Re-Densification Effect of Pressure-Injected Peptide-Hyaluronic Acid Combination on Male Androgenic Alopecia

Introduction: Mechanism of male androgenic alopecia (MAGA) is complex and leads to an excessive hair shedding and decreased hair density. Oral, topical, and injectable autologous treatments demonstrate ability to stimulate hair re-growth, but the response is suboptimal or plateaus off. Synthetic combination of the peptide complex and hyaluronic acid (P-HA) demonstrated hair regrowth in alopecia patients. Electronically-operated pneumatic injections (EPI) generate micro-trauma in the dermis and under wound-healing conditions may enhance regeneration effect of P-HA. Methods: Subjects seeking improvement of their male pattern hair loss (Hamilton-Norwood type 2-4) received the P-HA treatments through EPI. The course included 4 treatments every two weeks over the 8-week period. In 6 months, the hair growth was assessed comparative to baseline by global clinical photography and digital phototrichograms. The treatment safety and tolerability were documented through the whole study period. Results: Twelve men (30-45 years old) completed the treatment course with high tolerability and without adverse events. Post-treatment assessment of the previously bald areas showed improved coverage on the clinical photographs. The phototrichograms demonstrated statistically significant increase in terminal hair density by 36%, cumulative hair thickness by 37%, and follicular units by 20%;all contributing to a 38% increase in cumulated hair density (all p Conclusion: Electronic pneumatic injections are well tolerated and can be safely used for the needle-free administration of the peptide-hyaluronic acid combination in MAGA therapy. We achieved significant hair re-densification in the balding scalp. The exact role of the EPI-induced impact in the hair re-growth mechanism remains to be ascertained. .

The Pathogenesis and Treatment Progress of Androgenic Alopecia

Androgenic alopecia, also known as seborrheic alopecia, is the most common hair loss disorder in dermatology clinics, mainly characterized by hair follicle miniaturization and progressive hair loss. The etiology and pathogenesis of androgenic alopecia are not clear, but may be related to heredity and androgen metabolism. Currently, minoxidil and finasteride are the only two drugs approved by the U.S. Food and Drug Administration (FDA) for AGA treatment, other treatments include oral minoxidil, hair transplantation, low energy laser therapy (LLLT), platelet-rich plasma (PRP), Chinese medicine microneedles, and combination therapy. With the development of medicine and science, we have ushered in the era of biologics and targeted therapy. In recent years, a variety of signaling pathways for androgenic alopecia have been found, which may provide a basis for targeted therapy for androgenic alopecia.

Specific alterations of regional myocardial work in strength-trained athletes using anabolic androgenic steroids compared to athletes with genetic hypertrophic cardiomyopathy

Background:Strength-trained athletes using anabolic androgenic steroids(AAS)have left ventricular(LV)hypertrophy and myocardial fibrosis that can lead to sudden cardiac death.A similar feature was described in athletes with hypertrophic cardiomyopathy(HCM),which complicates the diagnosis for clinicians.In this context,we aimed to compare the LV function of the 2 populations by measuring global and regional strain and myocardial work using speckle-tracking imaging.Methods:Twenty-four strength-trained asymptomatic athletes using AAS(AAS-Athletes),22 athletes diagnosed with HCM(HCM-Athletes),and 20 healthy control athletes(Ctrl-Athletes)underwent a resting echocardiography to assess LV function.We evaluated LV global and regional strains and myocardial work,with an evaluation of the constructive work(CW),wasted work,and work efficiency(WE).Results:Compared to Ctrl-Athletes,both AAS-Athletes and HCM-Athletes had a thicker interventricular septum,with maj ored values in HCM-Athletes.LV strain was reduced in AAS-Athletes and even more in HCM-Athletes.Consequently,global WE was significantly diminished in both AAS and HCM-Athletes(93%±2%in Ctrl-Athletes,90%±4%in AAS-Athletes,and 90%±5%in HCM-Athletes(mean±SD);p<0.05).Constructive work and WE regional analysis showed specific alterations,with the basal septal segments preferentially affected in AAS-Athletes,and both septal and apical segments affected in HCM-Athletes.Conclusion:The regional evaluation of myocardial work reported specific alterations of the major LV hypertrophy induced by the regular use of AAS compared to the LV hypertrophy due to HCM.This finding could help clinicians to differentiate between these 2 forms of pathological hypertrophy.

Clinical Study on Application of Xinrun Tongluo Method Based on the Theory of Collateral Diseases in Treating Androgenic Baldness of Blood Heat Wind Dryness Syndrome

[Objectives]To explore the intervention effect of the representative formula of Xinrun Tongluo method,Liangxue Xiaofeng Powder,on the incidence of androgenic alopecia in the syndrome of blood heat and wind dryness.[Methods]A total of 72 patients with androgenic alopecia in Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine from October,2022 to June,2023 were randomly divided into a control group(36 cases,treated with Western medicine)and a treatment group(36 cases,treated with Chinese herbal formula+Western medicine).The short-term and long-term efficacy of the two groups of patients was compared.[Results]The hair microscopic signs and short-term and long-term efficacy of the treatment group were significantly better than those of the control group before and after treatment,with a statistically significant difference(P<0.05).[Conclusions]The representative formula of Xinrun Tongluo method is Liangxue Xiaofeng Powder,which has better clinical efficacy as an auxiliary Western medicine in the treatment of androgenic alopecia patients with blood heat and wind dryness syndrome,and is worthy of further promotion and application in clinical practice.

Evaluation of androgenic activity of Zingiber officinale and Pentadiplandra brazzeana in male rats

Aim: Aqueous extracts of Zingiber officinale and Pentadiplandra brazzeana were tested for their possible androgenic activity in male Wistar rats. Methods: The aqueous extracts of the two plants were gavaged separately to 2 groups of rats at a similar dose of 600 mg.kg^1.day-1 for 8 days. At the end of the treatment, the animals were killed and the blood, testis, epididymis, seminal vesicles and prostate were collected for biochemical analysis. Results: The aqueous extract of Z. officinale significantly increased in the relative weight of the testis, the serum testosterone level, testicular cholesterol level and epididymal α-glucosidase activity. The aqueous extract of P. brazzeana significantly increased the weights of the testis, seminal vesicles and prostate. It also significantly increased the serum and testicular testosterone level. The fructose, α-glucosidase and cholesterol levels in P. brazzeanatreated rats were increased by 28%, 35% and 114%, respectively. Conclusion: The aqueous extracts of both P. brazzeana and Z. officinale have an androgenic activity, which seems to be more potent with P. brazzeana than with Z. officinale. (Asian J Androl 2002 Dec; 4: 299-301)

An Assessment of Androgenic/Anti-androgenic Effects of GH Transgenic Carp by Hershberger Assay

Objective To evaluate the androgenic and anti-androgenic effects of GH （growth hormone） transgenic carp in male rats.Methods Hershberger assay was carried out in castrated male SD rats aged 4-5 weeks.Testosterone propionate （TP） （0.4 mg/kg BW） was administrated for a positive control,GH transgenic carp （3.0 g/kg BW）＋TP （0.4 mg/kg BW）,parental carp （3.0 g/kg BW） ＋ TP （0.4 mg/kg BW）,and flutamide （Flu） （3.0 g/kg BW） were used for negative controls,and vehicle was administered orally for a blank control.All groups were administrated for 10 consecutive days.At the end of the test,animals were anesthetized,then weights of accessory sex organ were measured.Serum testosterone （T）,luteinizing hormone （LH）,and Follicle-Stimulating Hormone （FSH） levels were detected.Results The weights ratios of the accessory sex organs and body weights showed no significant differences between the solvent control and the GH transgenic carp-treated groups.Serum concentrations of FSH,LH,and T of the rats treated with GH transgenic carp ＋ TP showed no significant changes,compared with those treated with TP only.Conclusion GH transgenic carp does not have any androgenic agonist or antagonist properties in vivo screening tests.

Primary molecular basis of androgenic gland endocrine sex regulation revealed by transcriptome analysis in Eriocheir sinensis

In crustaceans, the male sexual dif ferentiation and maintenance are specially regulated by androgenic gland(AG). However, little is known about the genes involved in the regulation process.RNA-Seq was performed on AG with ejaculatory duct(AG_ED) and ejaculatory duct(ED) as control in Eriocheir sinensis, one of the most important economic and ?shery crabs with typically sex dimorphism. A total of 925 unigenes were identi?ed as dif ferentially expressed genes(DEGs) and the expression of nine genes randomly selected was con?rmed by qRT-PCR. 667 unigenes were up-regulated in AG_ED, being supposed to be AG preferential genes. Among them, the full length of i nsulin-like androgenic gland factor( IAG) cDNA named as Es-IAG was obtained as a logo gene of AG, which together with the genes i nsulin-like receptor( INR), and s ingle insulin binding domain protein( SIBD), might constitute the sex regulation pathway. Several sex related genes were identi?ed, and their function will have to be investigated. Also,the identi?cation of j uvenile hormone epoxide hydrolase 1( JHEH1), ecdysteroid 22-hydroxylase( DIB) and e cdysone receptor( ECR) preliminarily clari?ed the molecular regulation mechanism of eyestalk-AG-testis axis, which plays important roles in molting and reproduction. The results will enhance our understanding for the molecular basis of the AG involved in male sex regulation in crabs.

Histological Characterization of Peppermint Shrimp (Lysmata wurdemanni) Androgenic Gland

The androgenic gland(AG) is an important endocrine gland for male reproductive function in crustaceans. In the present study, we investigated the histological characteristics of the androgenic gland of peppermint shrimp, Lysmata wurdemanni. The peppermint shrimp matures as male first, then some individuals may become euhermaphrodite after several moltings(transitional phase). Euhermaphrodite-phase shrimp acts as male at intermolts. However, it can be fertilized as a female immediately after molting. Considering the male reproductive function acts in its lifespan except for at larval stages, and female reproductive system starts to develop at transitional phase, we hypothesized that AG activity might be reduced to allow and promote vitellogenesis onset in early transitional phase and the following euhermaphrodite phase. So AG cell structure might be different in three phases in L. wurdemanni. The results showed that AG exists in the male in transitional and euhermaphrodite phases. The gland cell clusters surrounding the ejaculatory ducts locate at the roots of the fifth pereopods. The nucleus diameters are similar in the three phases while the nucleus-to-cell ratio is the lowest in euhermaphrodite phase. Our results indicated that for the individuals that will become euhermaphrodite, the cellular structure of AG changes since transitional phase. Male reproductive function which is still available in euhermaphrodite-phase shrimp should be due to the existence of the gland.

Androgenic regulation of novel genes in the epididymis

The epididymis is critically dependent on the presence of the testis. Although several hormones, such as retinoids and progestins, and factors secreted directly into the epididymal lumen, such as androgen binding protein and fibroblast growth factor, might play regulatory roles in epididymal function, testosterone （T） and its metabolites, dihydrotestosterone （DHT） and estradiol （E2）, are accepted as the primary regulators of epididymal structure and functions, with the former playing the greater role. To ascertain the molecular action of androgens on the epididymis, three complementary approaches were pursued to monitor changes in gene expression in response to different hormonal milieux. The first was to establish changes in gene expression along the epididymis as androgenic support is withdrawn. The second was to determine the sequence of responses that occur in an androgen deprived tissue upon re-administration of the two metabolites of T, DHT and E2. The third was to study the effects of androgen withdrawal and re-administration on gene expression in immortalized murine caput epididymidal principal cells. Specific responses were observed under each of these conditions, with an expected major difference in the panoply of genes expressed upon hormone withdrawal and re-administration; however, some key common features were the common roles of genes in insulin like growth factor/epidermal growth factor and the relatively minor and specific effects of E2 as compared to DHT. Together, these results provide novel insights into the mechanisms of androgen regulation in epididymal principal cells. （Asian J Androl 2007 July; 9： 545-553）

Bulbocavernosus muscle area measurement： a novel method to assess androgenic activity

Serum testosterone does not correlate with androgen tissue activity, and it is critical to optimize tools to evaluate such activity in males. Ultrasound measurement of bulbocavernosus muscle （BCM） was used to assess the relationship between the number of CAG repeats （CAGn） in the androgen receptor （AR） and the BCM size; the changes in the number of CAGn over age were also evaluated. Transperineal ultrasound measurement of the BCM was also performed. AR CAGn were determined by high performance liquid chromatography, and morning hormone levels were determined using immunoassays. Forty-eight men had CAG repeat analysis. Twenty-five were 〈30 years of age, mean 23.7 years （s.d, = 3.24） and 23 were 〉45 years of age, mean 53years （s.d. = 5.58）. The median CAGn was 21 （13-29）. BCM area was greater when the number of CAGn were 〈18 as compared to the number of CAGn 〉24 （P= 0.04）. There was a linear correlation between the number of CAGn and the BCM area R^2= 16% （P= 0.01）. In the 45 to 65-years-old group, a much stronger negative correlation （R^2 = 29%, P= 0.01） was noticed. In the 19 to 29-years-old group, no such correlation was found （R2 = 4%, P = 0.36）. In older men, the number of CAGn increased with age （R^2 = 32%, P= 0.01）. The number of CAGn in the AR correlates with the area of the BCM. Ultrasound assessment of the BCM is an effective surrogate to evaluate end-organ activity of androgens. The number of CAGn may increase with age.

An androgen induced hyperinsulinemic and hyperandrogenic anovulatory rat model

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Anabolic androgenic steroid-induced liver injury:An update

Anabolic androgenic steroids(AASs)are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic effects.These properties make them therapeutically beneficial in medical conditions such as hypogonadism.However,they are commonly bought illegally and misused for their anabolic,skeletal muscle building,and performanceenhancing effects.Supraphysiologic and long-term use of AASs affects all organs,leading to cardiovascular,neurological,endocrine,gastrointestinal,renal,and hematologic disorders.Hepatotoxicity is one of the major concerns regarding AASs treatment and abuse.Testosterone and its derivatives have been most often shown to induce a specific form of cholestasis,peliosis hepatis,and hepatic benign and malignant tumors.It is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors,upregulation of bile acid synthesis,and induction of hepatocyte hyperplasia.Most toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of AAS.However,some long-term consequences are irreversible.AAS-induced liver injury should be taken in consideration in patients with liver disorders,especially with the increasing unintentional ingestion of supplements containing AAS.In this paper,we review the most current knowledge about AAS-associated adverse effects on the liver,and their clinical presentations,prevalence,and pathophysiological mechanisms.

A combination therapy for androgenic alopecia based on quercetin and zinc/copper dual-doped mesoporous silica nanocomposite microneedle patch

A nanocomposite microneedle(ZCQ/MN)patch containing copper/zinc dual-doped mesoporous silica nanoparticles loaded with quercetin(ZCQ)was developed as a combination therapy for androgenic alopecia(AGA).The degradable microneedle gradually dissolves after penetration into the skin and releases the ZCQ nanoparticles.ZCQ nanoparticles release quercetin(Qu),copper(Cu^(2+))and zinc ions(Zn^(2+))subcutaneously to synergistically promote hair follicle regeneration.The mechanism of promoting hair follicle regeneration mainly includes the regulation of the main pathophysiological phenomena of AGA such as inhibition of dihydrotestosterone,inhibition of inflammation,promotion of angiogenesis and activation of hair follicle stem cells by the combination of Cu^(2+)and Zn^(2+)ions and Qu.This study demonstrates that the systematic intervention targeting different pathophysiological links of AGA by the combination of organic drug and bioactive metal ions is an effective treatment strategy for hair loss,which provides a theoretical basis for development of biomaterial based anti-hair loss therapy.

Characterization of distinct microbiota associated with androgenetic alopecia patients treated and untreated with platelet-rich plasma(PRP)

Background:Androgenic alopecia(AGA)is the most common type of hair loss in men,and there are many studies on the treatment of hair loss by platelet-rich plasma(PRP).The human scalp contains a huge microbiome,but its role in the process of hair loss remains unclear,and the relationship between PRP and the microbiome needs further study.Therefore,the purpose of this study was to investigate the effect of PRP treatment on scalp microbiota composition.Methods:We performed PRP treatment on 14 patients with AGA,observed their clinical efficacy,and collected scalp swab samples before and after treatment.The scalp microflora of AGA patients before and after treatment was characterized by amplifying the V3-V4 region of the 16 s RNA gene and sequencing for bacterial identification.Results:The results showed that PRP was effective in the treatment of AGA patients,and the hair growth increased significantly.The results of relative abundance analysis of microbiota showed that after treatment,g_Cutibacterium increased and g_Staphylococcus decreased,which played a stable role in scalp microbiota.In addition,g_Lawsonella decreased,indicating that the scalp oil production decreased after treatment.Conclusions:The findings suggest that PRP may play a role in treating AGA through scalp microbiome rebalancing.

Preliminary studies on form, structure and function of androgenic gland in Penaeus chinensis

SCIENTISTS have paid much attention to sex control of animals. Sex control of shrimp is a noticeable topic in the field of high technology in aquaculture. Increasing the proportion of female shrimps in a rearing population is undoubtedly a very effective path to obtain higher aquacultural production of Penaeus chinensis. But up to date, the mechanism of sex differentiation and determination in shrimp is not clear. In recent years, we have done some work on

Sex reversal and the androgenic gland (AG) in Macrobrachium rosenbergii: A review

The male giant freshwater prawn(Macrobrachium rosenbergii)generally exhibit faster growth rates compared to females of similar age.Consequently,the practice of culturing monosex(all-male)prawn can increase both the production yield and income.Manually selecting males for culture during the grow-out period has long been practiced in commercial prawn farming,but is labor-intensive and generally unsuccessful in producing a male monoculture.The androgenic gland(AG)is essential for sexual differentiation in prawn and development of male primary and secondary sexual characteristics.Microsurgical removal of the AG(andrectomy)from male prawn at an early development stage will transform the male into a fully-functioning neo-female.The M.rosenbergii androgenic gland-specific insulin-like hormone(Mr-IAG)plays critical roles in male spermatogenesis and male sexual development.RNA interference(RNAi)is a highly specific post-transcriptional interference or silencing of gene expression in cells.Silencing Mr-IAG had induced full and functional sex reversal of male to neo-female(genetic male with a female phenotype).Microsurgical removal of AG and RNAi are two different approaches to producing neo-females and both methods target the manipulation of AG for efficient sex-reversal.Neo-females can mate with normal males to produce all-male prawn progeny,which can be used for commercial prawn farming and to improve production efficiency and profitability.This article reviewed recent research related to the development and functions of AG and the testis and their interactions with morphological differentiation at various stages for male M.rosenbergii,aiming to increase understanding on this topic and facilitate discovery of new techniques for advancing M.rosenbergii aquaculture.

Sudden cardiac death in anabolic androgenic steroids abuse: case report and literature review

Anabolic androgenic steroids (AAS) have several adverse effects on the cardiovascular system that may lead to a sudden cardiac death (SCD).We herein report a case involving a 24-year-old male,AAS abuser with intramuscular delivery in the 6 months before,who suffered a cardiorespiratory arrest at home's bathtub when returning from New Year's party.A forensic autopsy was performed according to the guidelines of the Association for European Cardiovascular Pathology (AECVP).The body showed hypertrophy of skeletal musculature,with low amount of subcutaneous fat and no signs of injury (body mass index,BMh 26.8 kg/m^(2)).On internal examination,there were multiorgan congestion,acute pulmonary edema,and cardiomegaly (420 g) with severe coronary atherosclerosis and superimposed acute occlusive thrombosis at the left main trunk and left anterior descendant.Areas of scarring were located at the intersection between the posterior wall and the posterior third of the septum (postero-septal).At histology,acute myocardial infarction at the anterior third of the septum and the anterior wall,and subacute myocardial infarction at apical septum and apical posterior wall were detected.Other findings were small intramyocardial vessel disease and myocytes hypertrophy.Chemicotoxicological analysis in blood showed ethanol ((0.90 ±0.05) g/L),stanazolol (11.31 μg/L),nandrolone (2.05μg/L) and testosterone (<1.00μg/L).When confronted with a sudden death in a young athlete we must pay attention to the physical phenotype that may suggest AAS abuse and perform a detailed examination of the heart.Chemicotoxicological analysis is a key to establish the relationship between SCD and AAS abuse.

Androgen signaling inhibits de novo lipogenesis to alleviate lipid deposition in zebrafish

Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males.However,the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood,especially in teleosts.In this study,cyp17a1-/-zebrafish(Danio rerio)exhibited excessive visceral adipose tissue(VAT),lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis(DNL)enzymes.The assay for transposase accessible chromatinwithsequencing(ATAC-seq)results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/-fish compared to cyp17a1+/+male fish,including stearoyl-CoA desaturase(scd)and fatty acid synthase(fasn).Androgen response element(ARE)motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+male fish but not in cyp17a1-/-fish.Both androgen receptor(ar)-/-and wildtype(WT)zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue,lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis enzymes.The Ar agonist BMS-564929 reduced the content of VAT and lipid content,and down-regulated acetyl-CoA carboxylase a(acaca),fasn,and scd expression.Mechanistically,the rescue effect of testosterone on cyp17a1-/-fish in terms of phenotypes was abolished when ar was additionally depleted.Collectively,these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish,thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.

Alleviatory effect of isoquercetin on benign prostatic hyperplasia via IGF-1/PI3K/Akt/mTOR pathway

We evaluated the effect of isoquercetin(quercetin-O-3-glucoside-quercetin,IQ)as a functional component of Abeliophyllum disistichum Nakai ethanol extract(ADLE)on prostate cell proliferation and apoptosis and its effects on the IGF-1/PI3K/Akt/mTOR pathway in benign prostatic hyperplasia(BPH).Metabolites in ADLE were analyzed using UHPLC-qTOF-MS and HPLC.IQ was orally administered(1 or 10 mg/kg)to a testosterone propionate-induced BPH rat model,and its effects on the prostate weight were evaluated.The effect of IQ on androgen receptor(AR)signaling was analyzed in LNCaP cells.Whether IGF-1 and IQ affect the IGF-1/PI3K/Akt/mTOR pathway in BPH-1 cells was also examined.The metabolites in ADLE were identified and quantified,which confirmed that ADLE contained abundant IQ(20.88 mg/g).IQ significantly reduced the prostate size in a concentration-dependent manner in a BPH rat model,and significantly decreased the expression of AR signaling factors in the rat prostate tissue and LNCaP cells in a concentration-dependent manner.IQ also inhibited the PI3K/AKT/mTOR pathway activated by IGF-1 treatment in BPH-1 cells.In BPH-1 cells,IQ led to G0/G1 arrest and suppressed the expression of proliferation factors while inducing apoptosis.Thus,IQ shows potential for use as a pharmaceutical and nutraceutical for BPH.

Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.