BACKGROUND Cancer patients often suffer from severe stress reactions psychologically,such as anxiety and depression.Prostate cancer(PC)is one of the common cancer types,with most patients diagnosed at advanced stages ...BACKGROUND Cancer patients often suffer from severe stress reactions psychologically,such as anxiety and depression.Prostate cancer(PC)is one of the common cancer types,with most patients diagnosed at advanced stages that cannot be treated by radical surgery and which are accompanied by complications such as bodily pain and bone metastasis.Therefore,attention should be given to the mental health status of PC patients as well as physical adverse events in the course of clinical treatment.AIM To analyze the risk factors leading to anxiety and depression in PC patients after castration and build a risk prediction model.METHODS A retrospective analysis was performed on the data of 120 PC cases treated in Xi'an People's Hospital between January 2019 and January 2022.The patient cohort was divided into a training group(n=84)and a validation group(n=36)at a ratio of 7:3.The patients’anxiety symptoms and depression levels were assessed 2 wk after surgery with the Self-Rating Anxiety Scale(SAS)and the Selfrating Depression Scale(SDS),respectively.Logistic regression was used to analyze the risk factors affecting negative mood,and a risk prediction model was constructed.RESULTS In the training group,35 patients and 37 patients had an SAS score and an SDS score greater than or equal to 50,respectively.Based on the scores,we further subclassified patients into two groups:a bad mood group(n=35)and an emotional stability group(n=49).Multivariate logistic regression analysis showed that marital status,castration scheme,and postoperative Visual Analogue Scale(VAS)score were independent risk factors affecting a patient's bad mood(P<0.05).In the training and validation groups,patients with adverse emotions exhibited significantly higher risk scores than emotionally stable patients(P<0.0001).The area under the curve(AUC)of the risk prediction model for predicting bad mood in the training group was 0.743,the specificity was 70.96%,and the sensitivity was 66.03%,while in the validation group,the AUC,specificity,and sensitivity were 0.755,66.67%,and 76.19%,respectively.The Hosmer-Lemeshow test showed aχ^(2) of 4.2856,a P value of 0.830,and a C-index of 0.773(0.692-0.854).The calibration curve revealed that the predicted curve was basically consistent with the actual curve,and the calibration curve showed that the prediction model had good discrimination and accuracy.Decision curve analysis showed that the model had a high net profit.CONCLUSION In PC patients,marital status,castration scheme,and postoperative pain(VAS)score are important factors affecting postoperative anxiety and depression.The logistic regression model can be used to successfully predict the risk of adverse psychological emotions.展开更多
Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor bu...Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castrationresistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens [3]. Mechanisms of CRPC progression include AR amplification and overexpression [4], AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (ARVs) [4], and induction of intracrine androgen metabolic enzymes [3]. Current anti-androgen therapies including MDV3100 (Enzalutamide) and abiraterone have focused on the androgen-dependent activation of AR through its ligand-binding domain (LBD), but do not provide a continuing clinical benefit for patients with CRPC and presumably fail due to multiple mechanisms including the expression of AR-Vs lacking the LBD [5]. These AR-Vs signal in the absence of ligand and are therefore resistant to LBD-targeting AR antagonists or agents that repress androgen biosynthesis [6].展开更多
The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit a...The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.展开更多
Objective:Androgen deprivation therapy(ADT)is still the principal treatment option for prostate cancer(PCa).In addition to reactivation of androgen receptor signaling,the resistance of PCa to apoptosis during ADT also...Objective:Androgen deprivation therapy(ADT)is still the principal treatment option for prostate cancer(PCa).In addition to reactivation of androgen receptor signaling,the resistance of PCa to apoptosis during ADT also contributes to castration resistant PCa(CRPC).A previous study reported that gene transfer of IL-13Rα2 into PCa cells sensitized the cells to the IL-13R-targeted cytotoxin IL13Rα1,leading to apoptosis.Compared with IL-13Rα2,IL13Rα1 is more constitutively expressed in PCa cells,but its function in PCa remains to be established.Methods:We determined the role and expression of IL13Rα1 in PCa cancer cells using western blotting,flow cytometry,and cell proliferation assays.Co-immunoprecipitation and mass spectrometry were used to identify the proteins that interacted with IL13Rα1,to elucidate its function.Results:In this study,we showed that IL13Rα1 was selectively suppressed in androgen-deprived PCa cells and that its suppression tended to be associated with poor prognoses of PCa patients.IL13Rα1 overexpression promoted apoptosis and inhibited tumor growth under androgen-deprived or castrated conditions(P<0.01).Mechanistically,IL13Rα1 recruited and facilitated ubiquitin protein ligase E3C-mediated ubiquitination and degradation of hexokinase 2(HK2),resulting in glycolytic inhibition and eventually leading to PCa cell apoptosis.Furthermore,our data revealed that mutated ataxia-telangiectasia kinase phosphorylated and facilitated the selective ubiquitin proteasome-mediated degradation of HK2.Notably,IL13Rα1-overexpressing PCa cells were more susceptible to apoptosis and exhibited reduced tumor growth after exposure to the HK2 inhibitor,2-deoxy-D-glucose(P<0.01).Conclusions:Our data identified a tumor suppressor role for IL13Rα1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis.IL13Rα1-mediated signaling involving HK2 may therefore provide a novel treatment target and strategy for CRPC.展开更多
BACKGROUND The majority of patients with newly diagnosed metastatic prostate cancer(PC)initially respond to androgen deprivation therapy(ADT)and are classified as metastatic castration-sensitive PC(mCSPC).Following mo...BACKGROUND The majority of patients with newly diagnosed metastatic prostate cancer(PC)initially respond to androgen deprivation therapy(ADT)and are classified as metastatic castration-sensitive PC(mCSPC).Following months to years of ADT,the disease tends to become resistant to ADT.Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC.Following its implementation in routine care,this combined treatment strategy requires more detailed evaluation in a real-world setting.AIM To assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC.METHODS A multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed.This region includes approximately 1.1 million citizens and the oncology departments of Linköping,Jönköping,and Kalmar.All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included.The primary endpoint was progression-free survival(PFS)at 12 mo,and the secondary endpoints were PFS at 24 mo,overall survival(OS),treatment intensity,adverse events,and unplanned hospitalizations.Exploratory analyses on potential prognostic parameters were performed.RESULTS Ninety-four patients were eligible and formed the study cohort.PFS at 12 and 24 mo was 75%(95%CI:66–84)and 58%(46–70),respectively.OS at 12 and 24 mo was 93%(87–99)and 86%(76–96).A total of 91%of patients(n=86)were given docetaxel according to the standard protocol of 75 mg/m2 every 3 wk(6 cycles),while 9%(n=8)received a modified protocol of 50 mg/m2 every 2 wk(9 cycles).The average overall dose intensity for those commencing standard treatment was 91%.Univariate Cox regression analyses show that baseline PSA>180 vs<180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors(HR 2.86,95%CI:1.39–5.87,P=0.0041 and 3.36,95%CI:1.03–10.96,P=0.045).Following multivariate analysis,statistical significance remained for PSA(2.51,95%CI:1.21–5.19,P=0.013)but not for metastatic status(2.60,95%CI:0.78–8.65,P=0.12).Febrile neutropenia was recorded in 21%(n=20)of patients,and 26%(n=24)had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course.CONCLUSION Results from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.展开更多
Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumo...Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumoral androgens in maintaining androgen receptor (AR) transcriptional activity in mCRPC [1]. Based on this findings, it has been possible to develop drugs, blocking the key enzyme in the biosynthesis of androgens through the inhibition of cytochrome p450 17 (CYP17) such as Abiraterone Acetate (AA) and drugs which directly target the AR including Enzalutamide (E) and Orteronel. Before this new knowledge, mCRPC treatment benefited from chemotherapy with taxanes. Recently a new taxane, Cabazitaxel (C), was approved in second line setting in association with prednisone. Retrospective analyses have tried to clarify the current role of chemotherapy in mCRPC patients and the right chemotherapy sequence of use of chemotherapy compared to new hormonal agents. Moreover, it would be important to address changes in the endpoints used in clinical trials, based on the stage of disease including the presence tumor-related symptoms, in order to identify the right therapeutic strategy.展开更多
Purpose: To investigate electrocardiogram (ECG) changes after complete androgen blockade (CAB) achieved by either surgical or medical castration and compare the outcomes of the groups. Methods: Sixty-three consecutive...Purpose: To investigate electrocardiogram (ECG) changes after complete androgen blockade (CAB) achieved by either surgical or medical castration and compare the outcomes of the groups. Methods: Sixty-three consecutive men (between 58 - 86 years of age) requiring CAB for prostate cancer were enrolled in the study. Patients with diabetes mellitus, an additional malignancy, coronary heart disease, atrial fibrillation, heart failure or a medical history of cardiac event in the last 12 months were excluded from the study. Additionally, those who were taking medicine affecting heart rate were excluded. The participants were divided into two groups according to their modality of castration. The first group consisted of 35 patients who received bilateral orchiectomy plus anti-androgen medication. The second group contained 28 patients who accepted gonadotropin-releasing hormone (GnRH) plus anti-androgen therapy. After complete examinations and biochemical tests, the ECG leads of the patients were obtained conveniently. This was then repeated at three- and six-month visits. ECG findings (including heart rate, PR, QRS, QT, corrected QT (QTc) intervals and QT dispersion (QTd)) were recorded and analysed statistically. The groups were then compared in terms of pre- and post-treatment ECG outcomes. Results: Both groups revealed similarly lower heart rate and prolonged PR, QRS, QT, corrected QTc and QTd by the end of six months. By the end of three months, all variables had changed significantly in the orchiectomy group, whereas in the GnRH group, they had not. Conclusion: CAB may result in lower heart rate and prolonged QT, a condition associated with fatal cardiac arrhythmia and sudden death. Therefore, patients receiving CAB should be monitored closely for cardiac adverse effects.展开更多
Objective To investigate the therapeutic efficacy of castration with 125 I brachtherapy in middle and late stage prostate cancer. Methods Sixty-six patients with prostate cancer from 2004 to 2009 were analyzed,40 were...Objective To investigate the therapeutic efficacy of castration with 125 I brachtherapy in middle and late stage prostate cancer. Methods Sixty-six patients with prostate cancer from 2004 to 2009 were analyzed,40 were at clinical stage C and 26 were at clinical stage D,展开更多
Reprogramming of metabolism is a hallmark of tumors,which has been explored for therapeutic purposes.Prostate cancer(PCa),particularly advanced and therapy-resistant PCa,displays unique metabolic properties.Targeting ...Reprogramming of metabolism is a hallmark of tumors,which has been explored for therapeutic purposes.Prostate cancer(PCa),particularly advanced and therapy-resistant PCa,displays unique metabolic properties.Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes.Among the many nutrients,glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa.In addition to amino acid metabolism,glutamine is also widely involved in the synthesis of other macromolecules and biomasses.Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients.This review summarizes the metabolic landscape of PCa,with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa,and suggests novel therapeutic strategies.展开更多
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 heterogenei...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.展开更多
Androgen deprivation therapy(ADT)is the mainstay for the treatment of advanced prostate cancer.Since the clinical evolution from surgical orchiectomy,we have typically used ADT and orchiectomy to be synonymous terms f...Androgen deprivation therapy(ADT)is the mainstay for the treatment of advanced prostate cancer.Since the clinical evolution from surgical orchiectomy,we have typically used ADT and orchiectomy to be synonymous terms for castration.The goal of this study is to determine if,in contemporary medical practice,surgical and chemical castration provide for similar levels of diminishment of total and free testosterone.Further,what approaches should be used to most accurately measure testosterone levels in men with advanced prostate cancer and what cutoff values,for example for total testosterone 50 ng dl-1 or 20 ng dl-1,should be utilized.Studies available in the literature have been analyzed and compiled to address these questions.Finally,evidence is provided that free testosterone,the biologically active component,should be utilized to provide clinically relevant state of castration.展开更多
Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive...Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer(NEPC).This manuscript will focus on the new finding of human one cut domain family member 2(ONECUT2)transcription factor and its role in castration resistance,especially in NEPC.展开更多
Background:Ancient Egypt might be considered the cradle of medicine.The modern literature is somewhat too enthusiastic regarding the procedures given an Egyptian origin.The aim of the current paper is to briefly analy...Background:Ancient Egypt might be considered the cradle of medicine.The modern literature is somewhat too enthusiastic regarding the procedures given an Egyptian origin.The aim of the current paper is to briefly analyze the claims regarding urological and genital surgery in Egypt,in order to decide what the Egyptian actually do,and what has incorrectly been ascribed to them.Methods:The original sources as well as the modern literature was reviewed regarding surgery in ancient Egypt.Results:There is only one source indicating a urological procedure for medical indications in the Egyptian material.The Ebers papyrus can be interpreted as describing a surgical treatment for hydrocele.The sources are more abundant regarding male circumcision,while female circumcision is mainly documented from a later period.The suggestions that castration and lithotomy were performed are based on a lack of understanding of the sources.Conclusion:The ancient Egyptians did possibly treat hydrocele with a minor surgical procedure,but there are no indications in the sources that other urological procedures were performed.Circumcisions were common,but were not performed on a medical indication.These findings are in line with the general level of Egyptian surgery.展开更多
Background Many countries have already banned the use of antibiotics in animal husbandry,making it extremely difficult to maintain animal health in livestock breeding.In the livestock industry,there is an urgent need ...Background Many countries have already banned the use of antibiotics in animal husbandry,making it extremely difficult to maintain animal health in livestock breeding.In the livestock industry,there is an urgent need to develop alternatives to antibiotics which will not lead to drug resistance on prolonged use.In this study,eighteen castrated bulls were randomly divided into two groups.The control group(CK)was fed the basal diet,while the antimicrobial peptide group(AP)was fed the basal diet supplemented with 8 g of antimicrobial peptides in the basal diet for the experimental period of 270 d.They were then slaughtered to measure production performance,and the ruminal contents were isolated for metagenomic and metabolome sequencing analysis.Result The results showed that antimicrobial peptides could improve the daily weight,carcass weight,and net meat weight of the experimental animals.Additionally,the rumen papillae diameter and the micropapillary density in the AP were significantly greater than those in the CK.Furthermore,the determination of digestive enzymes and fermentation parameters showed that the contents of protease,xylanase,andβ-glucoside in the AP were greater than those in the CK.However,lipase content in the CK was greater than that in the AP.Moreover,the content of acetate,propionate,butyrate,and valerate was found to be greater in AP than those in CK.The metagenomic analysis annotated 1993 differential microorganisms at the species level.The KEGG enrichment of these microorganisms revealed that the enrichment of drug resistance-related pathways was dramatically decreased in the AP,whereas the enrichment of immune-related pathways was significantly increased.There was also a significant reduction in the types of viruses in the AP.187 probiotics with significant differences were found,135 of which were higher in AP than in CK.It was also found that the antimicrobial mechanism of the antimicrobial peptides was quite specific.Seven low-abundance microorganisms(Acinetobactersp.Ac1271,Aequorivita soesokkakensis,Bacillus lacisalsi,Haloferax larsenii,Lysinibacillussp.3DF0063,Parabacteroidessp.217,Streptomycessp.So13.3)were found to regulate growth performance of the bull negatively.Metabolome analysis identified 45 differentially differential metabolites that significantly different between the CK and the AP groups.Seven upregulated metabolites(4-pyridoxic acid,Ala-Phe,3-ureidopropionate,hippuric acid,terephthalic acid,L-alanine,uridine 5-monophosphate)improve the growth performance of the experimental animals.To detect the interactions between the rumen microbiome and metabolism,we associated the rumen microbiome with the metabolome and found that negative regulation between the above 7 microorganisms and 7 metabolites.Conclusions This study shows that antimicrobial peptides can improve the growth performance of animals while resisting viruses and harmful bacteria and are expected to become healthy alternatives to antibiotics.We demonstrated a new antimicrobial peptides pharmacological model.We demonstrated low-abundance microorganisms may play a role by regulating the content of metabolites.展开更多
Interleukin-6(IL-6)is a pleiotropic cytokine involved in prostate regulation and in prostate cancer(PC)development/progression.IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cell...Interleukin-6(IL-6)is a pleiotropic cytokine involved in prostate regulation and in prostate cancer(PC)development/progression.IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cells.The levels of IL-6 and respective receptors are increased during prostate carcinogenesis and tumor progression.Several studies reported that increased serum and plasma IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and are associated with a poor prognosis in PC patients.In PC treatment,patients diagnosed with advanced stages are frequently submitted to hormonal castration,although most patients will eventually fail this therapy and die from recurrent castration-resistant prostate cancer(CRPC).Therefore,it is important to understand the mechanisms involved in CRPC.Several pathways have been proposed to be involved in CRPC development,and their understanding will improve the way to more effective therapies.In fact,the prostate is known to be dependent,not exclusively,on androgens,but also on growth factors and cytokines.The signaling pathway mediated by IL-6 may be an alternative pathway in the CRPC phenotype acquisition and cancer progression,under androgen deprivation conditions.The principal goal of this review is to evaluate the role of IL-6 pathway signaling in human PC development and progression and discuss the interaction of this pathway with the androgen recepto pathway.Furthermore,we intend to evaluate the inclusion of IL-6 and its receptor levels as a putative new class of tumor biomarkers.The IL-6/IL-6R signaling pathway may be included as a putative molecular marker for aggressiveness in PC and it may be able to maintain tumor growth through the AR pathway under androgen-deprivation conditions.The importance of the IL-6/IL-6R pathway in regulation of PC cells makes it a good candidate for targeted therapy.展开更多
This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on...This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on our recent progress in the understanding of:1)The plasticity and dynamics of tumorestroma interaction;2)The significance of epigenetic reprogramming in conferring cancer growth,invasion and metastasis;3)New insights on altered junctional communication affecting PCa bone and brain metastases;4)Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy;5)Geneticbased therapy to co-target tumor and bone stroma;6)PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis;7)The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis;and 8)Characterization of imprinting cluster of microRNA,in tumorestroma interaction.This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation.This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications.We dedicate this article in our fond memory of Dr.Donald S.Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.展开更多
Objective:Although the utility of immunohistochemistry(IHC)for assessing mismatch repair(MMR)protein expression has been demonstrated in solid tumors including primary prostate cancer(PCa),its utility has not been ass...Objective:Although the utility of immunohistochemistry(IHC)for assessing mismatch repair(MMR)protein expression has been demonstrated in solid tumors including primary prostate cancer(PCa),its utility has not been assessed in castration-resistant PCa(CRPC).Methods:Tissue microarrays were constructed from 127 radical prostatectomies and 155 CRPC metastases from 50 patients.MMR(MLH1,MSH2,MSH6,and PMS2)expression was assessed by IHC and gene expression arrays.Associations between MMR protein expression in PCa and CRPC and biochemical recurrence(BCR)or time from diagnosis to death respectively were determined.Results:There was no correlation between levels of MMR protein and BCR.Absence of MSH2 and MSH6 was the most pronounced at 15%and 22%in PCa and 17.8%and 16%in CRPC patients,respectively.MSH2 and MSH6 protein were absent in 9.4%and 8%of PCa and CRPC respectively.Absence of individual MMR proteins did not correlate with BCR or time from diagnosis to death.However absent MSH2/MSH6 in CRPC was associated with shorter time to death(pZ0.0006).Loss of MSH2 was verified at the gene expression level.This finding correlated with microsatellite instability previously reported in this CRPC cohort.展开更多
Prostate cancer(PCa)is one of the most lethal cancers in western countries.Androgen receptor(AR)signaling pathway plays a key role in PCa progression.Despite the initial effectiveness of androgen deprivation therapy(A...Prostate cancer(PCa)is one of the most lethal cancers in western countries.Androgen receptor(AR)signaling pathway plays a key role in PCa progression.Despite the initial effectiveness of androgen deprivation therapy(ADT)for treatment of patients with advanced PCa,most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer(mCRPC).Constitutively transcriptional activated AR splice variants(AR-Vs)have emerged as critical players in the development and progression of mCRPC.Among AR-Vs identified to date,AR-V7(a.k.a.AR3)is one of the most abundant and frequently found in both PCa cell lines and in human prostate tissues.Most of functional studies have been focused on AR-V7/AR3 and revealed its role in regulation of survival,growth,differentiation and migration in prostate cells.In this review,we will summarize our current understanding of regulation of expression and activity of AR-Vs in mCRPC.展开更多
BACKGROUND Testosterone level of < 50 ng/dL has been used to define castrate level after surgery or after androgen deprivation treatment (ADT) in metastatic prostate cancer (PC). AIM To evaluate the effect of two d...BACKGROUND Testosterone level of < 50 ng/dL has been used to define castrate level after surgery or after androgen deprivation treatment (ADT) in metastatic prostate cancer (PC). AIM To evaluate the effect of two different castrate testosterone levels,< 50 and < 20 ng/dL, on biochemical relapse free survival (BRFS) in patients with nonmetastatic intermediate and high risk PC receiving definitive radiotherapy (RT) and ADT. METHODS Between April 1998 and February 2011;173 patients with intermediate and high risk disease were treated. Radiotherapy was delivered by either threedimensional- conformal technique to a total dose of 73.4 Gy at the ICRU reference point or intensity modulated radiotherapy technique to a total dose of 76 Gy. All the patients received 3 mo of neoadjuvant ADT followed by RT and additional 6 mo of ADT. ASTRO Phoenix definition was used to define biochemical relapse. RESULTS Median follow up duration was 125 months. Ninety-six patients (56%) had castrate testosterone level < 20 ng/dL and 139 patients (80%) had castrate testosterone level < 50 ng/dL. Both values are valid at predicting BRFS. However, patients with testosterone < 20 ng/dL have significantly better BRFS compared to other groups (P = 0.003). When we compare two values, it was found that using 20 ng/dL is better than 50 ng/dL in predicting the BRFS (AUC = 0.63 vs 0.58, respectively). CONCLUSION Castrate testosterone level of less than 20 ng/dL is associated with better BRFS and is better in predicting the BRFS. Further studies using current standard of care of high dose IMRT and longer ADT duration might support these findings.展开更多
Aim: Storage of testes-epididymides at refrigeration temperature is a promising method of short-term sperm preservation for use in reproductive biotechnology in dogs. This study aimed to determine the effect of storag...Aim: Storage of testes-epididymides at refrigeration temperature is a promising method of short-term sperm preservation for use in reproductive biotechnology in dogs. This study aimed to determine the effect of storage time at 4°C on the quality of Nigerian local dogs’ cauda epididymal spermatozoa recovered post-castration. Materials and Methods: Testes along with their epididymides collected immediately after castration of local dogs were either processed immediately (0th hour) or stored at 4°C in the refrigerator for 12th, 24th or 48th hours and then processed. Each storage group comprised 5 pairs of testes-epididymides. Sperm motility, concentration, livability, acrosome integrity and morphology from the various storage groups were evaluated and means with standard error of the mean (±SEM) were recorded. Results: Mean percent sperm motility at 0th hour (77.0 ± 2.6) decreased significantly (p 0.05) was found when the mean sperm concentrations (×107/ml) of the storage groups (5.86 ± 47, 5.24 ± 26 and 5.38 ± 31) were compared with the control (6.48 ± 0.75). Mean percent sperm livability did not differ significantly (p > 0.05) between the 0th, 12th, 24th and 48th hour groups (86.4 ± 1.5, 78.0 ± 3.1 and 75.0 ± 1.8 respectively). However, there was a significant decrease (p 0.05) was detected in the mean percent acrosome integrity between the 0th, 12th, 24th and 48th hour groups (90.0 ± 1.5, 83.0 ± 3.5, 84.6 ± 4.6 and 82.2 ± 3.9 respectively). A significant increase (p Conclusion: The current study has shown that viable spermatozoa can be recovered after 48 hours of storage at 4°C of the cauda epididymides of Nigerian local dogs.展开更多
文摘BACKGROUND Cancer patients often suffer from severe stress reactions psychologically,such as anxiety and depression.Prostate cancer(PC)is one of the common cancer types,with most patients diagnosed at advanced stages that cannot be treated by radical surgery and which are accompanied by complications such as bodily pain and bone metastasis.Therefore,attention should be given to the mental health status of PC patients as well as physical adverse events in the course of clinical treatment.AIM To analyze the risk factors leading to anxiety and depression in PC patients after castration and build a risk prediction model.METHODS A retrospective analysis was performed on the data of 120 PC cases treated in Xi'an People's Hospital between January 2019 and January 2022.The patient cohort was divided into a training group(n=84)and a validation group(n=36)at a ratio of 7:3.The patients’anxiety symptoms and depression levels were assessed 2 wk after surgery with the Self-Rating Anxiety Scale(SAS)and the Selfrating Depression Scale(SDS),respectively.Logistic regression was used to analyze the risk factors affecting negative mood,and a risk prediction model was constructed.RESULTS In the training group,35 patients and 37 patients had an SAS score and an SDS score greater than or equal to 50,respectively.Based on the scores,we further subclassified patients into two groups:a bad mood group(n=35)and an emotional stability group(n=49).Multivariate logistic regression analysis showed that marital status,castration scheme,and postoperative Visual Analogue Scale(VAS)score were independent risk factors affecting a patient's bad mood(P<0.05).In the training and validation groups,patients with adverse emotions exhibited significantly higher risk scores than emotionally stable patients(P<0.0001).The area under the curve(AUC)of the risk prediction model for predicting bad mood in the training group was 0.743,the specificity was 70.96%,and the sensitivity was 66.03%,while in the validation group,the AUC,specificity,and sensitivity were 0.755,66.67%,and 76.19%,respectively.The Hosmer-Lemeshow test showed aχ^(2) of 4.2856,a P value of 0.830,and a C-index of 0.773(0.692-0.854).The calibration curve revealed that the predicted curve was basically consistent with the actual curve,and the calibration curve showed that the prediction model had good discrimination and accuracy.Decision curve analysis showed that the model had a high net profit.CONCLUSION In PC patients,marital status,castration scheme,and postoperative pain(VAS)score are important factors affecting postoperative anxiety and depression.The logistic regression model can be used to successfully predict the risk of adverse psychological emotions.
基金partially supported by Major State Basic Research Development Program of China(Nos.2015CB910400 and 2012CB910400)National Natural Science Foundation of China(Nos.81472788 and 81272463)
文摘Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castrationresistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens [3]. Mechanisms of CRPC progression include AR amplification and overexpression [4], AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (ARVs) [4], and induction of intracrine androgen metabolic enzymes [3]. Current anti-androgen therapies including MDV3100 (Enzalutamide) and abiraterone have focused on the androgen-dependent activation of AR through its ligand-binding domain (LBD), but do not provide a continuing clinical benefit for patients with CRPC and presumably fail due to multiple mechanisms including the expression of AR-Vs lacking the LBD [5]. These AR-Vs signal in the absence of ligand and are therefore resistant to LBD-targeting AR antagonists or agents that repress androgen biosynthesis [6].
基金This work is supported in part by grants NIH/NCI CA140468,CA168601,CA179970,DOD PC130062,Ralph de Vere White endowment,US Department of Veterans Affairs,Office of Research and Development VA Merits I01 BX002653by resources from the VA Northern California Health Care System,Sacramento,California.
文摘The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.
基金supported by the National Natural Science Foundation of China(Grant Nos.81772760 and 82072850)the Natural Science Foundation of Shandong Province(Grant Nos.ZR2020YQ55 and ZR2020QH327),the Shandong Taishan Scholarship(Grant No.tsqn20161076)+1 种基金the Innovation Project of Shandong Academy of Medical Sciences(2020)the program for Outstanding PhD candidate of Shandong University(2020)and Academic promotion programme of Shandong First Medical University(LJ001).
文摘Objective:Androgen deprivation therapy(ADT)is still the principal treatment option for prostate cancer(PCa).In addition to reactivation of androgen receptor signaling,the resistance of PCa to apoptosis during ADT also contributes to castration resistant PCa(CRPC).A previous study reported that gene transfer of IL-13Rα2 into PCa cells sensitized the cells to the IL-13R-targeted cytotoxin IL13Rα1,leading to apoptosis.Compared with IL-13Rα2,IL13Rα1 is more constitutively expressed in PCa cells,but its function in PCa remains to be established.Methods:We determined the role and expression of IL13Rα1 in PCa cancer cells using western blotting,flow cytometry,and cell proliferation assays.Co-immunoprecipitation and mass spectrometry were used to identify the proteins that interacted with IL13Rα1,to elucidate its function.Results:In this study,we showed that IL13Rα1 was selectively suppressed in androgen-deprived PCa cells and that its suppression tended to be associated with poor prognoses of PCa patients.IL13Rα1 overexpression promoted apoptosis and inhibited tumor growth under androgen-deprived or castrated conditions(P<0.01).Mechanistically,IL13Rα1 recruited and facilitated ubiquitin protein ligase E3C-mediated ubiquitination and degradation of hexokinase 2(HK2),resulting in glycolytic inhibition and eventually leading to PCa cell apoptosis.Furthermore,our data revealed that mutated ataxia-telangiectasia kinase phosphorylated and facilitated the selective ubiquitin proteasome-mediated degradation of HK2.Notably,IL13Rα1-overexpressing PCa cells were more susceptible to apoptosis and exhibited reduced tumor growth after exposure to the HK2 inhibitor,2-deoxy-D-glucose(P<0.01).Conclusions:Our data identified a tumor suppressor role for IL13Rα1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis.IL13Rα1-mediated signaling involving HK2 may therefore provide a novel treatment target and strategy for CRPC.
基金the Declaration of Helsinki and was approved by the Regional Ethics Review board in Linköping,RegionÖstergötland,Sweden,No.2018/139–31.
文摘BACKGROUND The majority of patients with newly diagnosed metastatic prostate cancer(PC)initially respond to androgen deprivation therapy(ADT)and are classified as metastatic castration-sensitive PC(mCSPC).Following months to years of ADT,the disease tends to become resistant to ADT.Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC.Following its implementation in routine care,this combined treatment strategy requires more detailed evaluation in a real-world setting.AIM To assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC.METHODS A multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed.This region includes approximately 1.1 million citizens and the oncology departments of Linköping,Jönköping,and Kalmar.All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included.The primary endpoint was progression-free survival(PFS)at 12 mo,and the secondary endpoints were PFS at 24 mo,overall survival(OS),treatment intensity,adverse events,and unplanned hospitalizations.Exploratory analyses on potential prognostic parameters were performed.RESULTS Ninety-four patients were eligible and formed the study cohort.PFS at 12 and 24 mo was 75%(95%CI:66–84)and 58%(46–70),respectively.OS at 12 and 24 mo was 93%(87–99)and 86%(76–96).A total of 91%of patients(n=86)were given docetaxel according to the standard protocol of 75 mg/m2 every 3 wk(6 cycles),while 9%(n=8)received a modified protocol of 50 mg/m2 every 2 wk(9 cycles).The average overall dose intensity for those commencing standard treatment was 91%.Univariate Cox regression analyses show that baseline PSA>180 vs<180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors(HR 2.86,95%CI:1.39–5.87,P=0.0041 and 3.36,95%CI:1.03–10.96,P=0.045).Following multivariate analysis,statistical significance remained for PSA(2.51,95%CI:1.21–5.19,P=0.013)but not for metastatic status(2.60,95%CI:0.78–8.65,P=0.12).Febrile neutropenia was recorded in 21%(n=20)of patients,and 26%(n=24)had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course.CONCLUSION Results from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.
文摘Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumoral androgens in maintaining androgen receptor (AR) transcriptional activity in mCRPC [1]. Based on this findings, it has been possible to develop drugs, blocking the key enzyme in the biosynthesis of androgens through the inhibition of cytochrome p450 17 (CYP17) such as Abiraterone Acetate (AA) and drugs which directly target the AR including Enzalutamide (E) and Orteronel. Before this new knowledge, mCRPC treatment benefited from chemotherapy with taxanes. Recently a new taxane, Cabazitaxel (C), was approved in second line setting in association with prednisone. Retrospective analyses have tried to clarify the current role of chemotherapy in mCRPC patients and the right chemotherapy sequence of use of chemotherapy compared to new hormonal agents. Moreover, it would be important to address changes in the endpoints used in clinical trials, based on the stage of disease including the presence tumor-related symptoms, in order to identify the right therapeutic strategy.
文摘Purpose: To investigate electrocardiogram (ECG) changes after complete androgen blockade (CAB) achieved by either surgical or medical castration and compare the outcomes of the groups. Methods: Sixty-three consecutive men (between 58 - 86 years of age) requiring CAB for prostate cancer were enrolled in the study. Patients with diabetes mellitus, an additional malignancy, coronary heart disease, atrial fibrillation, heart failure or a medical history of cardiac event in the last 12 months were excluded from the study. Additionally, those who were taking medicine affecting heart rate were excluded. The participants were divided into two groups according to their modality of castration. The first group consisted of 35 patients who received bilateral orchiectomy plus anti-androgen medication. The second group contained 28 patients who accepted gonadotropin-releasing hormone (GnRH) plus anti-androgen therapy. After complete examinations and biochemical tests, the ECG leads of the patients were obtained conveniently. This was then repeated at three- and six-month visits. ECG findings (including heart rate, PR, QRS, QT, corrected QT (QTc) intervals and QT dispersion (QTd)) were recorded and analysed statistically. The groups were then compared in terms of pre- and post-treatment ECG outcomes. Results: Both groups revealed similarly lower heart rate and prolonged PR, QRS, QT, corrected QTc and QTd by the end of six months. By the end of three months, all variables had changed significantly in the orchiectomy group, whereas in the GnRH group, they had not. Conclusion: CAB may result in lower heart rate and prolonged QT, a condition associated with fatal cardiac arrhythmia and sudden death. Therefore, patients receiving CAB should be monitored closely for cardiac adverse effects.
文摘Objective To investigate the therapeutic efficacy of castration with 125 I brachtherapy in middle and late stage prostate cancer. Methods Sixty-six patients with prostate cancer from 2004 to 2009 were analyzed,40 were at clinical stage C and 26 were at clinical stage D,
基金This work was partially supported by the National Natural Science Foundation of China(No.81902611,No.82272886,and No.82200484)the Natural Science Foundation of Anhui Education Department(No.2022AH030118).
文摘Reprogramming of metabolism is a hallmark of tumors,which has been explored for therapeutic purposes.Prostate cancer(PCa),particularly advanced and therapy-resistant PCa,displays unique metabolic properties.Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes.Among the many nutrients,glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa.In addition to amino acid metabolism,glutamine is also widely involved in the synthesis of other macromolecules and biomasses.Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients.This review summarizes the metabolic landscape of PCa,with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa,and suggests novel therapeutic strategies.
文摘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.
文摘Androgen deprivation therapy(ADT)is the mainstay for the treatment of advanced prostate cancer.Since the clinical evolution from surgical orchiectomy,we have typically used ADT and orchiectomy to be synonymous terms for castration.The goal of this study is to determine if,in contemporary medical practice,surgical and chemical castration provide for similar levels of diminishment of total and free testosterone.Further,what approaches should be used to most accurately measure testosterone levels in men with advanced prostate cancer and what cutoff values,for example for total testosterone 50 ng dl-1 or 20 ng dl-1,should be utilized.Studies available in the literature have been analyzed and compiled to address these questions.Finally,evidence is provided that free testosterone,the biologically active component,should be utilized to provide clinically relevant state of castration.
文摘Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer(NEPC).This manuscript will focus on the new finding of human one cut domain family member 2(ONECUT2)transcription factor and its role in castration resistance,especially in NEPC.
文摘Background:Ancient Egypt might be considered the cradle of medicine.The modern literature is somewhat too enthusiastic regarding the procedures given an Egyptian origin.The aim of the current paper is to briefly analyze the claims regarding urological and genital surgery in Egypt,in order to decide what the Egyptian actually do,and what has incorrectly been ascribed to them.Methods:The original sources as well as the modern literature was reviewed regarding surgery in ancient Egypt.Results:There is only one source indicating a urological procedure for medical indications in the Egyptian material.The Ebers papyrus can be interpreted as describing a surgical treatment for hydrocele.The sources are more abundant regarding male circumcision,while female circumcision is mainly documented from a later period.The suggestions that castration and lithotomy were performed are based on a lack of understanding of the sources.Conclusion:The ancient Egyptians did possibly treat hydrocele with a minor surgical procedure,but there are no indications in the sources that other urological procedures were performed.Circumcisions were common,but were not performed on a medical indication.These findings are in line with the general level of Egyptian surgery.
基金financially supported by Research and application of corn straw forage and beef cattle high-efficiency and quality production technology (Provincial Education Science and Technology Innovation Project) (GSSYLXM-02)the Gansu beef cattle quality fattening project (GSAXMLZ-2021-01)+1 种基金the Application of Pingliang Red Bull Planting and Breeding Combined with High-efficiency Circular Production System Construction Technology Application (2020C-08)the local funding (GSSLCSX-2020-1)。
文摘Background Many countries have already banned the use of antibiotics in animal husbandry,making it extremely difficult to maintain animal health in livestock breeding.In the livestock industry,there is an urgent need to develop alternatives to antibiotics which will not lead to drug resistance on prolonged use.In this study,eighteen castrated bulls were randomly divided into two groups.The control group(CK)was fed the basal diet,while the antimicrobial peptide group(AP)was fed the basal diet supplemented with 8 g of antimicrobial peptides in the basal diet for the experimental period of 270 d.They were then slaughtered to measure production performance,and the ruminal contents were isolated for metagenomic and metabolome sequencing analysis.Result The results showed that antimicrobial peptides could improve the daily weight,carcass weight,and net meat weight of the experimental animals.Additionally,the rumen papillae diameter and the micropapillary density in the AP were significantly greater than those in the CK.Furthermore,the determination of digestive enzymes and fermentation parameters showed that the contents of protease,xylanase,andβ-glucoside in the AP were greater than those in the CK.However,lipase content in the CK was greater than that in the AP.Moreover,the content of acetate,propionate,butyrate,and valerate was found to be greater in AP than those in CK.The metagenomic analysis annotated 1993 differential microorganisms at the species level.The KEGG enrichment of these microorganisms revealed that the enrichment of drug resistance-related pathways was dramatically decreased in the AP,whereas the enrichment of immune-related pathways was significantly increased.There was also a significant reduction in the types of viruses in the AP.187 probiotics with significant differences were found,135 of which were higher in AP than in CK.It was also found that the antimicrobial mechanism of the antimicrobial peptides was quite specific.Seven low-abundance microorganisms(Acinetobactersp.Ac1271,Aequorivita soesokkakensis,Bacillus lacisalsi,Haloferax larsenii,Lysinibacillussp.3DF0063,Parabacteroidessp.217,Streptomycessp.So13.3)were found to regulate growth performance of the bull negatively.Metabolome analysis identified 45 differentially differential metabolites that significantly different between the CK and the AP groups.Seven upregulated metabolites(4-pyridoxic acid,Ala-Phe,3-ureidopropionate,hippuric acid,terephthalic acid,L-alanine,uridine 5-monophosphate)improve the growth performance of the experimental animals.To detect the interactions between the rumen microbiome and metabolism,we associated the rumen microbiome with the metabolome and found that negative regulation between the above 7 microorganisms and 7 metabolites.Conclusions This study shows that antimicrobial peptides can improve the growth performance of animals while resisting viruses and harmful bacteria and are expected to become healthy alternatives to antibiotics.We demonstrated a new antimicrobial peptides pharmacological model.We demonstrated low-abundance microorganisms may play a role by regulating the content of metabolites.
文摘Interleukin-6(IL-6)is a pleiotropic cytokine involved in prostate regulation and in prostate cancer(PC)development/progression.IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cells.The levels of IL-6 and respective receptors are increased during prostate carcinogenesis and tumor progression.Several studies reported that increased serum and plasma IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and are associated with a poor prognosis in PC patients.In PC treatment,patients diagnosed with advanced stages are frequently submitted to hormonal castration,although most patients will eventually fail this therapy and die from recurrent castration-resistant prostate cancer(CRPC).Therefore,it is important to understand the mechanisms involved in CRPC.Several pathways have been proposed to be involved in CRPC development,and their understanding will improve the way to more effective therapies.In fact,the prostate is known to be dependent,not exclusively,on androgens,but also on growth factors and cytokines.The signaling pathway mediated by IL-6 may be an alternative pathway in the CRPC phenotype acquisition and cancer progression,under androgen deprivation conditions.The principal goal of this review is to evaluate the role of IL-6 pathway signaling in human PC development and progression and discuss the interaction of this pathway with the androgen recepto pathway.Furthermore,we intend to evaluate the inclusion of IL-6 and its receptor levels as a putative new class of tumor biomarkers.The IL-6/IL-6R signaling pathway may be included as a putative molecular marker for aggressiveness in PC and it may be able to maintain tumor growth through the AR pathway under androgen-deprivation conditions.The importance of the IL-6/IL-6R pathway in regulation of PC cells makes it a good candidate for targeted therapy.
基金The authors thank the financial support from NIH/National Cancer Institute grants(2P01CA098912)the editorial assistance from Gary Mawyer.
文摘This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on our recent progress in the understanding of:1)The plasticity and dynamics of tumorestroma interaction;2)The significance of epigenetic reprogramming in conferring cancer growth,invasion and metastasis;3)New insights on altered junctional communication affecting PCa bone and brain metastases;4)Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy;5)Geneticbased therapy to co-target tumor and bone stroma;6)PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis;7)The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis;and 8)Characterization of imprinting cluster of microRNA,in tumorestroma interaction.This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation.This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications.We dedicate this article in our fond memory of Dr.Donald S.Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.
基金We thank the patients and their families who were willing to participate in the Prostate Cancer Donor Program.The investigators Drs.Robert Vessella,Bruce Montgomery,Evan Yu,Heather Cheng,Elahe Mostaghel,Paul Lange,and Martine Roudier for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Programhis research was supported by funding by the Pacific Northwest Prostate Cancer SPORE(P50CA97186),R01CA165573the Richard M.LUCAS Foundation.Colm Morrissey is a recipient of a Career Development Award from Jim and Catherine Allchin.
文摘Objective:Although the utility of immunohistochemistry(IHC)for assessing mismatch repair(MMR)protein expression has been demonstrated in solid tumors including primary prostate cancer(PCa),its utility has not been assessed in castration-resistant PCa(CRPC).Methods:Tissue microarrays were constructed from 127 radical prostatectomies and 155 CRPC metastases from 50 patients.MMR(MLH1,MSH2,MSH6,and PMS2)expression was assessed by IHC and gene expression arrays.Associations between MMR protein expression in PCa and CRPC and biochemical recurrence(BCR)or time from diagnosis to death respectively were determined.Results:There was no correlation between levels of MMR protein and BCR.Absence of MSH2 and MSH6 was the most pronounced at 15%and 22%in PCa and 17.8%and 16%in CRPC patients,respectively.MSH2 and MSH6 protein were absent in 9.4%and 8%of PCa and CRPC respectively.Absence of individual MMR proteins did not correlate with BCR or time from diagnosis to death.However absent MSH2/MSH6 in CRPC was associated with shorter time to death(pZ0.0006).Loss of MSH2 was verified at the gene expression level.This finding correlated with microsatellite instability previously reported in this CRPC cohort.
基金This work was supported by NIH(CA106504,CA169524)and DOD(W81XWH-15-1-0612)grants to YQThe authors apologize for not being able to cite many important studies related to this subject due to limited space.
文摘Prostate cancer(PCa)is one of the most lethal cancers in western countries.Androgen receptor(AR)signaling pathway plays a key role in PCa progression.Despite the initial effectiveness of androgen deprivation therapy(ADT)for treatment of patients with advanced PCa,most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer(mCRPC).Constitutively transcriptional activated AR splice variants(AR-Vs)have emerged as critical players in the development and progression of mCRPC.Among AR-Vs identified to date,AR-V7(a.k.a.AR3)is one of the most abundant and frequently found in both PCa cell lines and in human prostate tissues.Most of functional studies have been focused on AR-V7/AR3 and revealed its role in regulation of survival,growth,differentiation and migration in prostate cells.In this review,we will summarize our current understanding of regulation of expression and activity of AR-Vs in mCRPC.
文摘BACKGROUND Testosterone level of < 50 ng/dL has been used to define castrate level after surgery or after androgen deprivation treatment (ADT) in metastatic prostate cancer (PC). AIM To evaluate the effect of two different castrate testosterone levels,< 50 and < 20 ng/dL, on biochemical relapse free survival (BRFS) in patients with nonmetastatic intermediate and high risk PC receiving definitive radiotherapy (RT) and ADT. METHODS Between April 1998 and February 2011;173 patients with intermediate and high risk disease were treated. Radiotherapy was delivered by either threedimensional- conformal technique to a total dose of 73.4 Gy at the ICRU reference point or intensity modulated radiotherapy technique to a total dose of 76 Gy. All the patients received 3 mo of neoadjuvant ADT followed by RT and additional 6 mo of ADT. ASTRO Phoenix definition was used to define biochemical relapse. RESULTS Median follow up duration was 125 months. Ninety-six patients (56%) had castrate testosterone level < 20 ng/dL and 139 patients (80%) had castrate testosterone level < 50 ng/dL. Both values are valid at predicting BRFS. However, patients with testosterone < 20 ng/dL have significantly better BRFS compared to other groups (P = 0.003). When we compare two values, it was found that using 20 ng/dL is better than 50 ng/dL in predicting the BRFS (AUC = 0.63 vs 0.58, respectively). CONCLUSION Castrate testosterone level of less than 20 ng/dL is associated with better BRFS and is better in predicting the BRFS. Further studies using current standard of care of high dose IMRT and longer ADT duration might support these findings.
文摘Aim: Storage of testes-epididymides at refrigeration temperature is a promising method of short-term sperm preservation for use in reproductive biotechnology in dogs. This study aimed to determine the effect of storage time at 4°C on the quality of Nigerian local dogs’ cauda epididymal spermatozoa recovered post-castration. Materials and Methods: Testes along with their epididymides collected immediately after castration of local dogs were either processed immediately (0th hour) or stored at 4°C in the refrigerator for 12th, 24th or 48th hours and then processed. Each storage group comprised 5 pairs of testes-epididymides. Sperm motility, concentration, livability, acrosome integrity and morphology from the various storage groups were evaluated and means with standard error of the mean (±SEM) were recorded. Results: Mean percent sperm motility at 0th hour (77.0 ± 2.6) decreased significantly (p 0.05) was found when the mean sperm concentrations (×107/ml) of the storage groups (5.86 ± 47, 5.24 ± 26 and 5.38 ± 31) were compared with the control (6.48 ± 0.75). Mean percent sperm livability did not differ significantly (p > 0.05) between the 0th, 12th, 24th and 48th hour groups (86.4 ± 1.5, 78.0 ± 3.1 and 75.0 ± 1.8 respectively). However, there was a significant decrease (p 0.05) was detected in the mean percent acrosome integrity between the 0th, 12th, 24th and 48th hour groups (90.0 ± 1.5, 83.0 ± 3.5, 84.6 ± 4.6 and 82.2 ± 3.9 respectively). A significant increase (p Conclusion: The current study has shown that viable spermatozoa can be recovered after 48 hours of storage at 4°C of the cauda epididymides of Nigerian local dogs.
