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  Citation statistics : Table of Contents
   2018| May-June  | Volume 20 | Issue 3  
    Online since April 26, 2018

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The role of peroxisome proliferator-activated receptor gamma in prostate cancer
Catherine Elix, Sumanta K Pal, Jeremy O Jones
May-June 2018, 20(3):238-243
DOI:10.4103/aja.aja_15_17  PMID:28597850
Despite great progress in the detection and treatment of prostate cancer, this disease remains an incredible health and economic burden. Although androgen receptor (AR) signaling plays a key role in the development and progression of prostate cancer, aberrations in other molecular pathways also contribute to the disease, making it essential to identify and develop drugs against novel targets, both for the prevention and treatment of prostate cancer. One promising target is the peroxisome proliferator-activated receptor gamma (PPARγ) protein. PPARγ was originally thought to act as a tumor suppressor in prostate cells because agonist ligands inhibited the growth of prostate cancer cells; however, additional studies found that PPARγ agonists inhibit cell growth independent of PPARγ. Furthermore, PPARγ expression increases with cancer grade/stage, which would suggest that it is not a tumor suppressor but instead that PPARγ activity may play a role in prostate cancer development and/or progression. Indeed, two new studies, taking vastly different, unbiased approaches, have identified PPARγ as a target in prostate cancer and suggest that PPARγ inhibition might be useful in prostate cancer prevention and treatment. These findings could lead to a new therapeutic weapon in the fight against prostate cancer.
  9 4,219 489
Role of chemotherapy in prostate cancer
Rita Nader, Joelle El Amm, Jeanny B Aragon-Ching
May-June 2018, 20(3):221-229
DOI:10.4103/aja.aja_40_17  PMID:29063869
Chemotherapy in prostate cancer (PCa) has undergone dramatic landscape changes. While earlier studies utilized varying chemotherapy regimens which were found to be largely palliative in nature and hardly resulted in durable or meaningful responses, docetaxel resulted in the first chemotherapy agent that showed improvement in overall survival in metastatic castration-resistant prostate cancer (mCRPC). However, combination chemotherapy or any agents added to docetaxel have failed to yield incremental benefits. The improvement in overall survival as well as secondary endpoints of prostate-specific antigen (PSA) and time to recurrence when using docetaxel in the metastatic hormone-sensitive state has changed the standard of care for treatment of newly diagnosed de novo metastatic PCa. There are also promising results in locally advanced PCa and high-risk PCa in both the neoadjuvant and adjuvant settings. This review summarizes the historical as well as the more contemporary use of chemotherapeutic agents in PCa in varying states and phases of disease.
  9 4,039 699
Vitamin D in prostate cancer
Donald L Trump, Jeanny B Aragon-Ching
May-June 2018, 20(3):244-252
DOI:10.4103/aja.aja_14_18  PMID:29667615
Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited.
  7 4,842 841
Perspectives on the clinical development of immunotherapy in prostate cancer
Lisa M Cordes, James L Gulley, Ravi A Madan
May-June 2018, 20(3):253-259
DOI:10.4103/aja.aja_9_18  PMID:29582792
Despite impressive survival benefits with immunotherapy in patients with various solid tumors, the full potential of these agents in prostate cancer has yet to be realized. Sipuleucel-T demonstrated a survival benefit in this population, indicating that prostate cancer is an immunoresponsive disease; however, these results have not been matched by other agents. A large trial with ipilimumab in prostate cancer failed to meet its primary objective, and small trials with PD-1/PD-L1 inhibitors did not yield a significant improvement in overall response. However, several late-stage clinical trials are underway with other vaccines in prostate cancer. Reports of clinical benefit with immunotherapies, particularly when used in combination or a select population, have provided the framework to develop sound clinical trials. Understanding immunogenic modulation, antigen spread, biomarkers, and DNA-repair defects will also help mold future strategies. Through rational patient selection and evidence-based combination approaches, patients with prostate cancer may soon derive durable survival benefits with immunotherapies.
  6 5,079 749
Bone-targeted therapies to reduce skeletal morbidity in prostate cancer
Tanya B Dorff, Neeraj Agarwal
May-June 2018, 20(3):215-220
DOI:10.4103/aja.aja_12_18  PMID:29553053
Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including (1) bisphosphonates such as zoledronic acid, which directly target osteoclasts, (2) denosumab, a receptor activator of nuclear factor-kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and (3) radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer (mCRPC). Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.
  4 5,157 849
Utility of cell-free nucleic acid and circulating tumor cell analyses in prostate cancer
Theodore Gourdin, Guru Sonpavde
May-June 2018, 20(3):230-237
DOI:10.4103/aja.aja_1_18  PMID:29578115
Prostate cancer is characterized by bone metastases and difficulty of objectively measuring disease burden. In this context, cell-free circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) quantitation and genomic profiling afford the ability to noninvasively and serially monitor the tumor. Recent data suggest that ctDNA and CTC quantitation are prognostic for survival. Indeed, CTC enumeration using the CellSearch® platform is validated as a prognostic factor and warrants consideration as a stratification factor in randomized trials. Changes in quantities of CTCs using CellSearch also are prognostic and may be employed to detect a signal of activity of new agents. Molecular profiling of both CTCs and ctDNA for androgen receptor (AR) variants has been associated with outcomes in the setting of novel androgen inhibitors. Serial profiling to detect the evolution of new alterations may inform drug development and help develop precision medicine. The costs of these assays and the small quantities in which they are detectable in blood are a limitation, and novel platforms are required to address this challenge. The presence of multiple platforms to assay CTCs and ctDNA also warrants the consideration of a mechanism to allow comparison of data across platforms. Further validation and the continued development and standardization of these promising modalities will facilitate their adoption in the clinic.
  2 5,016 650
A rare polypyrimidine tract mutation in the androgen receptor gene results in complete androgen insensitivity syndrome
Shi-Min Yuan, Huan Huang, Chao-Feng Tu, Juan Du, Da-Bao Xu, Ge Lin, Guang-Xiu Lu, Yue-Qiu Tan
May-June 2018, 20(3):308-310
DOI:10.4103/aja.aja_32_17  PMID:28857053
  2 2,038 250
The transcription factor ZEB1 promotes an aggressive phenotype in prostate cancer cell lines
Octavio Orellana-Serradell, Daniela Herrera, Enrique A Castellon, Hector R Contreras
May-June 2018, 20(3):294-299
DOI:10.4103/aja.aja_61_17  PMID:29271397
It has been reported that one of the factors that promotes tumoral progression is the abnormal activation of the epithelial–mesenchymal transition program. This process is associated with tumoral cells acquiring invasive and malignant properties and has the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) as one of its main activators. However, the role of ZEB1 in promoting malignancy in prostate cancer (PCa) is still unclear. Here, we report that ZEB1 expression correlates with Gleason score in PCa samples and that expression of ZEB1 regulates epithelial–mesenchymal transition and malignant characteristics in PCa cell lines. The results showed that ZEB1 expression is higher in samples of higher malignancy and that overexpression of ZEB1 was able to induce epithelial–mesenchymal transition by upregulating the mesenchymal marker Vimentin and downregulating the epithelial marker E-Cadherin. On the contrary, ZEB1 silencing repressed Vimentin expression and upregulated E-Cadherin. ZEB1 expression conferred enhanced motility and invasiveness and a higher colony formation capacity to 22Rv1 cells whereas DU145 cells with ZEB1 silencing showed a decrease in those same properties. The results showed that ZEB1 could be a key promoter of tumoral progression toward advanced stages of PCa.
  2 2,471 344
Altered PIWI-LIKE 1 and PIWI-LIKE 2 mRNA expression in ejaculated spermatozoa of men with impaired sperm characteristics
Maria Giebler, Thomas Greither, Lisa Müller, Carina Mösinger, Hermann M Behre
May-June 2018, 20(3):260-264
DOI:10.4103/aja.aja_58_17  PMID:29286006
In about half the cases of involuntary childlessness, a male infertility factor is involved. The PIWI-LIKE genes, a subclade of the Argonaute protein family, are involved in RNA silencing and transposon control in the germline. Knockout of murine Piwi-like 1 and 2 homologs results in complete infertility in males. The aim of this study was to analyze whether the mRNA expression of human PIWI-LIKE 1–4 genes is altered in ejaculated spermatozoa of men with impaired sperm characteristics. Ninety male participants were included in the study, among which 47 were with normozoospermia, 36 with impaired semen characteristics according to the World Health Organization (WHO) manual, 5th edition, and 7 with azoospermia serving as negative control for the PIWI-LIKE 1–4 mRNA expression in somatic cells in the ejaculate. PIWI-LIKE 1–4 mRNA expression in the ejaculated spermatozoa of the participants was measured by quantitative real-time PCR. In nonazoospermic men, PIWI-LIKE 1–4 mRNA was measurable in ejaculated spermatozoa in different proportions. PIWI-LIKE 1 (100.0%) and PIWI-LIKE 2 (49.4%) were more frequently expressed than PIWI-LIKE 3 (9.6%) and PIWI-LIKE 4 (15.7%). Furthermore, a decreased PIWI-LIKE 2 mRNA expression showed a significant correlation with a decreased sperm count (P = 0.022) and an increased PIWI-LIKE 1 mRNA expression with a decreased progressive motility (P = 0.048). PIWI-LIKE 1 and PIWI-LIKE 2 mRNA expression exhibited a significant association with impaired sperm characteristics and may be a useful candidate for the evaluation of the impact of PIWI-LIKE 1–4 mRNA expression on male infertility.
  2 2,153 313
The path forward in prostate cancer therapeutics
Jeanny B Aragon-Ching, Ravi A Madan
May-June 2018, 20(3):213-214
DOI:10.4103/aja.aja_3_18  PMID:29536949
  1 4,138 320
Zinner's syndrome: clinical features and imaging diagnosis
Xiao-Song Jiang, Huan-Jun Wang, Jin-Hua Lin, Yan Guo, Can-Hui Sun, Ling Lin, Jian Guan
May-June 2018, 20(3):316-317
DOI:10.4103/aja.aja_21_17  PMID:28695865
  1 2,454 280
ASIC1a contributes to the symptom of pain in a rat model of chronic prostatitis
Song Fan, Zong-Yao Hao, Li Zhang, Jun Zhou, Yi-Fei Zhang, Shen Tai, Xian-Sheng Zhang, Chao-Zhao Liang
May-June 2018, 20(3):300-305
DOI:10.4103/aja.aja_55_17  PMID:29226878
This study aims to validate our hypothesis that acid-sensing ion channels (ASICs) may contribute to the symptom of pain in patients with chronic prostatitis (CP). We first established a CP rat model, then isolated the L5-S2 spinal dorsal horn neurons for further studies. ASIC1a was knocked down and its effects on the expression of neurogenic inflammation-related factors in the dorsal horn neurons of rat spinal cord were evaluated. The effect of ASIC1a on the Ca2+ ion concentration in the dorsal horn neurons of rat spinal cord was measured by the intracellular calcium ([Ca2+]i) intensity. The effect of ASIC1a on the p38/mitogen-activated protein kinase (MAPK) signaling pathway was also determined. ASIC1a was significantly upregulated in the CP rat model as compared with control rats. Acid-induced ASIC1a expression increased [Ca2+]i intensity in the dorsal horn neurons of rat spinal cord. ASIC1a also increased the levels of neurogenic inflammation-related factors and p-p38 expression in the acid-treated dorsal horn neurons. Notably, ASIC1a knockdown significantly decreased the expression of pro-inflammatory cytokines. Furthermore, the levels of p-p38 and pro-inflammatory cytokines in acid-treated dorsal horn neurons were significantly decreased in the presence of PcTx-1, BAPTA-AM, or SB203580. Our results showed that ASIC1a may contribute to the symptom of pain in patients with CP, at least partially, by regulating the p38/MAPK signaling pathway.
  1 1,961 294
Histological subtype is a significant predictor for inguinal lymph node metastasis in patients with penile squamous cell carcinoma
Jin-You Wang, Ming-Zhu Gao, De-Xin Yu, Dong-Dong Xie, Yi Wang, Liang-Kuan Bi, Tao Zhang, De-Mao Ding
May-June 2018, 20(3):265-269
DOI:10.4103/aja.aja_60_17  PMID:29286007
The present study aimed to investigate the relationship between histopathological subtype and the probability of inguinal lymph node metastasis (ILNM) in patients with penile squamous cell carcinoma (PSCC). The clinical records of 198 consecutive patients with PSCC were analyzed retrospectively. Primary lesions were reevaluated according to the 2016 World Health Organization (WHO) histopathological classification. We retrieved the clinicopathological factors from the medical records including age, clinical lymph node stage, pathological tumor stage, lymphatic invasion, and nerve invasion. Uni- and multivariate logistic regression analyses were used to explore the risk factors of ILNM. Multivariate analyses identified clinical lymph node stage (P = 0.000), pathological tumor stage (P = 0.016), histologic grade (P = 0.000), and risk group of histological subtypes (P = 0.029) as independent predictors for ILNM. Compared with the low-risk group of PSCC subtypes, the intermediate- (HR: 3.66, 95% CI: 1.30–10.37, P = 0.021) and high-risk groups (HR: 28.74, 95% CI: 2.37–348.54, P = 0.008) were significantly associated with ILNM. In conclusion, the histopathological subtype of the primary lesion is a significant predictor for ILNM in patients with PSCC.
  1 1,696 285
Intermittent, low-dose, antiandrogen monotherapy as an alternative therapeutic option for patients with positive surgical margins after radical prostatectomy
Kyung Hwa Choi, Seung Ryeol Lee, Young Kwon Hong, Dong Soo Park
May-June 2018, 20(3):270-275
DOI:10.4103/aja.aja_56_17  PMID:29271399
The aim of the present study was to determine whether oncologic outcomes and adverse events associated with active on/off intermittent antiandrogen monotherapy (daily bicalutamide, 50 mg per day) are comparable with those of standard external beam radiation therapy (EBRT) or combined androgen blockade (CAB) therapy in prostate cancers with positive surgical margins after radical prostatectomy. Two hundred twenty-three patients with positive surgical margins post-radical prostatectomy who underwent active surveillance (AS, n = 32), EBRT without hormone therapy (n = 55), intermittent antiandrogen monotherapy without EBRT (IAAM, n = 50), or CAB without EBRT (n = 86), between 2007 and 2014, were reviewed retrospectively. Pathologic outcomes, biochemical recurrence rates, radiological disease progression, and adverse events were collected from medical records. Biochemical recurrence rates, biochemical recurrence-free survival rates, and radiological recurrence were not different between the groups (P = 0.225, 0.896, and 0.284, respectively). Adverse event rates and severities were lower for IAAM compared with EBRT or CAB (both P < 0.05), but were comparable to those for AS (P = 0.591 and 0.990, respectively). Grade ≥3 adverse events were not reported in the IAAM or AS groups. Erectile dysfunction and loss of libido rates were lower in the IAAM group compared with the EBRT and CAB groups (P = 0.032). Gastrointestinal complications were more frequently reported in the EBRT group (P = 0.008). Active on/off IAAM treatment might be an appropriate treatment option for patients with positive surgical margins after radical prostatectomy. Furthermore, regarding oncologic outcomes, IAAM was comparable to standard EBRT but had a milder adverse event profile.
  1 1,851 271
Androgen receptor deficiency in monocytes/macrophages does not alter adiposity or glucose homeostasis in male mice
Katya B Rubinow, Barbara Houston, Shari Wang, Leela Goodspeed, Kayoko Ogimoto, Gregory J Morton, Christopher McCarty, Robert E Braun, Stephanie T Page
May-June 2018, 20(3):276-283
DOI:10.4103/aja.aja_54_17  PMID:29205180
Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor (AR) is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages (M-ARKO) were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition. Wild-type (WT) and M-ARKO mice (12–22 weeks of age, n = 12 per group) were maintained on a regular chow diet for 8 weeks and then switched to a high-fat diet for 8 additional weeks. At baseline and on both the regular chow and high-fat diets, no differences in lean mass or fat mass were observed between groups. Consistent with the absence of differential body weight or adiposity, no differences in food intake (3.0 ± 0.5 g per day for WT mice vs 2.8 ± 0.4 g per day for M-ARKO mice) or total energy expenditure (0.6 ± 0.1 Kcal h−1 for WT mice vs 0.5 ± 0.1 Kcal h−1 for M-ARKO mice) were evident between groups during high-fat feeding. Liver weight was greater in M-ARKO than that in WT mice (1.5 ± 0.1 g vs 1.3 ± 0.0 g, respectively, P = 0.02). Finally, M-ARKO mice did not exhibit impairments in glucose tolerance or insulin sensitivity relative to WT mice at any study time point. In aggregate, these findings suggest that AR signaling specifically in monocytes/macrophages does not contribute to the regulation of systemic energy balance, adiposity, or insulin sensitivity in male mice.
  1 2,058 323
Transcription and regulation of hepatitis B virus genes in host sperm cells
Ying Zhong, Dong-Ling Liu, Mohamed Morsi M Ahmed, Peng-Hao Li, Xiao-Ling Zhou, Qing-Dong Xie, Xiao-Qing Xu, Ting-Ting Han, Zhi-Wei Hou, Ji-Hua Huang, Lan Xu, Tian-Hua Huang
May-June 2018, 20(3):284-289
DOI:10.4103/aja.aja_46_17  PMID:29111540
To investigate whether transcription of hepatitis B virus(HBV) gene occurs in human sperm, total RNA was extracted from sperm of patients with chronic HBV infection(test-1), from donor sperm transfected with a plasmid containing the full-length HBV genome(test-2), and from nontransfected donor sperm(control), used as the template for reverse transcription-polymerase chain reaction(RT-PCR). Positive bands for HBV DNA were observed in the test groups but not in the control. Next, to identify the role of host genes in regulating viral gene transcription in sperm, total RNA was extracted from 2-cell embryos derived from hamster oocytes fertilized invitro by HBV-transfected(test) or nontransfected(control) human sperm and successively subjected to SMART-PCR, suppression subtractive hybridization, T/A cloning, bacterial amplification, microarray hybridization, sequencing and the Basic Local Alignment Search Tool (BLAST) search to isolate differentially expressed genes. Twenty-nine sequences showing significant identity to five human gene families were identified, with chorionic somatomammotropin hormone 2(CSH2), eukaryotic translation initiation factor 4 gamma 2(EIF4G2), pterin-4 alpha-carbinolamine dehydratase 2(PCBD2), pregnancy-specific beta-1-glycoprotein 4(PSG4) and titin(TTN) selected to represent target genes. Using real-time quantitative RT-PCR (qRT-PCR), when CSH2 and PCBD2(or EIF4G2, PSG4 and TTN) were silenced by RNA interference, transcriptional levels of HBV s and x genes significantly decreased(or increased)(P<0.05). Silencing of a control gene in sperm did not significantly change transcription of HBV s and x genes(P>0.05). This study provides the first experimental evidence that transcription of HBV genes occurs in human sperm and is regulated by host genes.
  1 3,001 342
Proton-pump inhibitor use does not affect semen quality in subfertile men
Sorena Keihani, James R Craig, Chong Zhang, Angela P Presson, Jeremy B Myers, William O Brant, Kenneth I Aston, Benjamin R Emery, Timothy G Jenkins, Douglas T Carrell, James M Hotaling
May-June 2018, 20(3):290-293
DOI:10.4103/aja.aja_35_17  PMID:28879865
Proton-pump inhibitors (PPIs) are among the most widely used drugs worldwide. PPI use has recently been linked to adverse changes in semen quality in healthy men; however, the effects of PPI use on semen parameters remain largely unknown specifically in cases with male factor infertility. We examined whether PPI use was associated with detrimental effects on semen parameters in a large population of subfertile men. We retrospectively reviewed data from 12 257 subfertile men who had visited our fertility clinic from 2003 to 2013. Patients who reported using any PPIs for >3 months before semen sample collection were included; 7698 subfertile men taking no medication served as controls. Data were gathered on patient age, medication use, and conventional semen parameters; patients taking any known spermatotoxic medication were excluded. Linear mixed-effect regression models were used to test the effect of PPI use on semen parameters adjusting for age. A total of 248 patients (258 samples) used PPIs for at least 3 months before semen collection. In regression models, PPI use (either as the only medication or when used in combination with other nonspermatotoxic medications) was not associated with statistically significant changes in semen parameters. To our knowledge, this is the largest study to compare PPI use with semen parameters in subfertile men. Using PPIs was not associated with detrimental effects on semen quality in this retrospective study.
  1 3,022 341
Commentary on “Altered PIWI-LIKE 1 and PIWI-LIKE 2 mRNA expression in ejaculated spermatozoa of men with impaired sperm characteristics”
De-Yi Liu
May-June 2018, 20(3):318-318
DOI:10.4103/aja.aja_67_17  PMID:29350206
  - 2,189 248
Microdissection testicular extraction for a patient with transverse testicular ectopia and testicular fusion
Chen Chen, Yi-Chun Wang, Ya-Min Wang, Chao Qin, Ning-Hong Song
May-June 2018, 20(3):306-307
DOI:10.4103/aja.aja_33_17  PMID:28869220
  - 1,802 219
Redo surgery for failed hypospadias treatment using a novel single-stage repair
Min Wu, Shu-Zhu Chen, Wei-Jing Ye, Yi-Dong Liu
May-June 2018, 20(3):311-312
DOI:10.4103/aja.aja_22_17  PMID:28675154
  - 2,041 283
MRI feature analysis of uncommon prostatic malignant tumors
Zhao-Yan Feng, Xiang-De Min, Liang Wang, Ba-Sen Li, Zan Ke, Pei-Pei Zhang, Zhen Kang
May-June 2018, 20(3):313-315
DOI:10.4103/aja.aja_12_17  PMID:28566559
  - 1,728 205