical shunt for vesicular acidification (− channels are likely a component of sour taste, Kir2.1 may also function in tandem with a proton pump for sour taste transduction in mammals (Caenorhabditis elegans results in reduced gustatory plasticity. We suggest a need to explore this functional role of Cl− channels in insect gustation.Scant information exists regarding the expression patterns or physiological role of chloride (Clte cells . It was tentials . Immunohtentials , suggestganelles . Also, Cfication . While C mammals . TogetheA full understanding of how individual odorants, tastants, or blends are detected, converted to neural signals and processed will depend on determining the functional relationships between all chemosensory gene families and the cells expressing them. Characterizing the response profiles of receptor complexes and comparing these responses among diverse mosquito species will further our understanding of how these successful animals have filled so many ecological niches and rapidly adapted to host availability.Recent advances in our ability to quickly and reliably edit target genes in the germline of mosquitoes should help uncover unknown roles of key molecular components of olfactory and gustatory tissues. These studies are tedious and costly, but clarity of function will help define convenient targets for the development of novel repellents and antifeedants. In addition to high-throughput chemical screens, sophisticated modeling and simulation software can be developed and used to discover the most likely compounds capable of selectively activating or blocking neural pathways associated with harmful mosquito behaviors. Central to the creation of new vector control strategies is achieving greater resolution of ORN/GRN/IR function and the interactions between receptor complexes, ion channels and host-derived ligands.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Adequate consumption of dietary protein is critical for the maintenance of optimal health during normal growth and aging. The current Recommended Dietary Allowance (RDA) for protein is defined as the minimum amount required to prevent lean body mass loss, but is often misrepresented and misinterpreted as a recommended optimal intake. Over the past two decades, the potential muscle-related benefits achieved by consuming higher-protein diets have become increasingly clear. Despite greater awareness of how higher-protein diets might be advantageous for muscle mass, actual dietary patterns, particularly as they pertain to protein, have remained relatively unchanged in American adults. This lack of change may, in part, result from confusion over the purported detrimental effects of higher-protein diets. This manuscript will highlight common perceptions and benefits of dietary protein on muscle mass, address misperceptions related to higher-protein diets, and comment on the translation of academic advances to real-life application and health benefit. Given the vast research evidence supporting the positive effects of dietary protein intake on optimal health, we encourage critical evaluation of current protein intake recommendations and responsible representation and application of the RDA as a minimum protein requirement rather than one determined to optimally meet the needs of the population.  Consuming adequate dietary protein is critical for maintaining optimal health, growth, development, and function throughout life. Dietary protein requirements in healthy adults (≥19 years old) are dictated largely by body mass and lean body mass, as well as net energy balance and physical activity . The EAROver the past decade, the potential muscle-related benefits achieved by consuming higher-protein diets  have become increasingly clear. Increased protein intake contributes to greater strength and muscle mass gains when coupled with resistance exercise , allows Skeletal muscle protein is dynamic and in constant flux, alternating between states of negative  and positive  protein balance, largely in response to fasting  and feeding , respectively. In the postabsorptive state, muscle protein serves as the primary repository of amino acids that is readily catabolized to release free amino acids that can be reincorporated into muscle protein or used to support other critical physiological needs, including serving as an energy substrate through carbon skeleton oxidation, as well as by providing gluconeogenic precursors to support euglycemia . In addiThe current DRIs for protein have been in place since 2005 but are not without limitations. The EAR and RDA were derived from meta-analyses of nitrogen balance studies . The nitSimilarly, the RDA may be sufficient to meet the dietary protein needs of healthy, relatively sedentary young adults, though investigators have argued that this recommendation should be reconsidered based on data from studies demonstrating the inadequacy of the RDA within certain populations when compared to greater requirements derived from the indicator amino acid oxidation method . AccordiThe benefits of consuming protein following resistance exercise training have been well-documented, especially as they relate to muscle hypertrophy and function . A recenConsuming higher amounts of protein during typical moderate energy-deficient weight loss diets  preservInadequate dietary protein intake challenges muscle and whole-body protein balance , negatively impacting muscle mass, function, adaptations to exercise, bone and calcium homeostasis, immune system response, fluid and electrolyte balance, enzyme production and activity, and hormone synthesis. In the absence of sufficient dietary protein intake, muscle is catabolized to provide amino acids to allow for continued endogenous protein synthesis in critical physiological tissues and organs  Figure . CertainWhile much focus has been placed on adult protein needs in the context of these disease states, the potential benefits of higher-protein intakes extend across the lifespan. Muscle loss and failure-to-thrive are particularly worrisome in the pediatric population, a time typically characterized by rapid growth and development. Recent meta-analysis shows that higher protein intakes in critically ill pediatric patients are associated with positive protein balance, improved clinical outcomes, and lower mortality . These eWhile the popularity of dietary protein has increased over the past decade or longer, largely because of its role in muscle health, there are still some in the media, clinical practice, and within academia  that perObservations of hypercalciuria from nearly a century ago in those consuming greater amounts of meat raised concerns that higher protein intakes resulted in increased bone resorption and, therefore, diminished bone mineral density . It was Higher-protein diets have also been labeled as damaging to the kidneys. Increased amino acid intake can potentiate renal workload and should be reduced in the presence of established renal disease. However, otherwise healthy kidneys are well-capable of adapting to protein intakes above the RDA and within the AMDR. The kidneys are faced with increased nitrogenous waste as more amino acids are oxidized for energy and/or directed towards gluconeogenesis as the relative percentage of energy intake derived from protein increases. In a recent evaluation of NHANES data, protein intake was directly associated with blood urea nitrogen (BUN) concentrations, but those in the highest decile for protein intake (~1.4 g/kg/d) still exhibited normal BUN  . This fiRecent studies have raised concerns about the potential for higher-protein intakes to increase systemic inflammation. One large-scale investigation showed that those in the greatest high-sensitivity C-reactive protein (hs-CRP) serum concentration quartile also had higher relative protein intakes than the lowest hs-CRP quartile . HoweverConcern has also been raised regarding potential connections between dietary protein intake and risk of cardiometabolic disease and cancer. These associations are typically confounded by misrepresentation of foods labeled as “protein-rich” which may, by their nature, be overall less-healthful nutrient-sparse food options, providing high amounts of total and saturated fats and processing additives  . To the An assessment of national dietary patterns shows that protein food intakes have remained relatively unchanged over the past decade , 5.58 (2007–2008), 5.74 2009–2010), 5.70 (2011–2012), 5.83 (2013–2014), 5.80 (2015–2016)), as intake data for the latest 2-year cycle are nearly identical to those from 10 years earlier ,79,80,81005–2006,, 5.70 (2In addition to the dietary protein and skeletal muscle considerations, the protein leverage hypothesis suggests that protein under-consumption increases appetite drive in an effort to ensure sufficient amino acid intake . The unfCertainly, food choices within macronutrient recommendations are critical, with a needed emphasis on nutrient-dense selections . Similar


Calcific aortic stenosis (AS) is the most frequent valvular heart disease in Western countries, affecting up to 13% of individuals over 75 years . The disThe disease is characterized by fibro-calcification of aortic valve cusps and concomitant left ventricular (LV) remodeling due to chronic pressure overload, which can evolve into overt heart failure. AS progresses very slowly until the onset of symptoms . A large majority of patients remain asymptomatic for a long period, though at increased risk for untoward events . Development of symptoms is a class I indication for aortic valve replacement (AVR). Today, about 300,000 AVR are performed annually worldwide, either via surgery (SAVR) or transcatheter implantation (TAVI). AVR is indeed the only treatment shown to improve survival. There is no pharmacological treatment to prevent or slow disease progression.The present research topic provides a comprehensive overview of AS clinical management with a special focus on valve prostheses, imaging and blood biomarkers as well as on recent advances on pathophysiology and valve biology.Musumeci et al. reviewed the different types of currently available prosthetic aortic valves and their limitations. It appears that thrombosis, infection, bioprosthesis calcification, and degeneration remain major issues, which could be addressed through innovative new generation prostheses.Regarding valve prostheses, the ideal prosthesis either mechanical or biological still do not exist. Current prosthesis can cause complications, which necessitate reoperation or lead to death in 50–60% of patients within 10 years post-implantation. In this research topic, Rachwan et al. report on a patient who presented with a thrombus on a bicuspid aortic valve in the setting of antiphospholipid syndrome (APLS). APLS is a systemic autoimmune disease defined by thrombotic events in patients persistently positive for antiphospholipid antibodies (aPL). In this case report, 4-months moderate-intensity anticoagulation efficiently eliminated the aortic valve thrombus. However, due to the rarity of this condition, whether conservative anticoagulation or AVR should be recommended remains to be determined. More generally, there is currently no clear recommendation on the choice of antithrombotic regimen for AS patients  and myocardial fibrosis, measured by cardiac magnetic resonance (CMR), with clinical outcomes. The findings on AVC are in line with a recent study showing that sex-specific AVC thresholds accurately identify severe AS and predicts AVR and death  embedded in extracellular matrix, valve endothelial cells (VECs) covering the leaflet, and circulating and resident immune cells. AS is now considered as an active multi-step process. Early steps of lesion development would occur through accumulation of lipids and free cholesterol within the fibrosa, followed by infiltration of inflammatory cells, e.g., macrophages and T lymphocytes. VICs then enter an osteogenic program, initiating calcium nodule formation, and valve calcification (Nordquist et al. compared mRNA expression in postnatal and adult valve tissues. This study nicely unveiled multiple conceivable processes that contribute to postnatal valve maturation and maintenance that may pave the way for elucidating mechanisms underlying valve defects.Nevertheless, the identification of novel biomarkers will necessitate a better understanding of aortic valve biology and mechanisms of disease. The review by fication . All theThus, this research topic highlights important unmet medical needs in AS. More basic and translational research is definitely required to clarify disease mechanisms, uncover new multi-biomarker-based diagnostic and prognostic tools, and develop more biocompatible and durable prostheses with the goal of improving patient outcome.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The imaging of primary and metastatic brain tumours is very complex and relies heavily on advanced magnetic resonance imaging (MRI). Utilisation of these advanced imaging techniques is essential in helping clinicians determine tumour response after initiation of treatment. Many options are currently available to treat brain tumours, and each can significantly alter the brain tumour appearance on post-treatment imaging. In addition, there are several common and uncommon treatment-related complications that are important to identify on standard post-treatment imaging.This article provides a review of the various post-treatment-related imaging appearances of brain neoplasms, including a discussion of advanced MR imaging techniques available and treatment response criteria most commonly used in clinical practice. This article also provides a review of the multitude of treatment-related complications that can be identified on routine post-treatment imaging, with an emphasis on radiation-induced, chemotherapy-induced, and post-surgical entities.Although radiological evaluation of brain tumours after treatment can be quite challenging, knowledge of the various imaging techniques available can help the radiologist distinguish treatment response from tumour progression and has the potential to save patients from inappropriate alterations in treatment. In addition, knowledge of common post-treatment-related complications that can be identified on imaging can help the radiologist play a key role in preventing significant patient morbidity/mortality.Contrast enhancement does not reliably define tumour extent in many low-grade or infiltrative gliomas.• Focal regions of elevated cerebral blood volume (rCBV) on dynamic susceptibility contrast (DSC) perfusion-weighted imaging are suggestive of tumour growth/recurrence.• Brain tumour treatment response criteria rely on both imaging and clinical parameters.• Chemotherapeutic agents can potentiate many forms of radiation-induced injury.• Ipilimumab-induced hypophysitis results in transient diffuse enlargement of the pituitary gland.•  Primary and metastatic brain tumours are frequently encountered in the daily practice of neuroimaging. Many options are currently available to treat these neoplasms and revolve around a combination of surgery, radiation, and/or novel chemotherapeutic agents. These treatment choices are ever growing and each results in alterations in pathophysiology that can drastically change the imaging appearance of the tumour. The interpretation of post-treatment imaging has therefore become much more complex, most notably with high-grade gliomas where the combination of radiation and anti-neoangiogenesis drugs can result in either increasing or decreasing local enhancement, irrespective of tumour progression/regression. For this reason, it is imperative that radiologists have a thorough understanding of the advanced imaging techniques available to image these tumours as well as the possible common treatment-related complications. The purpose of this review is to briefly review brain tumour imaging techniques, discuss the most commonly used brain tumour treatment response criteria implemented in clinical practice, and illustrate the broad range of post-treatment-related complications that can be identified on routine post-treatment imaging.Contrast-enhanced T1-weighted MRI imaging is the workhorse of brain tumour imaging. It is easy to perform and accurately depicts the margins of most brain metastases and dural-based lesions. However, regarding primary brain neoplasms, particularly gliomas, it is not as reliable because these tumours often demonstrate non-enhancing or infiltrative components  and an apparent diffusion coefficient (ADC) map. Many pathophysiological processes result in diffusion restriction; however, in the context of brain tumour imaging the most common aetiologies include abnormally high cellularity, cellular injury, and peritumoural oedema. Highly cellular tumours, such as lymphoma and many high-grade gliomas, result in decreased water diffusivity through a relative reduction in the extracellular space for protons to move about . KnowledDiffusion restriction in the setting of cellular injury has been well described in the literature in the setting of vascular infarction. In the postoperative setting, cellular injury is also very common with one study demonstrating new diffusion restriction surrounding the surgical cavity in 64% of resected gliomas, of which 93% went on to develop encephalomalacia on serial imaging, suggesting cellular injury Fig.  [3]. In Peritumoural oedema refers to the area of abnormal signal surrounding the enhancing component of a brain tumour. The problem with this term is that it encompasses two separate pathophysiological processes (vasogenic and infiltrative oedema) that have very different implications for treatment. In vasogenic oedema, there is increased fluid in the extracellular space due to alterations in vascular permeability resulting in leakage of plasma fluid and protein. This commonly occurs with metastatic lesions and non-infiltrating primary brain tumours and is typically reversible. It classically does not result in diffusion restriction and the area of abnormal signal is not considered to be within the margins of the tumour. The major clinical implication of vasogenic oedema is in regard to any mass effect it creates on adjacent normal structures. In infiltrative oedema, there is both perivascular infiltration of tumour and leakage of fluid into the extracellular space. This commonly occurs with higher grade infiltrating gliomas and makes it difficult to accurately define tumour margins. Theoretically, perivascular infiltration of tumour should decrease water diffusivity producing low ADC signal. However, many studies have shown that the areas of tumour infiltration are quite small and DWI is not very reliable for differentiating vasogenic from infiltrative oedema . In thesPWI is a noninvasive imaging technique for measuring brain tumour vascularity. It indirectly provides information on tumour angiogenesis and altered capillary permeability, both of which are present in many types of brain tumours. This is of particular importance on post-treatment imaging, as areas of increased perfusion can be suggestive of tumour growth or recurrence. The most commonly used perfusion techniques include dynamic susceptibility contrast (DSC), dynamic contrast-enhanced (DCE), and arterial spin labelling (ASL) MR imaging.DSC perfusion imaging measures perfusion by assessing susceptibility-induced T2* signal loss from the bolus of contrast as it passes through the capillary bed. This loss of signal is depicted as a signal intensity-time curve; the area under the curve is then calculated to derive the relative cerebral blood volume (rCBV) Fig. . Many brtrans, which represents the degree of permeability between the plasma and extravascular extracellular space [trans more truly reflects vascular permeability; however, when the blood-brain barrier is disrupted by tumour, ktrans becomes more representative of cerebral blood flow [trans of brain tumours likely occur because of the formation of immature hyperpermeable vessels, a common occurrence in growing/progression of brain tumours. Therefore, as with rCBV in DSC perfusion imaging, elevations in ktrans may also be a potential marker for tumour growth/recurrence [DCE perfusion imaging involves performing repeated T1-weighted imaging after contrast administration to produce a contrast signal time intensity curve. These data can then be analysed to calculate multiple parameters reflective of tumour vascularity. The most commonly calculated parameter is that of the transfer coefficient kar space . It is iood flow . Althougcurrence .ASL perfusion imaging is a non-contrast perfusion technique that uses inversion pulses to magnetically label water protons in inflowing arterial blood. By comparing the difference in signal between labelled images and non-labelled images, cerebral blood flow (CBF) can then be quantified. This technique has been widely established as a useful technique in assessing cerebral perfusion in stroke and dementia; however, more recent literature has demonstrated growing utility in brain tumour imaging. Although ASL imaging does not directly measure tumour blood volume, many studies have shown that blood volume and blood flow are strongly correlated, and therefore focal areas of elevated CBF on ASL imaging may be a marker for tumour growth/recurrence. Compared with DSC perfusion techniques, ASL has the added advantage of a higher signal-to-noise ratio (SNR) and no need for intravenous contrast. However, major limitations include longer scan time and lower spatial resolution compared with DSC perfusion imaging .1H-MR spectroscopy is an MRI technique that creates a quantitative representation of the distribution of metabolites within a specified region of brain tissue. This can be performed via a single- or multivoxel acquisition and is often used to better characterise areas of abnormal brain tissue. The normal spectrum of brain metabolites typically shows relative elevation of choline, creatine, and N-acetylaspartate (NAA) in relation to the other metabolites, reflecting the normal composition of brain tissue. These three metabolite peaks show a normal gradual increase in concentration from left to right, creating the so-called “Hunter’s angle”  signal after 1H nuclei [It is important to note that alternative brain tumour imaging techniques, such as chemical exchange saturation transfer (CEST) and sodium MR imaging, have been increasingly described in the literature. These techniques are primarily in the research stage but seem to show promise in better characterising tumours post treatment. For these reasons a discussion on brain tumour imaging cannot be complete without at least mentioning these techniques. CEST imaging is a novel form of MR imaging in which a radiofrequency pulse is applied resulting in saturation of a particular chemical species. Over time, this magnetic saturation is transferred to water molecules via an exchange of protons, resulting in a decrease in water signal. This decrease in water signal can then be detected and, from this, an indirect measurement of the originally saturated species can be obtained. Although many chemical species are currently being investigated, Park et al. have shown that CEST amide proton transfer (APT) imaging can reliably distinguish tumour progression from a treatment-related effect as well as improve the diagnostic accuracy when combined with conventional perfusion-weighted and contrast-enhanced T1-weighted imaging techniques . Sodium H nuclei . In postH nuclei .Although these imaging techniques appear to demonstrate clinical utility, more research is needed to establish whether these techniques can be routinely used for post-treatment imaging.It is imperative that radiologists be familiar with the treatment response criteria that referring clinicians are using to assess patients with brain tumours. Many of these algorithms rely heavily on imaging and therefore radiologists play an important role in dictating clinical management. Although each brain tumour behaves differently and carries different histological grades/aggressiveness, it is helpful to focus on the two main categories of brain tumours: high-grade gliomas and metastases.Historically, multiple different criteria were used to the assess treatment response of high-grade gliomas. The Levin criteria relied on qualitative changes in perilesional mass effect to ascribe treatment response . The WorIn addition to the RANO criteria, two radiological phenomena have been well described in the literature and require a further in-depth discussion. These include pseudoprogression and pseudoresponse.Pseudoprogression refers to the development of new or enlarging enhancement within the vicinity of a recently treated brain tumour. This imaging appearance initially mimics tumour progression, but should improve or stabilise on follow-up imaging . This phPseudoresponse refers to a rapid transient decrease in enhancement within a recently treated brain tumour. This imaging appearance initially mimics treatment response but careful inspection of the tumour often shows persistent T2 FLAIR hyperintensity and low ADC signal that worsens on follow-up imaging Fig. . This deMetastases are the most common cause for CNS malignancy in adults. Despite being so common, there is extensive variation in the literature regarding metastasis treatment and treatment response criteria. In fact, historically many clinical trials have actually excluded brain metastases from their inclusion criteria. In an effort to eliminate this confusion and standardise discussion of CNS metastases, in 2015 the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group released the Response Assessment Criteria for Brain Metastases. These treatment criteria focus on objective measurements of tumour size as well as clinical criteria such as corticosteroid use and clinical deterioration . These cRadiation-induced brain injury encompasses a wide variety of both clinical and radiological findings that result from fractionated or whole-brain radiation. These injury patterns are often described as an expression of time from the initiation of radiation under the following categories: acute (days to weeks), early delayed (weeks to months), and late delayed (months to years).Acute and early delayed radiation injury is thought to result from alterations in vascular permeability and disruption of the blood-brain barrier resulting in varying degrees of brain oedema/swelling. In contrast to late delayed injury, this alteration in physiology is usually reversible and resolves spontaneously without any histopathological correlate . In the 2 (PGE2), stimulating gliosis, and brain oedema [Late delayed radiation injury, on the other hand, is a much more serious form of injury due to a combination of vascular and glial injury resulting in irreversible and progressive white matter necrosis. The exact mechanism through which this occurs is not well understood but thought to be due to either vascular endothelial injury or direct parenchymal injury . The vasn oedema . Rosi etn oedema . AlthougAlthough it is helpful to understand the temporal relationship of radiation and the pathophysiology of brain injury, many find it more helpful to classify radiation-induced brain injury by the pattern visualised on imaging. What follows is an imaging-based discussion of radiation-induced complications organised by which anatomic structures are affected.As previously stated, radiation can have profound effects on the intracranial vasculature through irreversible endothelial injury. This is typically a late delayed injury manifesting months to years after radiation exposure. On imaging, radiation-induced vascular injury produces three main appearances: radiation-induced vasculopathy, radiation-induced vascular proliferative lesions, and radiation-induced mineralising microangiopathy.Radiation-induced vasculopathy refers to accelerated myointimal proliferation of vessel walls resulting in varying degrees of stenosis or occlusion . This prRadiation-induced vascular proliferative lesions include capillary telangiectasia and cavernous malformations (cavernomas). Formation of these lesions is thought to result from injury to the cerebral microcirculation, triggering focal regions of neoangiogenesis within the brain parenchyma . Larson Radiation-induced mineralising microangiopathy refers to the development of dystrophic microcalcifications in the brain parenchyma. Histopathologically, this process consists of calcium deposition within damaged vessel walls as well as surrounding necrotic brain tissue . On imagRadiation necrosis, as the name suggests, refers to a combination of vascular and parenchymal injury resulting in necrosis of either tumour or normal brain parenchyma. It is a delayed phenomenon that has a propensity for affecting the white matter and the deep laminae of the overlying cortex with relative sparing of the superficial cortex . The likRadiation-induced leukoencephalopathy is a term used to denote radiation-induced white matter injury, typically without frank necrosis. As with most forms of radiation injury, the pathophysiology is unclear but appears to result from either direct axonal injury or secondary white matter injury from vascular compromise. The incidence of leukoencephalopathy is also unclear; however, a retrospective study reported an incidence of 34% in patients who received whole-brain radiation treatment (WBRT) for brain metastases after 6 months of follow-up . ClinicaSMART syndrome is a rare clinical entity that consists of complex migraine-like symptoms in the setting of prior radiation exposure. It is more commonly seen in men  and is typically a late delayed phenomenon occurring in patients that received radiation doses of 50–64 Gy . ClinicaChemotherapeutic agents can result in direct toxicity to various structures of the central nervous system. The particular CNS structure involved and the degree to which they are affected vary depending on the drug administered and the dose that was given. Given the ever-growing list of new chemotherapeutic agents, each with its own toxic profile, a thorough discussion of CNS drug toxicity is beyond the scope of this article. However, that being said, it has been shown that most drugs tend to affect similar structures and produce similar patterns of injury on imaging. In addition, certain drugs can result in classic pathological imaging findings  that are easy to diagnose once familiar with their imaging appearance. What follows is a discussion of these common chemotherapy-related injury patterns.It has been widely described in the literature that of all the CNS structures, the white matter is particularly vulnerable to drug injury. Although the mechanism through which this occurs is poorly understood, it has been suggested that leukotoxic agents result in disruption of neural transmission, particularly in the neurobehavioural pathways, often resulting in the classic clinical presentation of “altered mental status”. This injury results in a drug-related toxic leukoencephalopathy, producing a clinical and radiographic picture similar to radiation-induced leukoencephalopathy. In fact, many chemotherapeutic agents can actually potentiate many of the radiation injuries previously discussed. The most common leukotoxic agent used in clinical practice is methotrexate; however, many other agents including carmustine, cisplatin, cytaribine, fluorouracil, and interleukin-2 have also been implicated , 51. TheAnother commonly discussed chemotherapy-related complication is that of ipilimumab hypophysitis. Ipilimumab (MDX-010) is a monoclonal antibody that works by suppressing cytotoxic T lymphocyte-associated antigen 4, which in turn augments the patient’s immune system to mount a response against malignant cells. This agent has become particularly effective for metastatic melanoma and renal cell carcinoma, where it is now widely used for patients with disseminated disease. However, augmentation of the immune response can result in many adverse autoimmune reactions throughout the body, such as colitis, dermatitis, and arthritis, to name a few. In the CNS, ipilimumab-induced hypophysitis is one of the better recognised autoimmune reactions described in the literature. Although this is thought to occur in < 5% of all ipilimumab-treated patients, these patients can clinically present with life-threatening hormonal imbalance, particularly hypercortisolism. On imaging, ipilimumab-induced hypophysitis results in diffuse enlargement of the pituitary gland, often hypointense on T1-weighted imaging, with variable thickening/enlargement of the infundibulum , 54. FolSurgical resection is a key component of treating many types of brain tumours, in particular, high-grade gliomas, large metastases, or extra-axial lesions with significant mass effect. Although usually uneventful, surgery does carry its own risks, with one study demonstrating a 3.4% risk of having at least one surgical complication in patients undergoing surgery for malignant brain tumours . The mosPrimary and metastatic brain tumours are frequently encountered in the daily practice of neuroimaging. The wide array of treatment options currently available to treat these tumours has made interpretation of post-treatment imaging quite complex. Knowledge of post-treatment imaging techniques, treatment response criteria, and commonly encountered treatment-related complications will simplify the approach to this challenging topic.