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ObjectiveTo screen out the transcriptomes related to the intervention of Wuzi Yanzongwan on the spermatogenic function of semi-castrated male mice， and to explore its potential mechanism in the intervention of the progress of low spermatogenic function. MethodBalb/c mice were randomly divided into sham-operated group， model group， testosterone propionate group（0.2 mg·kg-1·d-1， intramuscular injection） and Wuzi Yanzongwan group（1.56 g·kg-1·d-1， intragastric administration） according to body weight， with 12 mice in each group. The right testicle and epididymis were extracted from the model group and the drug administration group to construct the semi-castrated model of low spermatogenic function， while the fur and the right scrotum of the sham-operated group were only cut and immediately sterilized and sutured. At the end of the intervention， hematoxylin-eosin（HE） staining was used to observe the histopathology of testis， enzyme-linked immunosorbent assay（ELISA） was used to detect the levels of serum testosterone（T）， luteinizing hormone（LH） and follicle stimulating hormone（FSH）. The sperm count and motility of epididymis were measured by automatic sperm detector of small animal. Transcriptomic microarray technology was used to detect the mRNA expression level of testicular tissue in each group， the transcriptome of genes related to the regulation of Wuzi Yanzongwan was screened， and three mRNAs were selected for Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） to verify the transcriptome data. Through the annotation analysis of Gene Ontology（GO） and the signaling pathway analysis of Kyoto Encyclopedia of Genes and Genomes（KEGG）， the related functions of drugs regulating transcriptome were analyzed. ResultCompared with the sham-operated group， the testicular tissue of mice in the model group showed spermatogenic injury， contraction and vacuolization of the seminiferous tubules， reduction of spermatogenic cells at all levels， widening of the interstitial space， obstruction of spermatogonial cell development and other morphological abnormalities， and serum T significantly decreased， LH significantly increased（P<0.01）， and FSH elevated but no statistically significant difference， the count and vitality of epididymal sperm significantly decreased（P<0.01）. There were 882 differentially expressed mRNAs in the testicular tissues， of which 565 were up-regulated and 317 were down-regulated. Cluster analysis showed that these differentially expressed mRNA could effectively distinguish between the sham-operated group and the model group. Compared with the model group， the damage to testicular tissue in the Wuzi Yanzongwan group was reduced， the structure of the seminiferous tubules was intact， vacuolization was reduced， and the number of spermatogenic cells at all levels was significantly increased and arranged tightly. The serum T significantly increased， LH significantly decreased（P<0.01）， and FSH decreased but the difference was not statistically significant. The count and vitality of sperm in the epididymis were significantly increased（P<0.01）. Moreover， Wuzi Yanzongwan could regulate 159 mRNA levels in the testes of semi-castrated mice， of which 32 were up-regulated and 127 were down-regulated， and the data of the transcriptome assay was verified to be reliable by Real-time PCR. GO and KEGG analysis showed that the transcriptome functions regulated by Wuzi Yanzongwan were involved in the whole cell cycle process of sperm development such as sex hormone production of interstitial cells in testis， renewal， differentiation， metabolism， apoptosis and signal transduction of spermatogenic cells， and were closely related to the biological behaviors of signaling pathways such as spermatogenic stem cell function， endoplasmic reticulum protein processing and metabolic program. ConclusionWuzi Yanzongwan can effectively improve the low spermatogenic function of semi-castrated male mice， and its mechanism may be related to the regulation of testicular transcriptional regulatory network， the synthesis of sex hormones in testicular interstitial cells， the function of spermatogenic stem cells， the whole cell cycle process of spermatogenesis， as well as the expression of endoplasmic reticulum protein processing and metabolic program related genes transcription.
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Abstract Objective: To describe the behavior of total alkaline phosphatase (tALP) in patients with metastatic castration-resistant prostate cancer receiving radium-223 therapy, in a real-world scenario, and to describe overall survival (OS) among such patients. Materials and Methods: This was a retrospective study involving 97 patients treated between February 2017 and September 2020. Patients were stratified by the baseline tALP (normal/elevated). A tALP response was defined as a ≥ 30% reduction from baseline at week 12. For patients with elevated baseline tALP, we also evaluated treatment response as a ≥ 10% reduction in tALP after the first cycle of treatment. We defined OS as the time from the first treatment cycle to the date of death. Results: There was a significant reduction in the median tALP after each cycle of treatment (p < 0.05 for all). Data for tALP at week 12 were available for 71 of the 97 patients. Of those 71 patients, 26 (36.6%) responded. Elevated baseline tALP was observed in 47 patients, of whom 19 (40.4%) showed a response. Longer OS was observed in the patients with normal baseline tALP, in those with elevated baseline tALP that showed a response to treatment (≥ 10% reduction), and in those who received 5-6 cycles of therapy. Conclusion: The tALP may be used to predict which patients will benefit from treatment with a greater number of cycles of radium-223 therapy and will have longer OS.
Resumo Objetivo: Descrever o comportamento da fosfatase alcalina total (tALP) em pacientes com carcinoma de próstata metastático resistente a castração, submetidos a terapia com rádio-223 em um cenário do mundo real, e a sobrevida global (SG) desses pacientes. Materiais e Métodos: Estudo retrospectivo envolvento 97 pacientes, no período de fevereiro/2017 a setembro/2020. Os pacientes foram estratificados de acordo com a tALP basal (normal/elevada). A resposta à tALP foi definida como uma redução em relação à linha de base de ≥ 30% na semana-12. Para pacientes com tALP basal elevada, também foi avaliada a resposta ao tratamento como uma redução de ≥ 10% de tALP após o primeiro ciclo. A SG foi definida como o tempo entre o primeiro ciclo e a data do óbito. Resultados: A redução da tALP média após cada ciclo foi significativa (p < 0,05). A tALP na semana 12 estava disponível para 71 dos 97 pacientes. Desses 71 pacientes, 26 (36,6%) responderam. Dezenove (40,4%) dos 47 pacientes com tALP elevada apresentaram resposta. Foi observada uma SG mais longa nos pacientes com tALP basal normal, nos pacientes com tALP basal elevada que apresentaram resposta ao tratamento (redução de ≥ 10%) e nos pacientes que receberam 5-6 ciclos. Conclusão: A tALP pode ser usada para prever parte dos pacientes que se beneficiarão do tratamento com um maior número de ciclos e uma SG mais longa.
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Background: Androgen deprivation therapy (ADT) is indispensable part of treatment for metastatic prostate cancer (MPC) patients. There is documented association between ADT and adverse cardiovascular (CV) events, with variability between the different modes. However, there is dearth of evidence on the background CV risk factors of these group of patients at diagnosis. Aims and Objectives: We envisaged this retrospective observational study in the department of oncology to document the background CV risk factors of MPC patients at diagnosis, to help us better select the available ADTs based on their CV risks. Materials and Methods: Over a period of 2 years, all patients registered for treatment with a diagnosis of MPC, indicated for ADT, and available detailed history and background cardiological evaluation at presentation, were included in the study. As indirect indicators of CV risks, history of smoking, presence and treatment of dyslipidemia, and type 2 diabetes mellitus (T2DM), were documented. As direct indicators of CV risks, presence and treatment of hypertension, ischemic heart disease (IHD), congestive cardiac failure (CCF), ECG, and echocardiography changes suggesting cardiac morbidity were documented and the data were analyzed using descriptive statistical methods. Results: Indirect indicators: dyslipidemia, habit of smoking, and T2DM were found in 74%, 29.3%, and 13.3% patients, respectively. Direct indicators: Presence of hypertension, IHD, CCF, abnormalities in ECG, and echocardiography were found in 38.7%, 10.6%, 4%, 28%, and 34.6% patients, respectively. ST-T changes on ECG, low EF, and IHD on echocardiography were seen in 28.5%, 23%, and 26.9%, respectively. Conclusions: MPC patients have a substantial pre-existing CV risk at diagnosis. Our findings warrant a meticulous screening of all MPC patients for CV risk factors, to help in judicious selection of their ADT.
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Poly ADP-ribose polymerase (PARP) inhibitors are novel agents for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in recent years, and a variety of PARP inhibitors have been reported with clinical evidence for the beneficial. Although these drugs are actually of attributes with pharmacological similarities, due to the discrepancies in the molecular structure and pharmacodynamics, the respective efficacy and safety from clinical circumstances are quite varied. While it comes to the best clinical determination, the optimization for regimen is important on the basis of clinical exhaustiveness for the reports, in addition the laboratory examination for mCRPC, and either the tumorous genetic benchmark are necessarily being calculated.
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Objective:To analyze the clinical characteristics and prognostic value of prostate-specific antigen (PSA) dynamic features in patients with metastatic castration resistant prostate cancer (mCRPC) received abiraterone acetate (AA) therapy.Methods:The data of 89 patients with mCRPC who received AA therapy from January 2017 to June 2021 in Shanghai Tongji Hospital were retrospectively reviewed. The age of patients was (75.7 ± 8.3) years old, median PSA before AA was 56.88 (19.31, 143.75) ng/ml. The PSA dynamic features included PSA nadir (PSAN) and PSAN time. PSAN was defined as the lowest value of PSA after treatment, and PSAN time was defined as time to PSAN after AA treatment. PSAN was divided into 3 groups: PSAN1 (<0.1 ng/ml), PSAN2 (0.1- 4.0 ng/ml) and PSAN3 (>4.0 ng/ml) groups. PSA response was defined as a maximum PSA decline rate ≥50%, and no PSA decline after treatment was defined as primary resistance. Cox regressions adjusted to clinical factors were performed to evaluate the influence of PSA dynamic features on patients' radiographic progression-free survival (rPFS) and overall survival (OS). Log-rank test was used to evaluate the survival time of patients in different PSAN groups. Receiver operator characteristic (ROC) curve and area under the curve (AUC) were performed to analyze the predictive value of PSA dynamic features on survival outcomes of patients.Results:The follow-up time was 17 (12, 23) months, and 75 (84.3%) patients showed PSA responses. The median PSAN was 1.82 (0.01, 11.70) ng/ml, median PSAN time was 5.0(3.0, 9.5)months. Multivariate Cox regression indicated that PSAN was an independent risk factor for rPFS ( PSAN2: HR=5.308, P=0.017; PSAN3: HR=13.209, P<0.001), and PSAN time ≥ 5 months( HR=0.309, P<0.001)was an independent protective factor for rPFS. Also, the PSAN3 was an independent risk factor for OS( HR=9.459, P=0.048). Log-rank test indicated that the rPFS of PSAN1 group (median not reached) was significantly longer than PSAN2 [median 13.0(95% CI 8.2-17.8) months, P=0.001] and PSAN3 [8.0 (95% CI 4.1-11.9) months, P<0.001] groups. ROC curve and AUC showed that PSAN had a higher predictive value in rPFS outcomes compared with T stage, metastatic disease volume, and Eastern Cooperative Oncology Group (ECOG) score (0.82 vs. 0.69, 0.68, 0.53, P<0.05). PSAN had a higher predictive value in OS outcomes than metastatic disease volume and ECOG(0.83 vs. 0.63, 0.58, P<0.05). Conclusions:Lower PSAN needs longer PSAN time. PSAN is an independent risk factor for rPFS and OS, and PSAN time is an independent protective factor for rPFS.
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Androgen receptor (AR) plays a key regulatory role in the development of castration resistant prostate cancer (CRPC), and the level of constitutive active variants represented by androgen receptor variant 7 (AR-V7) is increasing during the progress of CRPC, which can be used as a molecular marker of disease progress and prognosis of patients with CRPC. It is an important target to overcome castration resistance and improve the quality of life and survival of patients. In this paper, the function of AR-V7 and its molecular regulation mechanism in CRPC are reviewed. The research shows that the generation of AR-V7 is related to the structural rearrangement of AR gene, gene amplification and the selective splicing of AR gene transcripts, and it is affected by the coordinated regulation of multiple signal pathway molecules such as TGF-β; AR-V7 changes the transport and nuclear localization mechanism of AR protein, and further affects the transcriptional expression of downstream target genes. AR-V7 antagonizes AR activity and blocks the differentiation process driven by AR and androgen, and inhibits the expression of tumor suppressor genes to stimulate the proliferation of tumor cells, thus promoting the progress of Pca. Related targeting studies have revealed AR-V7 targets and CRPC treatment strategies. Currently, they mainly focus on AR-V7 protein degradation, mRNA expression inhibition and N-terminal domain targeting intervention. With the development of in-depth research, the molecular mechanism of AR-V7 in the progress of Pca will be gradually clarified, which will certainly play a greater role in the prevention and treatment of CRPC.
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Objective:To compare the efficacy and safety of radium-223 in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients with and without homologous recombination repair (HRR) gene mutation.Methods:The clinical data of 27 patients with mCRPC bone metastases who received radium-223 therapy from April 2021 to November 2022 in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine were retrospectively analyzed. Among the 27 mCRPC patients, 18 patients carrying HRR gene mutations belonged to the HRD(+ ) group, and 9 patients without HRR gene mutation belonged to the HRD(-) group. The age of patients in HRD(+ ) group was 69.5 (63.8, 77.0) years old, alkaline phosphatase (ALP) was 243.0 (82.8, 301.3) U/L, prostate specific antigen (PSA) was 71.6 (7.3, 329.8) ng/ml, pain score was 3.0 (1.0, 5.0) points. Eastern Cooperative Oncology Group (ECOG) score ranged from 0 to 1 points in 7 cases, and 2 points in 11 cases. In the HRD(-) group, the median age was 72.0 (64.5, 76.5) years old, ALP was 88.0 (67.5, 260.6) U/L, PSA was 19.1 (1.1, 117.8) ng/ml, and pain score was 2.0 (0, 4.5) points. The ECOG score ranged from 0 to 1 in 4 cases, and 2 in 5 cases in the HRD(-) group. There was no significant difference in the above general data between the two groups ( P>0.05). All patients received radium-223 treatment every 4 weeks, no more than 6 times. The changes of ALP, PSA, pain score and hematological adverse reactions were compared between the two groups. Results:In the HRD(+ ) group, the median number of radium-223 treatment was 4.5 (3.0, 5.3) couses, 4 patients (22.2%) completed 6 courses, and 6 patients died of prostate cancer during follow-up. In the HRD(-) group, the median number of radium treatment was 4.0 (2.5, 6.0) couses, 3 patients (33.3%) completed 6 courses, and 1 patient died of prostate cancer during follow-up. There was no significant difference in the number of radium treatment courses between the two groups ( P=0.320). ALP in HRD(+ ) group was 101.8 (61.3, 147.0) U/L after radium-223 treatment, which was significantly lower than that before treatment ( P=0.002). ALP in HRD(-) group was 73.0 (64.0, 113.5) U/L after radium-223 treatment, and it was not significantly different from that before treatment ( P=0.327). The rate of ALP response (ALP decrease >10%) in HRD(+ ) group was significantly higher than that in HRD(-) group [83.3% (15/18) vs. 44.4% (4/9), P=0.037]. PSA was 105.9(5.2, 798.4) ng/ml in HRD (+ ) group after radium-223 treatment, and was 25.6(0.8, 1 031.0) ng/ml in HRD(-) group, and they were not significantly different from that before treatment ( P=0.145, P=0.386). There were no significant differences in the rate of PSA response (PSA decrease>10%) between HRD(+ ) group and HRD(-) group [38.9% (7/18) vs. 22.2% (2/9), P=0.386]. The median pain score of HRD(+ ) group was 3.0 (0, 4.0) points after treatment, which was significantly lower than that before treatment ( P=0.028). The pain score of HRD(-) group was 1.0(0, 3.0) points after treatment, and it was not significantly different from that before treatment ( P=0.129). There was no significant difference in pain relief rate between HRD(+ ) group and HRD(-) group [66.7% (12/18) vs. 44.4% (4/9), P=0.411]. The incidence of at least one hematological adverse event during radium-223 treatment in the HRD(+ ) group was higher than that in the HRD(-) group [77.8% (14/18) vs. 33.3% (3/9), P=0.039]. There was no significant difference in the incidence of grade 1-2 hematological adverse events between the two groups [72.2%(13/18) vs. 33.3%(3/9), P=0.097]. Only 1 patient in the HRD(+ ) group experienced grade 3 anemia during treatment which was recovered after blood transfusion. Conclusions:Compared to mCRPC patients without HRR gene mutation, patients with HRR gene mutations had better ALP response and bone pain relief after radium-223 treatment. The overall incidence of adverse events in the HRD(+ ) group is higher than that in HRD(-) group, and there was no significant difference in grade 1-2 hematological adverse events between the two goups. It is necessary to expand the sample size to further verify the conclusion.
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N6-adenosine methylation, a form of methylation of the adenosine N6 site, is often found in eukaryotic mRNA and is one of the most common forms of internal RNA modification. Studies have shown that m6A affects cellular biological processes by regulating gene expression; also the regulators of m6A play a key role in the occurrence and development of various cancers. Prostate Cancer (PCa) is a common malignant tumor in men, and the risk of the disease in men over 60 years of age is increasing year by year. With the aging population, the number of PCa can be expected to continue to rise. In recent years, the role of m6A in tumorigenesis has received widespread attention, but studies on m6A methylation modification in PCa are still limited; therefore, it is particularly important to further explore the relationship between m6A methylation and PCa. In this paper, we review the recent research progress on the role, mechanism, and application of m6A methylation modification in PCa, especially the detailed review of the mechanism of METTL3, FTO, YTHDF2, three classical m6A-related regulatory proteins in PCa; and the potential application of m6A in advanced PCa (e. g., destructive resistant prostate cancer, bone metastatic prostate cancer). From the perspective of methylation modification, this paper may provide some clues to find effective therapeutic strategies for early diagnosis, treatment, and prognosis of PCa, and more theoretical references to achieve individualized treatment.
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【Objective】 To observe the efficacy of abiraterone (AA) in the treatment of metastatic castration-resistant prostate cancer (mCRPC). 【Methods】 The clinical data of a newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) patient with high risk and high tumor load were analyzed. After operation and endocrine therapy, the disease evolution was observed. Relevant literature was reviewed. 【Results】 After laparoscopic radical prostatectomy, 6-month bicalutamide and androgen deprivation therapy (ADT), the total prostate specific antigen (tPSA) was reduced to the lowest of 0.51 ng/mL, and then increased month by month. After domestic abiraterone (trade name: Qingkeshu) in the 8th month was administered for 4 months, tPSA continued to increase to 12.39 ng/mL. The case was then diagnosed as mCRPC. The treatment was adjusted again in the 11th mouth and the patient received AA (trade name: Zeke) combined with prednisone and ADT, and tPSA decreased to 0.17 ng/mL 2 months later. After 14 months of treatment, tPSA remained at about 0.12 ng/mL. Systemic ECT examination indicated that the range of bone metastases decreased and some areas of nuclide concentration turned shallow without obvious adverse reactions. 【Conclusion】 AA combined with prednisone and ADT can produce rapid decline in PSA and a good response in mCRPC patients. It can also significantly slow the progression of bone metastasis and relieve pain symptoms without obvious adverse reactions. Long-term efficacy needs further observation.
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【Objective】 To analyze the correlation between the expressions of ZEB1, androgen receptor (AR), E-cadherin (E-Ca), N-cadherin (N-Ca) and clinicopathological features of prostate cancer patients with different risk levels, and to explore their significance. 【Methods】 The clinical data of 47 patients with prostate cancer treated during Nov.2013 and Jun.2021 were retrospectively analzyed. The patients were divided into medium-low risk group and high-risk group. The expressions of ZEB1, AR, E-Ca and N-Ca in the prostate cancer tissues of the two groups were detected with immunohistochemical staining. The relationship between the expressions and Gleason grade, prostate-specific antigen (PSA) level and TNM stage was analyzed. 【Results】 The positive expression rate of ZEB1 increased with higher risk, Gleason score, and PSA level (P<0.01); the strong positive expression rate of AR decreased with higher risk and Gleason score (P<0.05); the positive expression rate of E-Ca decreased with increased risk, Gleason score, and PSA level (P<0.05); the positive expression rate of N-Ca increased with the increased risk and Gleason score (P<0.01); the positive expression rate of ZEB1 increased with higher tumor stage and TNM stage (all P<0.01); the strong positive expression rate of AR decreased only with increased TNM stage (P<0.05). Patients whose first surgical specimen showing a higher expression level of ZEB1 were more likely to develop into castration-resistant prostate cancer CRPC (P<0.05). 【Conclusion】 ZEB1 and N-Ca levels increase with increased tumor aggressiveness, while AR and E-Ca levels decrease. ZEB1, AR, E-Ca and N-Ca play important roles in prostate cancer progression. ZEB1 can not only affect prostate cancer through epithelial stromal transformation (EMT), but also through AR. ZEB1 may also be related to the development of CRPC.
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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.
Subject(s)
Male , Humans , Glutamine/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapyABSTRACT
Cruzando o processo de subjetivação com a lógica que explica a forma contemporânea do laço social, é possível tanto extrair os elementos necessários à criança para se realizar (emancipar-se do Outro parental, para que, como sujeito, seja responsável por sua posição e seus atos; dotar-se de uma solução que lhe permita se inserir no laço social; que ela coloque sua vida em uma narrativa congruente com àquela coletivamente compartilhada) quanto buscar identificar o que contraria a sua realização (o apagamento da singularidade em favor de uma individualidade formatada pelas ideologias neoliberais e o discurso capitalista). Este artigo propõe uma reconstrução isolando conceitos (desejo, gozo, sintoma) para pensar como cada um aloja que é singular no coletivo sem se dissolver na massa e sem estilhaçá-lo no rochedo da singularidade
En el cruce del proceso de subjetivación con la lógica explicadora de la forma contemporánea del vínculo social, es posible extraer los elementos necesarios para que el niño se realice. Eso inclue la emancipación del Otro paterno, de modo que, como sujeto,sea responsable de su posición y sus actos, la dotación de una solución que le permita insertarse en el vínculo social y la capacidad de poner su vida en una narrativa congruente con la compartida colectivamente. Eso favore la búsqueda por identificar lo que va en contra de su logro: la eliminación de la singularidad en favor de una individualidad moldeada por ideologías neoliberales y discurso capitalista. Este artículo propone una reconstrucción aislando conceptos (deseo, goce, síntoma) para pensar cómo cada uno almacena lo singular en lo colectivo sin perder su individualidad o perturbar lo colectivo
At the crossroads of the child's process of subjectivation and the reasoning behind contemporary social link patterns, there lies the extraction of the elements needed for the infant's self-realisation. This involves emancipating oneself from the parental Other, so that one might -having attained selfhood -, be held accountable for one's position and actions, as well as be equipped with approaches to societal integration, in addition to constructing a life narrative which is compatible with collectively shared values. This highlights the challenge posed by current trends such as the eradication of singularity in favor of an individuality shaped by neoliberal ideologies and capitalist discourse. That the child must suffer from the characteristics of the contemporary social link represents an anthropological emergency that merits both clinical and political responses.Keywords:capitalist discourse; castration; humanization; social link; childhood
Le croisement du processus de subjectivation avec la logique ordonnant la forme contemporaine du lien social permet d'extraire les éléments requis par l'enfant pour se réaliser : s'émanciper de l'Autre parental pour que, comme sujet, il soit responsable desa position et de ses actes, se dote d'une solution qui lui permette de se loger dans le lien social, mette sa vie en récit de façon congruente avec celui collectivement partagé. D'où le repérage de ce qui y contrevient aujourd'hui : l'arasement de la singularité au profit de l'individualité formatée par les idéologies néolibérales et le discours capitaliste. L'enfant a à souffrir des caractéristiques du lien social contemporain et cette urgence anthropologique exige une réponse clinique et politique
Subject(s)
Anxiety, Castration , Community Networks , Capitalism , Psychoanalysis , Child , Symbolic InteractionismABSTRACT
Resumen El cáncer de próstata metastásico resistente a la castración (CPRC) es una neoplasia heterogénea letal entre los hombres. 30% de los tumores acumulan errores deletéreos en genes implicados en la respuesta al daño del ADN (DNA damage response en inglés, DDR). Algunos de estos genes asociados a cáncer son BRCA 1 y BRCA 2. Mutaciones en estos genes favorecen la pérdida o la modificación de la función provocando un cambio permanente y transmisible, lo que conduce al desarrollo de cáncer de próstata agresivo. El objetivo del estudio fue identificar mediante secuenciación dirigida (Next-generation sequencing; NGS) variantes génicas de BRCA 1 y BRCA 2 en el genoma de pacientes con CPRC del Hospital Central Militar. Es importante destacar que los resultados demostraron una serie de alteraciones clínicas, así como una pérdida de la función de las proteínas relacionadas con mecanismos de reparación del ADN. Curiosamente, algunas de las variantes en el gen BRCA, de las que se informa aquí, son de significado incierto, lo que nos ha sido comunicado por primera vez.
Abstract Metastatic castration-resistant prostate cancer (CRPC) is a heterogeneous lethal neoplasm among men. 30% of tumors harbor deleterious errors in genes involved in the DNA damage response (DDR). Some of these cancer-associated genes are BRCA 1 and BRCA 2. Mutations to these genes favor loss or modification of function causing a permanent and transmissible change, leading to the development of aggressive prostate cancer. The aim of the study was to identify by Next-generation sequencing (NGS) BRCA 1 and BRCA 2 gene variants in peripheral blood of patients with CRPC at the Hospital Central Militar. Importantly, the results demonstrated a number of clinical alterations, as well as a loss of function of proteins related to DNA repair mechanisms. Interestingly, some of the variants in the BRCA gene, reported here, are of uncertain significance, which has been reported to us for the first time.
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Self-castration and penile amputation are rare life-threatening types of genital self-mutilation. The microsurgical technique of penile replantation is the gold standard; however, there are conflicting reports of successful macrosurgical penile replantations. Being rare, this condition may even be mistaken as criminal genital mutilation. The surgical management of penile amputation evolves over a few case reports and case series; therefore, it is prudent to publish such rare phenomena to make more awareness among the clinicians to initiate prompt and effective treatment. We report a case of self-multiple penile amputations and castration in a 70-year-old man suffering from bipolar disorder who also had failed macrosurgical penile replantation. To the best of our knowledge, this is the first case of self-multiple penile amputation with castration reported in the literature. Although ours is a single case experience, yet the macrosurgical replantation in multiple penile amputations is likely to be unsuccessful
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Background: Novel feeding strategies should be developed to produce high-quality meat in current goat production systems. Objective: To evaluate the effects of castration and the association of spineless cactus with sugarcane bagasse or elephant grass hay on nutrient intake, digestibility, performance, feeding behavior and carcass traits of feedlot kids. Methods: A total of 24 male kids (12 castrated and 12 intact), with an average initial weight of 18.5 ± 3.8 kg were allotted to a completely randomized 2 x 2 factorial design (sugar cane bagasse or elephant grass hay; intact or castrated), and confined for 70 days. Results: Nutrient intake and animal performance were similar between treatments. Sugarcane bagasse increased, when compared to elephant grass hay, the digestibility of dry matter (66.12 vs 62.88; p=0.005), crude protein (74.26 vs 70.95; p=0.029) and non-fibrous carbohydrates (91.94 vs 83.07; p<0.001). The forage source affected the time spent resting, ruminating and total chewing time, but there was no effect of diet on feeding and rumination efficiencies. Elephant grass hay increased, when compared to sugarcane bagasse, hot carcass weight (9.87 vs 10.79; p=0.025) and hot carcass yield (43.81 vs 46.87; p=0.013). Intact kids produced heavier hot carcasses when compared with castrated kids (10.80 vs 9.86; p=0.014). Conclusion: Feeding intact or castrated kids with sugar cane bagasse or elephant grass hay do not affect nutrient intake and performance. Feedlot goats have improved carcass traits if kept intact and fed elephant grass hay.
Antecedentes: Se requiere desarrollar nuevas estrategias de alimentación para producir carne de alta calidad en los sistemas actuales de producción de cabras. Objetivo: Evaluar el efecto de la castración y asociación de palma forrajera con bagazo de caña de azúcar o heno de pasto elefante sobre la ingesta de nutrientes, digestibilidad, rendimiento, comportamiento de alimentación y caracteristicas de la canal de cabritos de engorde. Métodos: Un total de 24 cabritos (12 castrados y 12 intactos) con peso inicial promedio de 18,5 ± 3,8 kg fueron asignados a un diseño factorial 2 x 2 completamente al azar (bagazo de caña de azucar o heno de pasto elefante; castrados o intactos) y confinados durante 70 días. Resultados: La ingesta de nutrientes y el rendimiento animal fueron similares entre tratamientos. El bagazo de caña de azúcar aumentó, en comparación con el heno de pasto elefante, la digestibilidad de la materia seca (66,12 vs 62,88; p=0,005), de la proteína cruda (74,26 vs 70,95; p=0,029) y de los carbohidratos no fibrosos (91,94 vs 83,07; p<0,001). La fuente de forraje afectó el tiempo de descanso, de rumia, y el tiempo total de masticación, pero no hubo efecto de la dieta sobre la eficiencia alimentacia y de la rumia. El heno de pasto elefante aumentó, en comparación con el bagazo, el peso de la canal caliente (9,87 vs 10,79; p=0,025) y el rendimiento de la canal caliente (43,81 vs 46,87; p=0,013). Los animales intactos produjeron canales calientes más pesadas en comparación con los castrados (10,80 vs 9,86; p=0,014). Conclusión: La alimentación de cabritos enteros o castrados con bagazo de caña de azúcar o heno de pasto elefante no afecta la ingesta de nutrientes y el rendimiento. Los cabritos tienen mejores características de canal si se alimentan con heno de pasto elefante y se dejan enteros.
Antecedentes: Novas estratégias de alimentação devem ser desenvolvidas para produção de carne de qualidade nos atuais sistemas de produção de caprinos. Objetivo: Avaliar o efeito da castração e da associação da palma forrageira com o bagaço de cana de açúcar ou feno de capim elefante no consumo de nutrientes, digestibilidade, desempenho, comportamento ingestivo e características de carcaça de cabritos confinados. Métodos: Um total de 24 caprinos (12 castrados e 12 não castrados), com peso inicial médio de 18,5 ± 3,8 kg, distribuídos em um delineamento experimental inteiramente casualizado, em arranjo fatorial 2 x 2 (bagaço de cana de açúcar ou feno de capim elefante; inteiros ou castrados), confinados durante 70 dias. Resultados: O consumo de nutrientes e o desempenho dos animais foram semelhante entre os tratamentos. O bagaço de cana elevou, quando comparado com o feno, a digestibilidade da matéria seca (66,12 vs 62,88; p=0,005), proteína (74,26 vs 70,95; p=0,029) e carboidratos não fibrosos (91,94 vs 83,07; p<0,001). As fontes de fibra afetaram os tempos de ócio, ruminação e mastigação total, mas não houve efeito para as eficiências de alimentação e ruminação. O feno de capim elefante aumentou, quando comparado com o bagaço, o peso de caracaça quente (9,87 vs 10,79; p=0,025) e o rendimento de carcaça quente (43,81 vs 46,87; p=0,013). Os animais inteiros produziram carcaças quentes mais pesadas em comparação aos castrados (10,80 vs 9,86; p=0,014). Conclusão: Alimentar caprinos inteiros ou castrados com bagaço de cana ou feno de capim-elefante não interfere no consumo de nutrientes e desempenho. Caprinos confinados terão as características de carcaça melhoradas se mantidos intactos e alimentados com feno de capim elefante.
ABSTRACT
Castration-resistant prostate cancer (CRPC) is an important research focus in the field of prostate cancer. The adjustment of its diagnosis criteria also directly impacts the clinical diagnosis and treatment practice, as well as the design and implementation of the relevant clinical trials. The Prostate Cancer Clinical Trials Working Group (PCWG) has published several consensuses to provide further reference in clinical practice and trials design. In PCWG3, the recommended PSA cut-off value to confirmed CRPC diagnosis was further lowered from 2 ng / ml to 1 ng/ml. The update of PCWG3 may have a profound impact on the clinical diagnosis, treatment and trials design of prostate cancer in the future.
ABSTRACT
Objective:To investigate the risk factors for progression to castration-resistant prostate cancer (CRPC) in metastatic prostate cancer (mPCa) patients who underwent androgen deprivation therapy (ADT).Methods:One hunred mPCa patients underwent ADT were followed up from January 2014 to December 2020 in the Affiliated Central Hospital of Shenyang Medical University. Retrospective analyze the patient′s Gleason score, initial PSA value, minimum prostate specific antigen (nPSA) and time when PSA drops to the lowest point (TTN), and record the state of lymph node metastasis and bone metastasis. Single factor Kaplan-Meier analysis and multivariate Cox regression analysis were used to explore the related risk factors affecting the progress of CRPC.Results:A total of 82 cases (82%) of ADT patients progressed to CRPC. Univariate Kaplan-Meier analysis showed that Gleason score, PSA initial value, lowest nPSA and time to TTN, lymph node metastasis and bone metastasis are risk factors for CRPC ( P<0.01 or<0.05); Multivariate Cox regression analysis showed that Gleason score, initial PSA value, nPSA and TTN are independent risk factors for PCa patients to progress to CRPC ( P<0.01 or<0.05). Conclusions:This study demonstrated that Gleason score, lymph node metastasis, bone metastasis, initial PSA value, nPSA and TTN are risk factors for the progression of CRPC. Patients with higher Gleason grade, higher nPSA, shorter TTN, lymph node and bone metastasis have shorter PFS and higher risk of progression to CRPC.
ABSTRACT
Prostate cancer is the most common male malignant tumor in the world, and its death toll is second only to lung cancer. Androgen deprivation therapy (ADT) is a major treatment for prostate cancer besides radical surgery. ADT treatment will lead to the inevitable progression of prostate cancer patients to castration-resistant prostate cancer (CRPC). The current research results have confirmed that the transformation from androgen deprivation prostate cancer (ADPC) to CRP is related to the reactivation of the androgen receptor signal pathway. In this review, the research progress on the mechanism of the androgen receptor signaling pathway in CRPC was reviewed in order to provide a scientific basis and new ideas for the diagnosis and treatment of CRP.
ABSTRACT
There are few studies about the treatment of metastatic castration-resistant prostate cancer (mCRPC) with darolutamide. This paper reports a case that an 83-year-old patient complained of dysuria. His initial diagnosis was metastatic hormone sensitive prostate cancer(mHSPC). Androgen deprivation therapy (ADT) plus bicalutamide was performed. Re-examination of bone scan after half a year revealed that there were more than two new bone metastases, which was considered entering mCRPC. Due to the patient’s advanced age, post medical history of epilepsy, type 2 diabetes and cardiac radiofrequency ablation, long-term use of phenobarbital and repaglinide, the therapy was changed to ADT plus darolutamide to avoid drug contraindications. Re-examination of bone scan after 10 months revealed decreased metabolism in some metastases, and tPSA declined continuously.
ABSTRACT
Objective:To analyze the efficacy and safety of radium-223 in the treatment of metastatic castration resistant prostate cancer (mCRPC).Methods:The clinical data of 22 patients with mCRPC treated with radium-223 in the Chongqing University Cancer Hospital from January 2021 to January 2022 were analyzed retrospectively. The average age was (70.7±1.3)years old. There were 7 cases with ECOG score of 1 and 15 cases with ECOG score of 2. There were 7 cases with grade 2 and 15 cases with grade 3 bone metastasis. For mCRPC, 1 case (4.6%) received first-line treatment, 4 cases (18.2%) received second-line treatment, 10 cases (45.5%) received third-line treatment, 4 cases (18.2%) received fourth-line treatment, and 3 cases (13.6%) received fifth-line treatment. The median time from the diagnosis of mCRPC to the start of radium-223 treatment was 29 (20, 34) months. Radium-223 (55kbq/kg) was injected intravenously every 4 weeks for up to 6 cycles. Before treatment, the median alkaline phosphatase (ALP) was 147.0 (101.8, 212.5)U/L, the median prostate specific antigen (PSA) was 44.7(20.2, 99.1)ng/ml, and 6 patients (27.3%) were complicated with grade 1-2 anemia. The median hemoglobin was 115.0 (103.8, 122.5) g/L, the average neutrophil was (3.0 ± 0.3)×10 9/L, and the average platelet was (169.8 ± 17.0)×10 9/L. The overall survival (OS), radiographic progression-free survival time (rPFS), time to PSA progression, PSA response rate, pain response rate, and time to pain progression were analyzed. Stratified analysis was carried out according to the number of treatment lines experienced before radium-223 treatment. At the same time, the main adverse reactions during radium-223 treatment were analyzed. Results:The mean number of treatment courses with radium-223 was 2.7(ranging 1 to 6), with 4 patients completing 6 courses, 12 (54.6%) completing ≥ 3 courses, and 10 (45.5%) completing < 3 courses. Thirteen patients (59.1%) were treated with radium-223 alone and 9 (40.9%) in combination with other treatments (1 of docetaxel chemotherapy, 2 of enzalutamide, 3 of olaparib, and 3 of estramustine phosphate). None of the patients in this group were treated with bisphosphonates. Ten patients (45.5%) in this group died, all due to disease progression. The median overall survival time of the 22 cases was 11.0 (2.2, 19.8) months. Three patients (13.6%), 7 patients (31.8%), 3 patients (13.6%), and 1 patient (4.5%) showed radiographic progression at 2, 3, 4, and 10 months after treatment, respectively, while the remaining 8 patients (36.4%) did not show radiographic progression during the follow-up period, and the median radiographic progression free time for the 22 patients was 4.0 (3.1, 4.9) months. There were four cases (18.2%) showed PSA response, of which three cases (13.6%) showed PSA rising again later, and one case (4.5%) showed continuous PSA decline. The median time to PSA progression for the 22 patients was 3.6 (2.2, 5.1) months. Fifteen patients (68.2%) experienced pain response at 1 month of treatment, of whom 5 (22.7%) experienced increased pain later and 10 (45.5%) experienced sustained pain relief. The median time to pain progression was 5.5 (3.5, 7.6) months in 22 patients. No patients received radiotherapy or surgery for pain, and no patients experienced fracture. In this group, 7 patients (31.8%) had a post-treatment ALP decrease ≥30% from baseline. Major adverse events during radium-223 treatment were all grade 1 to 2 events, no grade ≥3 adverse events, and no treatment discontinuers due to adverse events.Conclusions:Radium-223 resulted in high pain response rates and prolonged OS, rPFS and time to PSA progression in patients with mCRPC. Adverse effects were low during treatment. The conclusions need to be validated by further expansion of the sample size and extended follow-up.