Androgen Receptor (AR) is an essential transcription factor for the development of secondary sex characteristics, spermatogenesis and carcinogenesis. Recently AR has been implicated in the development and progression of breast and prostate cancers. Although some of the functions of the AR are known but the mechanistic details of these divergent processes are still not clear. Therefore understanding the regulatory mechanisms of the functioning of the AR in ER-/AR+ breast cancer will provide many novel targets for the purpose of therapeutic intervention.Using bioinformatics tools, we have identified 75 AR targets having prominent roles in cell cycle, apoptosis and metabolism. Herein, we validated 10 genes as AR targets by studying the regulation of these genes in MDA-MB-453 cell line on stimulation by androgens like 5α-dihydrotestosterone (DHT), using RT-qPCR and ChIP assay. It was observed that all the identified genes involved in cell cycle except MAD1L1 were found to be up regulated whereas expression of apoptosis related genes was decreased in response to DHT treatment. We performed an exhaustive, rigid-body docking between individual ARE and DNA binding domain (DBD) of the AR protein and it was found that novel residues K567, K588, K591 and R592 are involved in the process of DNA binding. To verify these specific DNA-protein interactions electrostatic energy term calculations for each residue was determined using the linearized Poisson–Boltzmann equation. Our experimental data showed that treatment of breast cancer cells with DHT promotes cell proliferation and decreases apoptosis. It was observed that bicalutamide treatment was able to reverse the effect of DHT.Taken together, our results provide new insights into the mechanism by which AR promotes breast cancer progression. Moreover our work proposes to use bicalutamide along with taxanes as novel therapy for the treatment of TNBCs, which are positive for downstream AR signalling. Androgen receptor (AR) belongs to a family of intracellular steroid hormone receptors that function as ligand dependent transcription factor which regulates target gene expression. The full length AR protein is a 110 kDa phosphoprotein, which mediates its physiological functions by binding to its ligand testosterone or after its conversion to 5α-dihydrotestosterone (DHT) by 5α-reductases. AR is responsible for mediating a myriad of physiological function of the androgens like male sexual development, spermatogenesis, maintaining bone mineral density, stimulating erythropoiesis, production of prostate-specific proteins and it also regulates several aspects of cell metabolism like lipid biosynthesis . AR has Breast cancer is a heterogeneous disease that encompasses a range of phenotypically distinct tumour types and accounts for 1.38 million new cases of breast cancer worldwide, with a mortality rate of more than 458,000 cases . Traditiin silico, revealing the critical nucleic acid and protein residues required for this interaction to take place. Computational docking was performed in order to reveal key residues involved in the stabilization process of the nucleic acid and AR DBD. No assumptions of specific types of DNA-protein contacts were made, albeit, predictions of interactions were based on binding energies.In order to understand the genomic actions of the AR, the gene expression profiling of the putative AR targets was studied and the AR binding was shown using the ChIP-qPCR. Considerable amount of sequence variability was found in the individual AREs, prompting us to study the binding of the AREs and the AR DBD , whereas LNCaP cells were maintained in RPMI 1640 medium. Androgen-regulation experiments were performed in trypsinized cells which were allowed to adhere to the culture flask overnight and then transferred into media supplemented with 10% charcoal-stripped FCS . The following day media was replaced with fresh charcoal-stripped complete medium supplemented with 10 nM of the DHT  or vehicle control. Cells were harvested at various time point for the purpose of performing RNA isolation and ChIP experiments.Cancer cell lines MDA-MB-453 and LNCaP were obtained from cell repository at National Centre for Cell Sciences (NCCS), Pune, India. MDA-MB-453 cells were cultured in L15 media supplemented with 10% FBS 2O2 in methanol (PBS) for 30 minutes. Fixed cells and tissue were given 3 washes each with PBS and antigen retrieval was performed with 10mM citrate buffer in hot water bath for 10 minutes and 15 minutes respectively for the cells and the tissue samples. IHC was done on cells and tissue sections using 1:50 dilution of Her2 Antibody  and incubated overnight at 4°C. The tissue sections and the cells were washed with PBS, incubated with HRP conjugated secondary antibody for 1 hour at room temperature and developed with DAB (diaminobenzidine) as chromogen and hematoxylin staining was used as the counter stain.Immunohistochemistry (IHC) procedure were done as described earlier . Brieflyin silico approach to identify novel genes, which are directly under the transcriptional regulation of AR in breast cancer cell line MDA-MB-453. Genes having prominent role in cell cycle, apoptosis and metabolism were sourced from the cell cycle gene database , apoptosis gene database (www.deathbase.org) and metabolic gene database (www.humancyc.org) respectively. All the gene sequences were retrieved from the Ref_Seq database at National Center for Biotechnology Information [http://mbs.cbrc.jp/research/db/TFSEARCHJ). Scoring was based on the number of nucleotides in the query sequence that matched with the consensus sequence. The putative ARE sequence with the highest score was reported for each gene and cut off threshold score of 85 and the above were considered to be a significant hit.In the present study, we used an ormation . ApproxiTotal RNA isolation, reverse transcription and RT-qPCR were done as described earlier –21. MDA-7 cells were fixed with formaldehyde  at room temperature for 10 minutes. Reaction was stopped by adding glycine solution for 5 minutes at room temperature and two washes were given with ice-cold PBS . After the wash, cells were resuspended in PBS buffer having protease inhibitor cocktail II  and cells were collected by scraping them from dish into 15mL conical tubes and centrifuging at 720 x g at 4°C for 10 minutes. Supernatant was discarded and pellet was suspended in 80μl of ice-cold EZ-Zyme Lysis Buffer (supplemented with Protease Inhibitor Cocktail II). Then cells were lysed with lysis buffer by snap freezing in liquid nitrogen and thawing them on 37°C and the freeze-thaw cycle was repeated 3 more times. The cell nuclei thus extracted were subjected to chromatin digestion so as to give a smear of DNA prominently lying in range of 200–500bp by incubating at 37°C for 10 minutes with EZ-Zyme Enzymatic cocktail, provided with the EZ-Zyme Chromatin Prep Kit (Millipore). Positive control Anti-RNA Polymerase II antibody, negative control normal Mouse IgG  or Androgen Receptor antibody ChIP Validated Antibody (Millipore) were added separately and incubated for 2 hour at 30°C followed by incubation with fresh Protein A agarose magnetic beads. Cleaved chromatin was immunoprecipitated using the Magna ChIP A/G kit (Millipore). Protein A/G magnetic beads were pelleted with the magnetic separator and supernatant was completely removed. Precipitated chromatin complexes were removed from the beads through 30-min incubation with 500 μl of elution buffer . Finally, the protein–DNA cross-links were reversed by incubation at 65°C for 4 hours. ChIPed DNA fragments were purified using spin columns and the DNA fragments thus obtained were analyzed by qPCR DNA using 2μl of the ChIPed DNA, SYBR Select Master Mix  and Chip primers  of the target genes. Internal control primers were taken at regions far from the site of the AR site in the coding region, where there no AR binding. Primer design was done by using primer 3 software, while using the default parameters were 23 nucleotides was the optimal primer length; primer t test. P-value calculations were done using the Sigma Plot software and the resulting data are presented as the mean±SD (n ≥3). In all the experiments, P < 0.05 was considered to be statistically significant.Statistical differences were determined using the Student’s www.rcsb.org/pdb/home/home.do). Refinement of the structure by energy minimization was done using molecular dynamics NAMD package with AMBER99SB force field [The coordinates of the 3D structure of rat AR-DBD (PDB-ID 1R4I) were retrieved from RCSB Protein Data Bank (PDB)  and MUSCLE (https://www.ebi.ac.uk/Tools/msa/muscle/) programs by using their servers [0 to 600 with tilt of 50 as global changes.Multiple Sequence Alignment was performed by ClustalW  is systematically moved over the other molecule (the stationary molecule) in a complete translational and rotational search. Interaction energies for all configurations of the two molecules were evaluated as correlation functions, which were efficiently computed using the fast fourier transforms. The properties of both molecules are mapped onto grids. For each orientation of the moving molecule, the moving molecule is centred at each grid point and the interaction energy is calculated as the sum of the electrostatics and van der Waals terms. A cubic grid 128 Å on a side with 1-Å grid spacing (≈2.1 million points) and a set of 28,800 orientations for the moving molecule (≈7.5° spacing) gave over 60 billion configurations of the two molecules. The top several thousand configurations were retained. DOT also gives a complete grid of interaction energies with the energy mapped to the grid point at which the moving molecule is centred, so that the distribution of favourable energy configurations can be easily determined.The DOT van der Waals energy is proportional to the number of moving molecule atoms that lie within a favourable interaction layer surrounding the stationary molecule . The sha−1·e−1 for AR-DBD as the stationary molecule. All the structures of DNA docked in the DBD binding site of AR-DBD, the analysis of its interactions, and the images were prepared by using VMD.The electrostatic energy in DOT is calculated as the set of point charges representing the moving molecule placed within the electrostatic potential of the stationary molecule . Partial3/ well) were seeded in a 96 well plate  in L15 media with 10% FBS and they were allowed to adhere overnight. DMSO stock solutions of paclitaxel/5-fluorouracil and water solution of cyclophosphamide monohydrate were dissolved in culture medium to get the desired final concentrations. The following day media was replaced by media containing the indicated concentrations of the drugs, paclitaxel, 5-fluorouracil and cyclophosphamide  and the cells were grown for 48 hours at 37°C following the drug addition. In all the experiments involving DHT or bicalutamide  treatment, tripsinized cells were allowed to adhere overnight in the 96 well plates. The following day, media was replaced with L-15 medium with 10% charcoal-stripped FCS  for 24 h followed by replacement of the media with fresh charcoal-stripped medium supplemented with 10 nM of the DHT (Sigma) or vehicle control for 24 hrs. After 48 hrs of incubation with drugs, MTT powder  was dissolved 5mg/ml in L-15 without phenol red. The solution was filtered through a 0.2 μm filter and added to each culture well being assayed, to equal one-tenth the original culture volume and incubated for 3 hrs at 37°C. In all the experiments one set of wells, having only cells and medium, but no drug was taken as the control. Thereafter, the MTT containing medium was removed and the converted dye was solubilised with acidic isopropanol (0.1 N HCl in absolute isopropanol). Absorbance of converted dye was measured at a wavelength of 570 nm with background subtraction at 630nm using a multiwell spectrophotometer. The average values from triplicate samples was determined after subtraction of the average value for the blanks and the values thus obtained were plotted as a fraction of the control cells which were taken as 100% viable.MDA-MB-453 cells  and 20 μg/ml RNAse solution for 30 minutes on ice. Cell cycle distribution and DNA content was determined using the using FACS Aria II Special Order Research Product  with an argon laser set to excite at 488 nm.3 x 10www.cyclebase.org, www.itb.cnr.it/cellcycle/), Apoptosis gene database (www.deathbase.org) and metabolic gene database (www.humancyc.org). Initial Prioritization of the genes selected for the purpose of analysis was based on the relation of the gene to AR function and role in carcinogenesis. In order to determine the presence of putative ARE(s), 5kb upstream and downstream of the transcriptional start site (TSS) of all these genes were scanned by using “TFSEARCH" version 1.3, transcription factor binding software. After initial screening of 576 genes, the resultant 75 hits having potential ARE(s) were tabulated. High scoring matches that were homo polymeric in the left or right half of the consensus sequence were excluded from the hits. Finally 10 genes were selected, on the basis of "TFSEARCH" hit score, gene expression and the distance of the putative AR binding sites from the TSS using a strategy shown in flowchart (In order to gain better understanding of the androgen receptor (AR) regulatory networks, we sought to identify novel Androgen response elements (AREs) which are under the direct transcription control of androgen receptor. A total of 576 candidate genes having role in cell cycle, apoptosis and cellular metabolism were sourced from the cell cycle gene database  using ChIPed DNA fragments as template to prove the physical occupancy of AR to these promoters upon DHT stimulation . We wereThe DNA binding domain (DBD) is a highly conserved domain among the nuclear receptors (NRs). The AR-DBD contains two conserved motifs namely, P box (GSCKV), which interacts with the major groove of the DNA, while the second motif, D box (ASRND), which play a role in DBD-mediated AR dimerization. Surface representation of AR binding to its ARE is illustrated in In order to understand how the extensive positive potential created by androgen receptor influences DNA binding, we performed rigid-body dockings with DOT, a computational docking tool for macromolecular interactions . StudiesSequence alignment of the AREs present in all the 10 genes  under stIn order to decipher the DNA-protein contact points between the AR-DBD and ARE(s), 5 genes namely, AATK, CDT1, KLF6, LIPH and SGOL2 were selected on the basis of TF search score, fold enrichment in ChIP-qPCR experiments for the purpose of interaction studies. As mentioned earlier, the molecular interaction maps of DNA-AR supports well the outcome of alignment results, as it was showing interactions with the key residues of P-box namely K563, V564, R568 . Our dat50 values of the chemotherapeutic drugs paclitaxel, 5-fluorouracil and cyclophosphamide were determined to be 17.62μM, 0.506 μM and 3.45 μM respectively  or both. It was observed that there was a significant increase in the cell survival on DHT treatment as compared to the vehicle treated cells, even in presence of IC50 concentration of the 3 therapeutic drugs, suggesting that AR reverses the chemotherapeutic drug induced apoptosis in MDA-MB-453 cells  adjuvant and neoadjuvant chemotherapy for the treatment of breast cancer ,57. Paclectively . The eff53 cells . We obse53 cells . Similar53 cells . We spec53 cells . It can 53 cells . In ordeectively . An increctively . Furtherectively . MDA-MB-ectively . There w50 concentration of the drugs, suggesting a chemopreventive effect of AR . Our data shows that AR-DBD has two distinct DNA binding sites, indicating that the behavior of AR protein is not specific, albeit the lowest energy pose of AREs tends to orient themselves quite similarly . The ele50 concentration of the drug. Bicalutamide is known to prevent nuclear localization of AR and therefore no binding was observed in the presence of bicalutamide in combination with a drug or bicalutamide alone (Recent literature suggests that AR is emerging as a interesting target for breast cancer therapy in ER-/AR+ tumors and some triple negative breast cancers (TNBCs), which are enriched for AR signalling pathways ,61. Due de alone . Howeverde alone . Thus wede alone . Our datde alone . The actS1 Fig(A) ChIP assay were performed with AR antibody or control IgG antibody in LNCaP cells treated with 10nM/L of DHT or vehicle control for 24 hrs. The fold enrichment of coprecipitating DNA was determined by qPCR for the indicated promoters. Error bars are means ± SD of three independent experiments; . (B) Standard PCR for the AR, IgG and input DNA was performed for the indicated genes.(TIF)Click here for additional data file.S2 Fig(A-B) ChIP-qPCR showing the binding of AR to CDT promoter in presence of cyclophosphamide and 5'-Fluorouracil (C-D) ChIP-qPCR showing the binding of AR to KLF promoter in presence of cyclophosphamide and 5'-Fluorouracil. All the means and standard deviation are obtained from three independent experiments. Gel picture below shows the standard PCR validation of the result Cyclo: Cyclophosphamide; Fluoro: 5'-Fluorouracil, M: Marker, 1: Input, 2: Untreated control, 3: DHT +Pac,: 4: DHT+ Bic +Pac, 5: Bic + Pac, 6: Bic.(TIF)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.


In an iterated non-cooperative game, if all the players act to maximize their individual accumulated payoff, the system as a whole usually converges to a Nash equilibrium that poorly benefits any player. Here we show that such an undesirable destiny is avoidable in an iterated Rock-Paper-Scissors (RPS) game involving two rational players, X and Y. Player X has the option of proactively adopting a cooperation-trap strategy, which enforces complete cooperation from the rational player Y and leads to a highly beneficial and maximally fair situation to both players. That maximal degree of cooperation is achievable in such a competitive system with cyclic dominance of actions may stimulate further theoretical and empirical studies on how to resolve conflicts and enhance cooperation in human societies. The solution concept of Nash equilibrium (NE) plays a fundamental role both in classic game theory and in evolutionary game theory Many non-cooperative games have only a unique NE. When such a game is played by highly rational players who act to maximize their individual accumulated payoff, it is unavoidable that the system will sooner or later converge to this unique equilibrium situation. Unfortunately, however, it is usually the case that the NE of a non-cooperative game is an unfavorable or even miserable destiny for all the players. Let's consider the two-player Prisoner's Dilemma (PD) game as a simple example. The cooperative situation of both players choosing not to confess is much better than the defection situation of both players choosing to confess, but the latter is the unique NE of this game while the former is not passively in the sense that they try to maximize individual gains by making best responses to the inferred/experienced strategy of the opponent, we assume that one of the players might act more proactively. An intelligent and rational player may ask the following question: how should I design my own strategy so that my rational opponent(s), in best response to me, for sure will adopt certain strategy that is most beneficial to me? In later discussions we refer to such a strategy as a cooperation-trap (CT) strategy, as it has the effect of trapping an opponent in a cooperation state. When optimized, such a CT strategy offers high and maximally fair accumulated payoffs to both players.In this paper we study the issue of cooperation in the itererated two-player Rock-Paper-Scissors (RPS) game, which is a fundamental non-cooperative game with cyclic dominance among its action choices , see In a literature search for related studies, we found that an early paper of Grofman and Pool The present effort can be regarded as an extension of the Grofman-Pool theory to the iterated RPS game, which has the additional difficulty of having more than two action choices that are related by a rotation symmetry see . This saConsider two players X and Y playing the RPS game for an indefinite number of rounds. At every game round each player can choose one action among three candidate actions tion see . For exaWhen We now develop CT strategies for player X, and begin with the simplest case of memoryless strategies, namely at every game round player X does not consider her and her opponent's prior actions nor the outcomes of prior plays but chooses actions As player Y is sufficiently intelligent, he will figure out the strategy of X after a small number of game repeats. Alternatively, with the aim of promoting cooperation from player Y, player X may also explicitly inform Y about her strategy parameters, which are If the strategy of player X have the following property that If the payoff parameter If These shortcomings of the memoryless CT strategy can be eliminated by increasing the memory length of the CT strategy.Recent laboratory experiments carried at Zhejiang University When the payoff parameter On the other hand, when It turns out that the optimal CT strategy of unit memory length has the following quantitative properties:If If If If m+1)-th game round. It is a simple exercise to check that, if To completely eliminate these undesirable features, player X can increase the memory length of her CT strategy and therefore be more non-tolerant to defection. There are many ways of implementing such an idea. When If the payoff parameter As clearly demonstrated in We have demonstrated in this paper that fair cooperation can be achieved in the two-player iterated RPS game. Such a highly cooperative state brings maximal accumulated payoff to the group, and it is not enforced by external authorities but by the proactive decision of one player to adopt an optimal cooperation-trap strategy. The basic designing principle of such optimal CT strategies should be generally applicable to other two-player iterated non-cooperation games.For the optimal CT strategies to work, the passive player Y is assumed to be considerably rational so that he adopts a best response strategy to that of his opponent X to maximize his accumulated payoff, while the proactive player X is assumed in addition to be wise enough so that she does not exploit the cooperation state of her opponent too much but is satisfied with a fair share of the total accumulated group payoff. This latter assumption might be a little bit too strong, but maybe it is not strictly necessary as player Y will punish X for defection behaviors.For the iterated RPS game, it appears to be impossible for the proactive player X to design a CT strategy which brings higher expected payoff per game round to herself than to her opponent. However, this is not a general conclusion. For some other game systems, notably the iterated PD game When strategic interactions occur in biological systems Cooperation in a finite-population RPS game system with more than two players may be much more difficult to achieve than the case of two players. A recent theoretical investigation by one of the present authors The iterated two-player RPS game might also serve as a simple system to quantitatively measure the degree of rationality of single human subjects. For example, an experiment can be arranged as follows. A human subject Y plays repeatedly with a fixed opponent X which is actually a computer implementing an optimal CT strategy. But Y does not know that he is playing with a computer and assumes he is playing with another human subject. By analyzing the evolution trajectory of player Y's action choices, we may quantitative measure the learning behavior of player Y and his tendency of making rational decisions. We are discussing with colleagues about the possibility of carrying out such an experimental study.


AR and asthma, often seen in younger adults and had social- psychological burden, are common chronic diseases. The objective of the study was to determine and compare the prevalence of anxiety and depression in allergic rhinitis (AR) and asthmatics.Subjects without known psychiatric diseases were consecutively recruited from pulmonary and allergy out-patient clinics at the third level hospitals. Diagnosis of asthma and AR was based on GINA and ARIA guideline, respectively. Only patients without asthma were chosen for AR group in order to compare with asthma. Depression and anxiety symptoms were evaluated using Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI).Study group consisted of 60 patients-30 with asthma and 30 with AR. All patients had moderate-to severe diseases. AR group was younger; but the mean disease duration was not significantly statistically different. AR group had higher education history than those of asthmatics. Number of smokers in both groups were equal. Female gender was predominant in both groups. In asthmatics, 53.3% had positive skin prick test with aeroallergens. Polysensitization rate was 56.25% and 63.3% in asthmatics and AR group, respectively. The most common sensitization pattern was mite plus mould sensitization. The mean BDI and BAI scores were 11.47±11.14 and 15.22±11.31 in the whole group. Both BDI and BAI scores were significantly statistically different in the study groups (Table AR patients without asthma seem to have better coping mechanism than that of asthmatics.


In the past decades, the field of prostate cancer (PCa) biology has developed exponentially and paralleled with that has been the growing interest in translation of laboratory findings into clinical practice. Based on overwhelming evidence of high impact research findings which support the underlying cause of insufficient drug efficacy in patients progressing on standard androgen deprivation therapy (ADT) is due to persistent activation of the androgen receptor (AR) signaling axis. Therefore, newer agents must be discovered especially because newer ADT such as abiraterone and enzalutamide are becoming ineffective due to rapid development of resistance to these agents. High-throughput technologies are generating massive and highly dimensional genetic variation data that has helped in developing a better understanding of the dynamic repertoire of AR and AR variants. Full length AR protein and its variants modulate a sophisticated regulatory system to orchestrate cellular responses. We partition this multicomponent review into subsections addressing the underlying mechanisms of resistance to recent therapeutics, positive and negative regulators of AR signaling cascade, and how SUMOylation modulates AR induced transcriptional activity. Experimentally verified findings obtained from cell culture and preclinical studies focusing on the potential of natural agents in inhibiting mRNA/protein levels of AR, nuclear accumulation and enhanced nuclear export of AR are also discussed. We also provide spotlight on molecular basis of enzalutamide resistance with an overview of the strategies opted to overcome such resistance. AR variants are comprehensively described and different mechanisms that regulate AR variant expression are also discussed. Reconceptualization of phenotype- and genotype-driven studies have convincingly revealed that drug induced resistance is a major stumbling block in standardization of therapy. Therefore, we summarize succinctly the knowledge of drug resistance especially to ADT and potential avenues to overcome such resistance for improving the treatment outcome of PCa patients. Androgen receptor (AR) blockers have been incorporated in the backbone of PCa therapeutics. Mutation and amplification of AR gene, growth factor mediated signaling induced activation of AR, overexpression of nuclear receptor co-activators, alternative splicing variants and steroid metabolism enzymes are widely studied biological mechanisms that underpin castration resistant prostate cancer (CRPC) phenotype. Substantial fraction of information has been added into the existing pool of knowledge, and dysregulation of intracellular signaling networks in PCa lends credence to the mantra that increasing molecular understanding is catalyzing the generation of AR antagonists. Mounting evidence has provided a platform to investigate systematically not only the molecular complexity of CRPC, leading to the identification of disease pathways and modules, but also changes in the recruitment and regulatory effect of AR on transcription as PCa progresses.First generation AR antagonists such as bicalutamide and nilutamide gained appreciation but agonistic properties were noted in AR over-expressing PCa cells, which raised some concerns for the use of these agents in human PCa patients. Whereas, enzalutamide was reported to be effective against AR over-expressing PCa cells and proved to be a valuable addition in the arsenal of molecular therapeutics for treating PCa after approval in 2012 by US FDA. VCaP prostate cancer cells have endogenously amplified AR gene and enzalutamide exerted inhibitory effects on proliferation of VCaP cells. Moreover, the activity of mutation bearing AR (W741C) was also notably reduced upon treatment with enzalutamide. Bicalutamide induced AR conformational change facilitated its interaction with FxxLF or LxxLL motif-containing co-activators. On the contrary, enzalutamide did not promote AR interaction with co-activators. We will now address some specific example of AR activation in the context of CRPC and subsequent metastasis (mCRPC) of PCa.Lupron and other LHRH agonists are worthwhile options as part of ADT for PCa patients. Using multipronged approach, by combining antagonists such as bicalutamide with Lupron can prevent its harmful side effects . There aLower treatment dose of ARN-509 and absence of any risk of seizures in patients as compared to enzalutamide treatment makes it a potent anti-androgen than enzalutamide. However, F876L mutant AR carrying cancer cell lines did not show any response to ARN-509. Moreover, F876L mutant AR was identified in plasma DNA from ARN-509-treated patients with progressive CRPC .CYP17 is also chemically inhibited by Orteronel, also known as TAK-700. Considerably higher specificity for 17,20-lyase than for 17α-hydroxylase by Orteronel is a hallmark feature that differentiates it from abiraterone. More importantly, Orteronel associated manageable toxicities and its chronic administration without steroids makes it a drug of choice. Orteronel induced durable declines in PSA in mCRPC patients .Although there are encouraging advancements in our understanding related to the intricacies that mediate androgen metabolism and thereby regulate AR activation , we stilSubstantial information has been added into the landscape of co-activator/co-repressor complexes associated with AR Figure , and it MID1 is a microtubule-associated ubiquitin E3 ligase frequently overexpressed in PCa cells. MID1 bound purine-rich repeats regions in AR mRNA have been identified experimentally. Targeted inhibition of MID1 in AR overexpressing DuCaP cells notably reduced decreased protein levels of AR . Skp2  chelator with considerable activity against KDM4. SD70 treated PCa cells and displayed a marked decrease in AR target gene expression ,13.This section reviews mounting research work summarizing information on alteration in transcriptional network of sumoylated AR, various ways in which AR and its associated proteins are SUMOylated and how SENP-1 deconjugates SUMO from AR to enhance AR induced expression of target genes. Targeting of SENP-1 using chemical and synthetic agents is also discussed.th position downstream to the core of the second synergy control motif in AR. AR bearing the G524D substitution displayed a higher transcriptional activity than wild type AR. Moreover, SUMOylation-deficient AR mutant (K386R/K520R), also induced significant target gene expression [It has previously been convincingly revealed that N-terminal transactivation domain of AR undergoes covalent modification by SUMOs at two conserved lysine that may influence AR efficiency in stimulating expression of target genes. Increasingly it is being realized that SUMOylated AR shows a lower transcriptional activity Figure . It is npression . Heat stpression . Rapidlypression   is a member of the brassinosteroids (BR) with notable activity against LNCaP prostate cancer cells expressing functional AR. EBR exerted its biological effects via activation of polyamine catabolic machinery in prostate cancer cells. Interfering with spermidine-spermineacetyltransferase (SSAT), an essential enzyme in polyamine catabolic machinery, dramatically impaired EBR induced apoptosis .Urolithins, Walnut polyphenol metabolites have been shown to inhibit AR mediated upregulation of PSA in LNCaP cells Figure . Data obCurcumin analogues efficiently inhibited AR activity in prostate cancer cells .Pygeum africanum considerably blocked intramolecular amino/carboxy (N/C)-terminal interaction of the AR [Imidazopyridine derivatives have been shown to inhibit both PI3K/Akt and AR induced signaling in LNCaP cells . Atraricf the AR . Furanodf the AR . Shown iRosmarinus officinalis extract-treated 22Rv1 and LNCaP cells [C/EBP homologous protein was noted to be an essential regulator of AR degradation in aP cells . Levels aP cells . Shown iMurraya koenigii promoted shuttling of AR from nucleus to cytoplasm. Ligand-induced AR phosphorylation at Ser-81 was also notably repressed in Mahanine treated prostate cancer cells [AZD3514, an orally bioavailable drug has potent activity against AR induced signaling. AZD3514 exerted inhibitory effects on AR expression and ligand-driven nuclear accumulation of AR . Shown ier cells . Novel Ner cells .There is a recent research reporting newly identified surfaced exposed pocket on DNA binding domain of AR and targeting of this site considerably inhibited transcriptional activity of full-length AR and its splice variants . MethylsThere are some exciting pieces of evidences obtained from in-vitro studies that have started to shed light on the underlying mechanisms of enzalutamide resistance. Significant inhibition of AR nuclear accumulation by enzalutamide was documented in a wide ranging cell culture and pre-clinical studies. However, in a recent study nuclear accumulation of full length AR was noted in androgen depleted PCa cells expressing either AR-V7 or ARv567es. Mice inoculated with AR-V7-knockdown cells were sensitive to enzalutamide induced tumor growth inhibition. Serial passage of the relapsed tumors in enzalutamide treated castrated mice gave rise to the tumors that were enzalutamide resistant. RNA-seq analysis revealed upregulated expression of ARv567es and AR-V7 in resistant tumors .There is recent evidence suggesting that enzalutamide exposure induced glucocorticoid receptor (GR) expression in prostate cancer cells. Mechanistically it was shown that enzalutamide exerted growth inhibitory effects but co-treatment with Dexamethasone (Dex) reversed this growth inhibition. More importantly gene silencing of GR restored sensitivity of cancer cells to enzalutamide. Data obtained from ChIP-seq experiments indicated that AR bound DNA binding sites identified after DHT treatment were bound by GR after Dex treatment .AZD5363 and enzalutamide have been shown to delay development of resistance against enzalutamide in preclinical models. Combinatorial approach effectively induced regression of tumor in xenografted mice at time of castration .Enzalutamide exposure induced autophagic response in prostate cancer cells that operated through activation of AMP-dependent protein kinase (AMPK) and the suppression of mammalian target of rapamycin (mTOR). Gene silencing of AMPK inhibited autophagic response and induced apoptosis. Combinatorial approach consisting of enzalutamide and autophagy inhibitors notably inhibited tumor growth in mice orthotopically implanted with ENZA-resistant cells . HoweverThere is a direct piece of evidence emphasizing on the fact that Enzalutamide or bicalutamide increased macrophage infiltration in prostate cancer cells that resulted in an enhanced prostate cancer cell invasion. Mechanistically it was shown that Enzalutamide or bicalutamide downregulated AR-induced PIAS3 expression and enhanced pSTAT3-CCL2 signaling cascade. ASC-J9, an AR degradation enhancer exerted inhibitory effects on STAT3 phosphorylation/activation. CCR2 antagonist treatment also impaired Enzalutamide or bicalutamide mediated increase in cell invasion . It has Twist is involved in epithelial-to-mesenchymal transition and metastasis and a therapeutic target. Co-treatment with Enzalutamide and vaccine directed against Twist resulted in considerably enhanced overall survival of TRAMP mice . SteroidNiclosamide, an FDA-approved antihelminthic drug efficiently induced AR-V7 protein degradation and AR-V7 mediated transcriptional activity ,51. InhiIt is becoming progressively more understandable that AR gene rearrangements stimulated expression of truncated AR variant proteins lacking the AR ligand-binding domain and synthesis of full-length AR was repressed. AR variant proteins tactfully induced AR transcriptional network in the absence of full-length AR or androgens . It has It has also been highlighted in a recent report that androgen depletion considerably enhanced interactions between splicing factors and AR pre-mRNA as evidenced by identification of two RNA splicing enhancers and their binding proteins ASF/SF2 and U2AF65  promoter-driven ARv567es transgenic mouse was developed. Detailed analysis revealed that ARv567es induced epithelial hyperplasia after 16 weeks and invasive adenocarcinoma was noted after 1 year in mice ,34. AR-VIt is also interesting to note that although gene network reported to be regulated by full length AR and C-terminally truncated variant of AR is overlapping, there are some genes which are exclusively triggered by AR variant, specifically, RHOB which is shown to be involved in the increased migration , and thuClassical NF-κB intracellular signaling operating through p65/p50 heterodimer is constitutively activate in prostate cancer cells. Noncanonical NF-κB pathway involves the processing of p100 to NF-κB2/p52 and prostate cancer cells chronically treated with Enzalutamide have been shown to display higher levels of NF-κB2/p52. NF-κB2 expressing LNCaP and C4-2B cells had a higher expression of AR-V7 splice variant. NF-κB2 silencing in VCaP and CWR22Rv1 cells significantly reduced AR-V7 splice variant expression . It is iVav3, a Rho GTPase guanine nucleotide exchange factor is involved in enhancing transcriptional activity of AR3 and ARv567es. Interfering with Vav3 resulted in significantly reduced nuclear accumulation of AR3 and data obtained from co-immunoprecipitation assay revealed that Vav3 interacted with AR3 . In accoEmerging evidence as presented in this short review article clearly suggesting that the development of novel AR-targeting agents is not a distant possibility any more, and such developments are welcome news for PCa patients especially for those who develop CRPC and subsequent mCRPC after ADT. In the context of ADT especially the introduction of novel ADTs such as enzalutamide and abiraterone is a significant therapeutic advancement for the treatment of PCa; however, these agents are rapidly developing resistance largely contributed by the expression of AR variants and other resistance pathways. Therefore any developments of novel strategies for overcoming resistance to ADT or delaying and/or preventing the development of resistance would revolutionize in the better treatment of PCa patients after the surgical management.


Androgen receptors (ARs) play a critical role in the development of prostate cancer. Targeting ARs results in important salutary effects in this malignancy. Despite mounting evidence that ARs also participate in the pathogenesis and/or progression of diverse tumors, exploring the impact of hormonal manipulation of these receptors has not been widely pursued beyond prostate cancer. This review describes patterns of AR expression in a spectrum of cancers, and the potential to exploit this knowledge in the clinical therapeutic setting. Treatments targeting androgen receptors (ARs) have demonstrated efficacy in patients with prostate cancer. Despite a wealth of reports indicating that ARs may contribute to the growth and/or progression of numerous other malignancies, their precise role in cancers beyond those of the prostate is poorly understood. The aim of this review is to illuminate current data in the literature regarding the expression and functional impact of ARs in a range of solid tumors Table , and to The goal of androgen deprivation or suppression therapy is to reduce the levels of male hormones (androgens) . The majAndrogens stimulate AR+ cells to proliferate. Since the vast majority of prostate cancers are AR+, androgen deprivation (suppression) treatment was a rational approach for this malignancy, and has become a cornerstone of treatment for advanced prostate cancer Table  8]. And. And8]. Surgical removal of the testes (castration or orchiectomy).Luteinizing hormone-releasing hormone (LHRH) analogs . These drugs halt testosterone production by the testicles.Examples of these agents include leuprolide, goserelin, triptorelin, and histrelin . When LHLuteinizing hormone-releasing hormone (LHRH) antagonists. LHRH antagonists such as degarelix work like LHRH agonists, but they reduce testosterone levels more rapidly and do not induce a tumor flare like the LHRH agonists do .Anti-androgens. Anti-androgens impede the body's ability to use androgens, usually by blocking the androgen receptor. Even after orchiectomy or during treatment with LHRH analogs, the adrenal glands still synthesize small amounts of androgens. Drugs of this type include flutamide, bicalutamide, and nilutamide .Other androgen-suppressing drugs. Estrogens were once the main alternative to orchiectomy for men with advanced prostate cancer. Because of their toxic effects   and progesterone receptors (PR) are expressed in 33.3% (13/69) and 86.9% (60/69), respectively, in the pleomorphic adenoma subtype [S3]. AR positivity has also been documented in salivary duct carcinomas . Nasser et al. [S2] reported a series of 78 formalin-fixed, paraffin-embedded salivary gland tumors with strong positivity for AR in 100% (14/14) of carcinoma ex-pleomorphic adenomas and 100% (6/6) of salivary duct carcinomas. Fan et al. [S5] reported AR positivity rates as high as 92% (11/12) in salivary duct carcinomas. AR reactivity was also seen in 20% (2/10) of acinic cell carcinomas, 20% (2/10) of mucoepidermoid carcinomas, and 20% (2/10) of adenoid cystic carcinomas [S2]. In the same study all 26 benign salivary gland tumors were negative for expression of AR [S2].Remarkable similarities between breast cancer and salivary gland tumors have been documented [S1-S3]. Not only is HER2/In regard to treatment, Locati et al. [S7] reported a complete remission with androgen deprivation therapy in a patient with recurrent AR-expressing adenocarcinoma of the parotid gland. Kuroda et al. [S8] reported a partial response after one course of anti-androgen therapy and palliative chemotherapy with paclitaxel in a patient with advanced salivary duct carcinoma.BRAF, RAS and RET, all described in thyroid cancer, are not known to account for the gender disparity [S10].Thyroid cancer is the most frequently occurring endocrine-related malignancy . The most common form of thyroid cancer is papillary (~79%), followed by follicular (~14%), medullary (~2%), anaplastic (~1%) and other histological subtypes (~4%) [S11]. There are significant rates of recurrence with current therapeutic approaches such as surgery or radioactive iodine therapy [S9]. Because both benign and malignant thyroid lesions are more common in women than in men, it has been suggested that sex hormones play a role. Certainly somatic mutations in Bléchet et al. [S12] showed AR positivity by immunohistochemistry (IHC) in 14% (4/28) of medullary thyroid carcinomas. Testosterone increased dose-dependent proliferation of AR+ human papillary thyroid cancer cell lines; whereas flutamide, inhibited testosterone-induced cell proliferation [S13]. Wiseman et al. [S14] examined differentiated thyroid cancer and found AR+ in 50.5% (50/99) compared to 2% (2/100) of benign lesions. Prinz et al. [S15] showed AR+ in 17 of 31 cases of thyroid cancer, including 80% (4/5) of papillary carcinomas and 80% (4/5) of follicular adenomas. Despite high AR expression in thyroid cancer, there are only anecdotal reports of therapeutic hormonal manipulation [S16].Ishibashi et al. [S17] examined patients with thymoma and found AR+ nuclear immunoreactivity by IHC in 15% of patients (20/132). Mimae et al. [S18] studied thymic epithelial tumors (103 thymomas and 37 thymic carcinomas) and found that 23.6% expressed AR. The World Health Organization (WHO) classified epithelial thymic tumors into six types including A, AB, B1, B2, B3, and thymic carcinoma. Because the histological differential diagnosis between type B3 thymoma and thymic carcinoma can be challenging, Khoury et al. [S19] proposed that AR might be useful for pinpointing the diagnosis, particularly because cytoplasmic AR was found in 58.8% (10/17) of type B3 thymomas versus 0% (0/12) of thymic carcinomas [S19]. Preclinical data suggest that blocking AR with 5-alpha-dihydrotestosterone can initiate apoptosis in thymoma cells [S20].Several publications have documented that these benign hormone-dependent tumors, particularly the ones prone to affecting adolescent males, express AR . IHC results showed AR+ in 75% (18/24) of nasopharyngeal angiofibroma cases [S23]. Montag et al. [S24] showed that AR is expressed in 38.4% (5/13) of patients. These results translated to the clinic where 4 of 5 patients with juvenile nasopharyngeal angiofibroma demonstrated an average shrinkage of 44% following flutamide [S25].Bianchini et al. [S26] studied tissue from 15 patients with laryngeal carcinoma but found no expression of AR (0%) [S26]. Virolainen et al. [S27] found 10% (1/10) AR positivity in cell lines derived from laryngeal squamous cell carcinoma and 0% (0/9) AR positivity in non-laryngeal head and neck squamous tumors. Mattox et al. [S28] evaluated flutamide in patients with laryngeal carcinoma and, surprisingly, short-lived partial responses were seen in 3 of 9 patients. AR levels did not correlate with response [S28].AR reactivity was present in 40% of melanomas; however, it was also observed in 41% of normal skin [S29]. In contrast, a different report  discerned AR positivity in only 4% of cases [S30]. Morvillo et al. [S31] showed ARs in human melanoma cell lines, with tumor growth after exposure to dihydrotestosterone versus significant inhibition of proliferation after tamoxifen or flutamide [S32]. Ketoconazole, an androgen synthesis inhibitor, was shown to abrogate the metastatic potential of melanoma cell lines in mice [S33].Katona et al. [S34] and Izikson et al. [S35] reported AR expression in 65% (20/31) and 78% (25/32), respectively, of basal cell carcinoma cases; they suggested that the expression was high enough to help distinguish basal cell carcinoma from other skin conditions with low or negative AR expression, such as benign trichoblastic tumors and desmoplastic trichoepithelioma.Limited studies of AR in sarcomas have been performed.in vitro was stimulated by estradiol, progesterone, and 5 alpha-dihydrotestosterone; whereas growth was abrogated by AR antagonists as fulvestrant, mifepristone, and hydroxiflutamide. Interestingly, higher levels of AR correlated with a higher degree of differentiation. In preclinical models, the adrenal androgen synthesis inhibitor ketoconazole prompted apoptosis in human osteosarcoma cells [S38].AR+ has been demonstrated in 28.5% (8/28) to 50.8% (33/65) of osteosarcomas . Proliferation of osteosarcoma cell lines We were unable to find AR expression data regarding gastrointestinal stromal tumors in the literature . In 1980, Walker et al. [S41] reported steroid receptors in malignant skeletal malignancies, including four cases of osteosarcoma, two chondrosarcomas, one malignant giant cell tumor, and one Ewing's sarcoma. Cytoplasmic AR and PR were expressed in three of seven cases (43%) [S41]. Ziegler et al. [S42] found 0% (0/22) AR expression in tissue from 22 patients with Kaposi's sarcoma.There was no AR staining in embryonal carcinoma, mature teratoma, seminoma, or mixed germ cell tumors, although trace AR expression was found in 3 out of 5 cases of endodermal sinus tumors [S43]. In a small study of seminomas, AR expression was detected in 45% of cases (N = 18) [S44].vis-a-vis tumor shrinkage, but did prolong survival in the subgroup with hormonal receptor positivity. A phase II trial of flutamide, a nonsteroidal antiandrogen, in 25 patients with advanced renal cell cancer, demonstrated one partial response for more than nine months and two patients maintained stable disease for six and 15 months, respectively [S15]. AR expression was seen in 25% (3/12) of biopsied patients.AR expression has been demonstrated in 14.2% (3/21), 14.8% (27/182) and 42% (5/12) of renal cell carcinomas [S45-S47]. AR positivity was associated with a significantly better progression-free survival (PFS) compared to AR negativity in renal cancer [S45]. Brown et al. [S46] demonstrated AR immunoreactivity in 5 of 12 of patients with primary and in 1 of 5 of patients with metastatic clear cell renal cell carcinoma. Based on a small number of patients, Nakano et al. [S15] hypothesized that hormonal manipulation exerted no antineoplastic effect Because chemotherapy is effective in only a minority of patients with adrenocortical carcinomas, steroidogenesis inhibitors such as ketoconazole, mitotane, etomidate and metyrapone, have been used as single agents or combined with cytotoxic chemotherapy [S48]. Barzon et al. [S49] found that 38% (6/16) of patients with adrenocortical carcinoma were AR+ by IHC analysis. Rossi et al. [S50]] demonstrated AR RNA in human adrenocortical cancer cell lines. Ketoconazole reduces adrenal steroid biosynthesis by inhibiting cytochrome P450-dependent adrenal enzymes and is effective in reducing hormonal levels in virilizing adrenocortical carcinomas. However, generally no tumor shrinkage has been seen .in vitro as well as in vivo in mouse xenograft models with human AR-expressing bladder cancer cell lines attenuated proliferation and tumor growth [S56]. Hameed et al. [S57] assessed the combination of ketoconazole and all-trans retinoic acid in 16 patients with superficial bladder cancer, and demonstrated tolerable toxicity and reduced recurrence rate, albeit in the context of a small uncontrolled study.AR positivity has been found in 13% to 51% of bladder tumors [S53-S55] but not in normal bladder tissue [S55]. Loss of AR correlated with higher grade tumors [S55]; on the other hand, AR positivity was more frequent (71%) in metastatic disease than in primary tumors [S54]. There was no significant difference in the rate of AR positivity between men and women, despite the fact that bladder cancer is more common in men [S53]. Androgen blockage by flutamide The discussion of prostate cancer herein is limited as AR and prostate cancer has been reviewed extensively elsewhere. Briefly, prostate cancer is a prime example of the potential for therapeutically manipulating hormonal levels Table . This isKaiser et al. [S62] found AR expression in 70.5% (12/17) of non-small cell lung cancer cases. Rades et al. [S63] retrospectively found 31% (20/64) AR positivity in patients who received radiation for stage II/III non-small cell lung cancer.Kaiser et al. [S62] mentioned that hormonal receptor expression was almost non-existent in the small cell lung cancer cell lines. Maasberg et al. [S64], however, demonstrated growth stimulation by testosterone and growth inhibition by flutamide in selected AR+ small cell lung cancer cell lines.AR positivity has been found in 12.5% (2/16) to 39% (46/117) of gastric cancers [S65-S67]. AR positivity may correlate with poorer survival [S66].Yamashita et al. [S68] found AR positivity in two cases of human esophageal cancer xenografts implanted into nude mice; tumor progression was fueled by testosterone and inhibited by castration. Tihan et al. [S69] documented AR reactivity in 45% (5/11) of adenocarcinomas and 21.4% (3/14) of squamous cell carcinomas of the esophagus, respectively. Esophageal cancer seems to be more frequent in men than in women. However, no difference in the rate of positivity between genders was seen, though the numbers of patients were small, precluding definite conclusions. Interestingly, survival was similar regardless of AR status [S69]. Of possible interest, the Survival Epidemiology and End Results (SEER) registries database showed that patients with prostate cancer are less likely to develop esophageal adenocarcinoma [S70]. The relationship between these facts and treatment with androgen deprivation remains unexplored.Tumor progression in a nude mice xenograft model was stimulated by testosterone and inhibited by the anti-androgen cyproterone acetate [S71]. However, Targarona et al. [S72] found no AR expression in 12 biopsies of exocrine pancreatic neoplasia. A phase II study of the anti-androgen flutamide in an unselected population of 14 patients with advanced pancreatic adenocarcinoma yielded no objective responses [S73]. Subsequently, a randomized trial showed encouraging prolongation of median survival to 8 months in the flutamide group compared to 4 months in the placebo group [S74]. A counterpoint, however, is the fact that patients with advanced pancreatic carcinoma have lower than expected testosterone secondary to malnutrition and consumption [S75]. In a preclinical model Konduri et al. [S76] did not show any significant improvement from combining flutamide with gemcitabine or bevacizumab. Since estrogen receptors may also be expressed in pancreatic cancer; the relationship between androgen and estrogen, when designing clinical trials testing hormonal blockade, will be particularly important in malignancies that express both receptors .Tutton et al. [S79] confirmed that colon tumor cell proliferation was enhanced by testosterone and cell growth was attenuated by flutamide. Stebbing et al. [S80] found cytosolic AR in 39% (9/23) of rectal and 38% (5/13) of cecal adenocarcinomas. Several authors have described AR positivity in almost all samples of both colon tumors and normal mucose , while others have shown smaller, but still significant, percentage of AR positivity  [S83]. Further, ketoconazole has antiproliferative effects in human colon cancer cell lines [S84]. In preclinical rat models, cell proliferation in colon tumors was triggered by testosterone and inhibited by flutamide [S79]. However, the fact that normal colorectal mucosa expresses AR might blunt the usefulness of AR inhibitors in colorectal cancer.Ishizuka et al. [S85] documented AR expression in 52.9% (14/27) of patients with desmoid tumors. Goserelin, a gonadotropin releasing hormone agonist, resulted in stable disease in two patients with desmoid tumors for 4 and 16 months, respectively [S86]. Bauernhofer et al. [S87] reported a case of inoperable intra-abdominal desmoid tumor that decreased in size after treatment with goserelin acetate and low-dose tamoxifen for 17 months.In preclinical studies, testosterone stimulated proliferation of glioblastoma multiforme cell lines [S88]. Chung et al. [S89] documented AR positivity in 40% (4/10) of glioblastoma multiforme cases, 28% (5/18) of grade I/II astrocytomas and 75% (3/4) of anaplastic astrocytoma. Lee et al. [S90] found AR+ in 42% (8/19) of patients with meningioma.One study demonstrated the expression of AR by immunohistochemistry in 100% (30/30) of normal epithelium, 100% (30/30) of low-grade cervical intraepithelial neoplasia, and 63% (19/23) of high-grade cervical intraepithelial neoplasia, as well as in 23% (3/13) of invasive squamous cell carcinoma. The authors suggested the loss of AR expression is a common occurrence in malignant cervical transformation [S91]. Even so, the fact that significant subsets of gynecologic cancers express AR may have clinical relevance.Yang et al. [S92] found that AR positivity was the most robust variable associated with the risk of endometrial cancer. Ito et al. [S93] found AR reactivity in 88.6% (39/44) of endometrial carcinomas. Brys et al. [S94] found AR expression in 8% (1/12) of normal endometrium compared to 16% (4/25) of endometrial cancers. The reasons for this variability may relate to lack of standardized methodology.A review of 65 cases of uterine sarcoma revealed 0% (0/65) AR+ [S95]. In contrast, Moinfar et al. [S96] found AR reactivity in 45% (9/20) of malignant endometrial stromal neoplasms. As benign leiomyomas are responsive to hormonal manipulation; Leitao et al. [S97] showed AR expression in 32% (6/19) of benign uterine leiomyoma and in 40% (10/25) of uterine leiomyosarcoma. AR positivity was predictive of a lower risk of recurrence although, after controlling for stage, AR was not significantly associated with overall survival improvement [S97].Testosterone binding sites have been found in 43% of normal ovaries, 40% of benign ovarian tumors, and 60.5% of ovarian adenocarcinomas [S98]. Elattar et al. [S99] noted that AR-expressing epithelial cells in ascitic fluid from patients with ovarian cancer were stimulated by dihydrotestosterone and inhibited by bicalutamide. AR expression was significantly reduced in paired samples after chemotherapy which might explain the lack of response to hormonal blockade in heavily pre-treated patients [S99]. Jones et al. [S100] studied steroid cell ovarian tumors, finding AR immunoreactivity in 64% (9/14) of samples. High AR expression in 18% (28/154) of epithelial ovarian cancer was reported [S101]. Patients with AR-positive serous tumors had improved disease-specific survival [S101]. Additionally, reports of transsexuals who developed ovarian cancer in the setting of androgen supplementation suggest a carcinogenic role for AR [S102]. In regard to treatment, a phase II trial of goserelin and bicalutamide in 35 patients with epithelial ovarian cancer did not prolong PFS . Because chemotherapy reduces AR expression, anti-androgen therapy may be more effective early in the disease [S104]. One study demonstrated dissimilar AR reactivity within a single ovarian neoplasm, attesting to tumor heterogeneity [S105]. In a phase II trial, 32 patients with advanced ovarian neoplasia received a minimum of two months of flutamide resulting in one complete response for 73 weeks, one partial response for 44 weeks, and partial responses in 28% (9/32) for a median of 24 weeks [S106]. A case report documented a patient with Leydig cell ovarian tumor, an androgen-producing neoplasm, which responded to the GnRH-analogue triptoreline [S107]. Because androgen receptors are frequently expressed in epithelial ovarian cancer, investigation of newer anti-androgens in this disease may be worthwhile [S108].in situ [S115]. Breast cancer cell lines may be at least AR-dependent . Other preclinical studies in human breast cancer cell lines showed that AR overexpression induced tamoxifen resistance which was reversed by the AR antagonist bicalutamide [S118]. In regard to treatment, Gucalp et al. [S119] report on a multicenter phase II trial bicalutamide for patients with AR+/ER−/PR− breast cancer showed a clinical benefit rate of 19%.Peters et al. studied invasive breast ductal adenocarcinomas, finding 56% AR positivity by IHC, and expression was inversely associated with 10-year survival [S109]. In HER2/−positive breast malignancies, AR expression was found in 85.6% (89/104). AR-negative/estrogen receptor-negative was the most aggressive phenotype and correlated with high-grade tumors [S110]. Similarly, Hu et al. [S111] documented AR positivity in 78.7% of 1,467 patients with breast cancer. Pristauz et al. [S112] studied the relationship between AR and BRCA mutations in a population of patients constituted by 32% (43/135) BRCA1 and 13% (18/135) BRCA2. Interestingly, AR reactivity was seen in 30% (13/43) of BRCA1 and in 78% (14/18) in BRCA2, suggesting that many ER−/PR− BRCA-mutant tumors are actually AR positive [S112]. A higher number of breast carcinomas were found to express AR (77%) compared to ER (61%) and PR (60%) in 980 cases, with more than 50% of triple negative tumors expressing AR [S113]. The fact that AR+ was lost by the time of autopsy (5/11) implies loss of AR expression in end-stage metastases [S114]. From a molecular standpoint, Collins et al. [S115] studied 2,171 invasive breast malignancies with tissue microarrays, dividing them into luminal-A (64%), luminal-B (15%), basal-like (11%), and HER2 (6%). AR expression was seen in 77% of invasive breast malignancies divided into luminal-A (91%), luminal-B (68%), basal-like (32%), and HER2 (59%). Interestingly, AR expression was seen in 86% of 246 cases of ductal carcinoma Lessons from prostate cancer: During the last several decades, androgen deprivation Table  has beenFinally, there are novel therapeutic agents including the once-daily androgen receptor signaling inhibitor enzalutamide, previously called MDV3100 , 33  pathway has been hailed as a possible target for suppressing prostate malignancies Figure , as the While both EGFR and AR directly stimulate cell growth, AR apparently indirectly exerts stimulation of EGFR synthesis by paracrine or autocrine mechanisms . In addiOther mechanisms promoting resistance may include genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment in prostate cancer. The synthesis of constitutively active AR variants lacking the canonical ligand-binding domain may also promote resistance .AR is ubiquitously expressed across malignancies. Drawing definitive conclusions about rates of expression is however challenging, mainly due to the lack of standardized AR measurement methods and the relatively small number of patients tested for AR expression. Importantly, there is a paucity of studies of androgen manipulation in AR+ tumors other than prostate cancer. Importantly, some tumors such as salivary gland ductal tumors have AR positivity rates approaching 100%. Anecdotal reports and small studies in a variety of malignancies suggest that AR-positive tumors may respond to hormonal manipulation. Of interest, breast and gynecologic tumors also have high rates of AR positivity Table . Further


INa and ICa, slightly decreases by the suppression of IKr and IKs, and substantially increases by the suppression of IK1. Hyperkalemia affects the block formation in a complex, biphasic way. We provide examples of reentry formation due to the studied effects and have concluded that the suppression of IK1 should be the most effective way to prevent waveblock at the areas of abrupt change in anisotropy.Waveblock formation is the main cause of reentry. We have performed a comprehensive numerical modeling study of block formation due to anisotropy in Ten Tusscher and Panfilov (2006) ionic model for human ventricular tissue. We have examined the border between different areas of myocardial fiber alignment and have shown that blockage can occur for a wave traveling from a transverse fiber area to a longitudinal one. Such blockage occurs for reasonable values of the anisotropy ratio (AR): from 2.4 to 6.2 with respect to propagation velocities. This critical AR decreases by the suppression of  Cardiac arrhythmias are one of the largest causes of death in the industrialized world . In mostS1S2 stimulation. Later, two main classes of unaffected break formation mechanisms were identified. The first class deals with the wavebreaks that occur at the heterogeneity of cardiac tissue, which can either be due to the different properties of cardiac cells in different regions o from 5.4 mM to 20 mM.For most of the parameters of the TP06 model, which describes normal conditions, we used values listed in Tables 1 and 2 of , which cτ = 0.005 ms, the space step h = 125 μm, and flow di, dj ∈  and one of them is equal to zero. For example for Ji+1/2,0, di = 1/2 and dj = 0, etc. Here superscript indexes are related to time, and subscript—to space. Transmembrane potential was determined at the mesh points, whereas flow and coupling coefficients were set in half-integer nodes. In 2D simulations, we used , which is within the widely accepted values for ionic models o), typical for ischemia, affect the formation of blocks at the anisotropic boundary.Overall, we found that we can always obtain a waveblock at some critical AR, and its value decreases with an increase in the frequency of stimulation. In addition to frequency, other factors can also affect block formation. In the next section, we examine how the conductivity of main ionic channels and external conditions, such as elevation of the outer potassium concentration  on the critical AR see . In Fig INa affect the critical AR. We see that at low frequency and normal INa (the blue line), the critical ratio is 3.7. However, if the frequency increases to 2.5 Hz, the ratio decreases to 3.3. The minimal stimulation period under normal conditions in TP06 is about 300 ms, and for high frequencies, the critical AR decreases dramatically to approximately 2.9 and becomes heavily dependent on the stimulation rate. We also see that the decrease in GNa to 75%, 50%, and 25% progressively decreases the critical AR. This occurs for all frequencies of stimulation. For short periods, we also see that a block of INa results in a decrease of the critical AR, and the curves for lower values of INa are slightly above the curves for higher INa values. Quantitatively, for 75% of INa, the critical AR changes to 3.6 for long periods (3% decrease) and to approximately 2.7 for short periods (7%). If the GNa is further decreased to 50%, the ratio progressively decreases to 3.4 (9%) and 2.4 (17%) for longer and shorter periods respectively, and for 25% of GNa, the typical change is around 26% to 32%.GNa reduce the critical AR, the probability of block formation consequently increases. All of these results can be easily explained: the decrease in sodium current INa causes a decrease in the excitability of cardiac cells and results in a block formation.Therefore, one can see that as both frequency and ICaL affects block formation , the critical AR increases with a block of ICaL.We can explain such behavior as follows: the shifting of a vertical asymptote is caused by the effect of g of APD . For lonIKr and IKs separately to 75%, 50%, and 25% of their normal values. Rapid delayed rectifier current IKr (GKr is available (0.5% change), and APD slightly elongates , the cells were depolarized and demonstrated self-oscillations. In this research, however, we limited our study to moderate changes of the ionic current, and we concluded that a moderate inhibition of IK1 to 15–50% prevents block formation at low frequencies of stimulation and does not notably affect block formation at high frequencies of stimulation.The decrease of IK1 changes the critical anisotropy in an unexpected way, we performed additional simulations that highlighted the effects of IK1. In particular, we switched off IK1 at different phases of action potential formation and observed whether such modification eliminated the effects of IK1 change. As we can see in AR ≈ 6.0 at 1Hz and 25% GK1, while at 100% GK1 and 1Hz, the block occurs at AR ≈ 3.7.In order to investigate why the inhibition of IK1 only at the wavefront (set its conductance to 25% GK1 for dV/dt > 0), while for all other phases, we used 100% GK1. We found that the critical AR at 1Hz was AR ≈ 6.0. However, if we did the same for the repolarization phase only (25% GK1 for dV/dt < 0 and 100% GK1 for dV/dt > 0), the effect of the partial block of IK1 completely disappeared, and the block occurred at AR ≈ 3.7. Hence, we concluded that the change in the AR occurred because of the effects of IK1 during the upstroke of the action potential. To locate the exact phase of the upstroke, where the effect of IK1 is most important, we blocked it separately either before or after activation of INa. In our model, INa is activated if V > −50 mV. Therefore, we conducted similar simulations in which we either blocked IK1 on the upstroke when INa ≈ 0 (V < −50mV), or we did it for nonzero INa when V > −50mV. We found that in the first case, when IK1 was blocked before activation of INa, the critical AR ≈ 6.0, while in the second case, when IK1 was blocked after activation of INa, AR ≈ 3.7. Hence, we concluded that in normal conditions IK1 makes it more difficult to reach the excitation threshold of the tissue, and hence the reduction of IK1 makes front propagation possible over a wider range of AR. This can also explain why IK1 current, whose value is small compared to INa, can still have a substantial effect on wave propagation.First, we blocked K+ concentration results in a complex, nonmonotonous change in critical anisotropies (K+]o) for several stimulation frequencies. .Finally, we studied the effect of hyperkalemia , one of otropies . Before K+]o = 8 mM for 0.5 Hz and 4.6 for 1 Hz. A further increase of [K+]o until approximately 12 mM results in a steep decline of the critical AR until approximately 2.3 for 0.5 Hz and 2.2 for 1 Hz, which is even lower than under normal conditions. An additional increase of [K+]o does not influence block formation significantly. At high frequencies of stimulation (2.5 Hz), the critical AR is 3.4 under normal conditions and monotonically decreases to 1.6 with an increase of [K+]o.One can see that at low frequencies (0.5 Hz or 1 Hz), the critical AR starts growing from 3.72 under normal conditions to a maximum value of around 4.8 at [K+]o shifts the resting potential to less negative values. That, on the one hand, brings the resting potential closer to the excitation threshold. On the other hand, such depolarization results in partial inactivation of the sodium channels. As a result, we see an increase of the critical AR. However, a further increase in [K+]o substantially decreases the availability of sodium channels, which in turn decreases the excitability of cardiac cells and results in a decrease of the critical AR. These effects are apparent at low stimulation frequency. At high stimulation frequency, however, the sodium current is already partially suppressed, and thus, the first phase of the AR increase is absent.This complex behavior can be explained as follows: the increase of [K+]o = 8 mM, whereas the horizontal asymptote did not change significantly. This change corresponds with increased excitability, but no change in APD , and b, c, and d are free parameters. The values of the parameters for all curves shown in Figs All the dependencies above were fitted with the following function:In previous sections, we have shown that a waveblock can occur at the border between areas with orthogonal fiber orientation. Here, we analyze how this waveblock can result in sustained patterns of excitation.K+]o = 10 mM). It is possible to initiate the reentry in similar systems under normal conditions, but the AR should be two times higher  should be the most effective in arrhythmia prevention. On the contrary, class I (blocking INa) and class IV (blocking ICa) antiarrhythmic agents increase the probability of block formation, decreasing critical anisotropy and critical frequency. Class III (affecting IKr) antiarrhythmic drugs play no part in our block formation scenario.Our main conclusion is that such a block is possible, and that it occurs for reasonable values of the AR (between 2.4 and 6.2 with respect to the velocities of propagation). Changes in the conductivity of ionic currents have a substantial effect on the critical AR. From the results explained above, Note that the waveblock in this situation occurs only for the waves propagating from the region with slower propagating velocity to the region with faster propagating velocity, since density of the current decreases at such a boundary. If the wave propagates in the opposite direction  and ICa (with nifedipine), or in hyperkalemia (in a media with higher K+ concentration). For human cardiac cells, a similar study could potentially be done using IPS cells o concentration; (List 2) contains dependencies of AR on [K+]o with fixed stimulation frequencies. These data were used in Figs The table contains pairs of periods of stimulation ((XLSX)Click here for additional data file.


While this evidence is extremely encouraging, it is still preliminary. A number of key studies need to be completed before solithromycin’s true potential for use in pregnancy can be ascertained.Intrauterine infection–inflammation is a major cause of early preterm birth and subsequent neonatal mortality and acute or long-term morbidity. Antibiotics can be administered in pregnancy to prevent preterm birth either prophylactically to women at high risk for preterm delivery, or to women with diagnosed intrauterine infection, prelabor rupture of membranes, or in suspected preterm labor. The therapeutic goals of each of these scenarios are different, with different pharmacological considerations, although effective antimicrobial therapy is an essential requirement. An ideal antibiotic for these clinical indications would be (a) one that is easily administered and orally bioactive, (b) has a favorable adverse effect profile (devoid of reproductive toxicity or teratogenicity), (c) is effective against the wide range of microorganisms known to be commonly associated with intra-amniotic infection, (d) provides effective antimicrobial protection within both the fetal and amniotic compartments after maternal delivery, (e) has anti-inflammatory properties, and (f) is effective against antibiotic-resistant microorganisms. Here, we review the evidence from clinical, animal, and  Preterm infants are at high risk of adverse outcomes, including both acute and long-term disability and death –4. EvideIn order to successfully prevent intra-amniotic infection-associated preterm birth and associated neonatal sequelae, an effective antibiotic therapy needs to be a core component of any pharmaceutical solution. Ideally an antibiotic administered antenatally for preterm birth prevention should (a) be easily administered and orally bioactive; (b) have a favorable adverse effect profile in pregnancy (devoid of reproductive toxicity or teratogenicity); (c) exhibit efficacy against the wide range of microorganisms known to be commonly associated with intra-amniotic infection; (d) be able to provide effective antimicrobial protection within both the fetal and amniotic compartments after maternal delivery; (e) possess anti-inflammatory properties; and (f) be effective against antibiotic-resistant microorganisms.solithromycin. We suggest that solithromycin is the first antibiotic that may meet all of the above-mentioned criteria and as such has the potential to represent an exciting and major new advance in obstetric and perinatal medicine. We highlight the key indications where solithromycin may be of most benefit, and identify areas where further research is needed in order to facilitate the introduction of solithromycin into obstetric practice.In this review, we discuss the key properties, benefits, and potential obstetric and perinatal applications of the novel antibiotic Intrauterine infection and inflammation play a well-recognized role in the etiology of spontaneous preterm labor and birth, particularly in early preterm deliveries or those complicated by preterm prelabor rupture of membranes (PPROM) , 9, 12. Ureaplasma parvum, Ureaplasma urealyticum, and Mycoplasma hominis, are the most common group of microorganisms isolated from the amniotic cavity of preterm deliveries  or Ureaplasma spp.   . High coUreaplasma spp. infection and prevents fetal inflammatory response  for the treatment of community-acquired pneumonia and a variety of other indications , 57. It asma sp. , 71.Like other macrolides, solithromycin contains a 14-atom lactone ring structure and selectively binds to the peptide exit tunnel of the bacterial ribosome, blocking subunit assembly, and mRNA translation and protein synthesis . It has Ureaplasma spp., Mycoplasma spp., Group B streptococci, staphylococci, and Chlamydia trachomatis .Solithromycin has been shown to exhibit excellent activity against many of the microbial species known to be associated with infection-associated preterm delivery Table , includichomatis , 73, 74.in vitro . ImportaNeisseria gonorrhoeae infection at oral, rectal, and genital sites . Al. Alex vipartment  suggestspartment A (82). LImportantly, we have also shown in sheep that significant solithromycin levels in the amniotic cavity (the primary site of infection in this context) are achieved after maternal administration Figure A 82); r; r82); rMacrolides  are considered safe to use in pregnancy and have been administered to pregnant women for decades. Two recent, large studies of pregnancies in Canada and Israel  reported no evidence of congenital malformations  associated with antenatal exposure to erythromycin, azithromycin, or clarithromycin  , 84. ExpA potential concern around increased risk of congenital heart disease and maternal erythromycin exposure  was raised in a study by Kallen , again uNevertheless, if solithromycin is to be administered in pregnancy, it needs an excellent safety profile, particularly in light of its ability to cross the placenta (unlike other macrolides) that could theoretically increase the potential for adverse fetal effects. Studies to date show that its tolerability is high and its side-effects profile is favorable compared to other antibiotics. A phase 2 comparator study in adults showed that at the standard oral dose the most common adverse event was diarrhea (4.7%) followed by flatulence and nausea (1.6% each); no cardiac or neurological side effects were reported and the adverse event rate was significantly lower than in patients taking levofloxacin . In a seAvailable data suggest that the risks of developmental toxicity and/or teratogenesis with solithromycin are extremely low. The effects of orally administered solithromycin on male and female fertility and early embryonic development to implantation have been evaluated in rats and rabbits (Cempra Inc.: unpublished findings on file). No changes were noted in estrus cycles or sperm parameters in the Segment I study at the maximum dose tested (220 mg/kg). In Segment II studies, some maternal toxicity was observed at the highest dose . The “no observed adverse effect limit” for developmental toxicity was 110–220 mg/kg. No evidence of a teratogenic effect on the fetuses was evident in any treatment group.in vitro genetic toxicology assays and was not mutagenic or clastogenic in any of these assays. In our recent sheep studies, solithromycin-treated animals exhibited no clear evidence of hepatotoxicity  after exposure to a non-infectious inflammatory stimulus -9 expression) in human monocytes and peripheral blood mononuclear cells at concentrations ~10–40 μM , 107. Imstimulus . Solithrstimulus . These fin vitro study of human placental tissues, we confirmed the anti-inflammatory properties of solithromycin in human placentas, reporting inhibition of pro-inflammatory cytokine production by the antibiotic; however, this effect was only observed at relatively high concentrations  at which a decline in cell viability was observed in this model  supplied the solithromycin used in the pertinent studies included in this review, and provided comments on the manuscript, but had no involvement in the design of the studies or the analysis of the data. 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.


Burn injuries are a huge public health issue for children throughout the world, with the majority occurring in developing countries. Burn injuries can leave a pediatric patient with severely debilitating and deforming contractures, which can lead to significant disability when left untreated. Rehabilitation is an essential and integral part of pediatric burn treatment. The aim of this article was to review the literature on pediatric burn rehabilitation from the Medline, CINAHL, and Web of Science databases. An attempt has been made to present the basic aspects of burn rehabilitation, provide practical information, and discuss the goals and conceptualization of rehabilitation as well as the development of rehabilitation philosophy and strategies. It has been reported that over half a million children are hospitalized with burn injuries each year throughout the world, with the majority occurring in developing countries. The injuries can lead to severe functional, social, and psychological impairment.–3 PediatIn this article, we reviewed literature from the Medline, CINAHL, and Web of Science databases. We herewith share the basic aspects of burn rehabilitation, provide practical information, and discuss wider issues such as the goals of rehabilitation, the conceptualization of rehabilitation, and the development of rehabilitation philosophy and strategies.Human development and behavior emerge from active engagement with the surrounding world. Embodiment refers to the self-organizational grounding of complex systems in physical experience and interactions. Thus, embodiment is the claim that our perception, body awareness, thinking, feelings, self-consciousness, desires, and motivations, that is to say the way we behave, experience, and live in the world are contextualized by our being active agents with this particular type of body One currTo emphasize children’s embodied experiences in pediatric rehabilitation, we have focused on family-centered, relationship-based, activity-focused, and positive feedback interventions as the central principle of the well-being of the child and his/her family. Family-centered and relationship-based interventions are provided to allow the patients to feel like genuine partners of the medical staff in their treatment and rehabilitation process. Rehabilitation should be thoroughly committed to collaborating with children and their families in all aspects of patient care. Within this partnership, the opinions of the patients and their families are recognized and respected. Activity-focused interventions are consistent with the current models of intervention for children with disabilities and handicaps. In these interventions, effective movement experiences are at the heart of active motor learning processes in the acquisition of developmental skills that are important for daily activities. A passive approach typically consists of the interventions directed toward reducing secondary impairments such as joint limitations or soft-tissue contractures associated with muscle tone disorders. However, it is not administered within the context of purposeful activities. Intrinsic motivation is more desirable and results in better functional activity and outcomes; patients are more likely to engage in the task willingly and to work to improve their skills, which will increase their functional activities and capabilities. Previous studies suggest that positive feedback can increase intrinsic motivation in comparison to lack of positive feedback or negative feedback. Additionally, positive feedback is related to self-efficacy and intrinsic motivation. These intervention rules are derived from one of the most important theories of child education developed by Vygotsky, known as the Zone of Proximal Development (ZPD). The ZPD More recently, based on motor control and learning principles, the emphasis has been shifted away from paying attention to what was thought to be the underlying cause of a child’s movement difficulties to models that emphasize the importance of motor learning within the context of performing tasks. Therapeutic approaches focusing on changing the task and the environment rather than a child’s impairments can be a viable treatment strategy. A task-oriented approach is based on models of the motor learning principles of spaced practice and intermittent feedback and is used to facilitate real-world activities. This approach involves the practice of goal-directed, functional movement and is performed in a natural environment. In addition, it involves a variety of practices to help patients derive optimal control strategies for solving motor problems. Such active training in functional tasks within a meaningful environment is known to improve motor control, functional recovery, and strength. Therapeutic activities should vary and enhance the patient’s active participation. The setup of the environment should include all factors that might regulate a specific task practice. Lastly, appropriate feedback should be available to enhance both motor learning and relearning processes.It is very important that pediatric burn units realize the need for a child psychiatrist and a psychotherapist in their rehabilitation team. Good psychotherapy along with burns-related treatment will go a long way to enhance the QOL of these patients. To creatBurn rehabilitation should start at the time of the burn injury to achieve optimal individual functioning, activity, and long-term QOL. Early rehabilitation focused on long-term goals, with a collaborative team approach, is very important to prevent post-acute sequelae, such as scarring and joint contractures, and to achieve early functional recovery. Better rehabilitation goals are achieved using treatments such as pain control, pressure garments, splinting and positioning, exercise, and ongoing mental and psychosocial support and education of the child and his/her family.The most important point is that burn rehabilitation is a multidisciplinary, coordinated team approach with the family at the center. A multidisciplinary team is required in every recovery stage because the treatment and care of a child with a burn injury includes the child’s physical and psychological state as well as complex family and social issues. A multidisciplinary team including doctors, nurses, occupational and physical therapists, social workers, psychiatrists, music therapists, play therapists, teachers, and volunteers is involved in assessing and planning the medical care and rehabilitation process for the child and his/her family . ComprehEducating and providing information to the family can prevent misunderstanding about the physical treatment and alleviate stress and anxiety about post-burn psychological and emotional responses.,13According to the ICF model, impairments in body structures and functions are consequences of a disorder or pathological process. Physiologic functions of the body and its structures are lead functional limitation of the child’s daily activities and participation involved in routines of social life. Hypertrophic scarring is common following a burn injury and may cause significant functional and cosmetic impairment. Scar management following a burn injury is a long and often painful process; it is not something that can be carried out for a few weeks and then abandoned, but is something that must continue for many months to minimize post-burn complications. There is no consensus regarding the best treatment to reduce or prevent hypertrophic scarring. However,Early commencement of rehabilitation is the key to compliance with treatment and maximizing long-term outcome. Children with burn injuries suffer severe pain at the time of the burn and during treatment and rehabilitation. As pain has adverse physiological and emotional effects and slows down the functional recovery process, pain management is essential to better outcomes during all stages of treatment and rehabilitation.,17 The pA burn injury can be a traumatic experience with social, physical, and psychological consequences.,20 Most Continuing rehabilitation after discharge from a hospital environment is required to ensure the functional recovery and social reintegration of patients and their families. Effective discharge planning can aid functional recovery, and the patients can continue their improvement outside of a hospital setting in a more home-like and social environment. Following treatment and rehabilitation during the hospital stage, physical complications are particularly challenging in pediatric patients. It is well recognized that programs based on exercise therapy can have a significant impact upon children’s physical and psychosocial well-being.During the rehabilitation process, information about the daily lives of the children and their families should be obtained for different environments, such as the home and school, and family relations; lifestyles, and socioeconomic and cultural factors should also be considered. The most significant limitations of the long-term QOL for burned children do not appear to be functional impairment, but rather physiological issues and social participation. The disfigurement, unhappiness with their appearance, social anxiety, maladaptive coping, and social discomfort are more likely to influence long-term QOL, compared to the physical results of severe burn injuries. Monitoriet al., suggested that the key elements for psychosocial support following burn injury in a family support program are (a) normalizing the family member’s reactions to the burn; (b) advice, support, and information regarding scar permanence, realistic outcome expectations, acceptance of altered appearance, and potential aftereffects of the burn; (c) support in understanding how a burned individual may change or respond following injury and advice regarding constructive methods of coping with altered family dynamics and aftereffects of burns; and (d) advice to enable family members and their burned relatives to effectively address potentially uncomfortable social encounters.[Burned children reported lowered QOL, particularly related to scarring and appearance; however, they reported normative self-concept. This may be because of self-concept being a psychological trait, whereas Health Related Quality of Life (HRQoL) is influenced by societal norms and expectations. Psychosocial support is necessary to build positive coping strategies and manage the unpleasant social experiences that may reduce QOL. Long-tercounters.Return to normal daily activities, such as attending school, should be encouraged and supported by return-to-school visiting programs and burnRecently, pediatric burn rehabilitation has been focused on meaningful, practical, sustainable activities that relate to the child’s social life. Burn injuries present significant barriers to community integration, but many children can successfully return to school and other activities. All members of a burn management team interact throughout a child’s recovery and social integration period, from the burn onset to the long term. Pediatric burn rehabilitation is not only about minimizing the effect of physical impairment but also helping the burned children gain independence in the community and improving the QOL of the children and their families.