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   Table of Contents - Current issue
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July-August 2020
Volume 22 | Issue 4
Page Nos. 335-440

Online since Thursday, June 18, 2020

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REVIEW  

Low-intensity pulsed ultrasound for regenerating peripheral nerves: potential for penile nerve p. 335
Dong-Yi Peng, Amanda B Reed-Maldonado, Gui-Ting Lin, Shu-Jie Xia, Tom F Lue
DOI:10.4103/aja.aja_95_19  PMID:31535626
Peripheral nerve damage, such as that found after surgery or trauma, is a substantial clinical challenge. Much research continues in attempts to improve outcomes after peripheral nerve damage and to promote nerve repair after injury. In recent years, low-intensity pulsed ultrasound (LIPUS) has been studied as a potential method of stimulating peripheral nerve regeneration. In this review, the physiology of peripheral nerve regeneration is reviewed, and the experiments employing LIPUS to improve peripheral nerve regeneration are discussed. Application of LIPUS following nerve surgery may promote nerve regeneration and improve functional outcomes through a variety of proposed mechanisms. These include an increase of neurotrophic factors, Schwann cell (SC) activation, cellular signaling activations, and induction of mitosis. We searched PubMed for articles related to these topics in both in vitro and in vivo animal research models. We found numerous studies, suggesting that LIPUS following nerve surgery promotes nerve regeneration and improves functional outcomes. Based on these findings, LIPUS could be a novel and valuable treatment for nerve injury-induced erectile dysfunction.
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ORIGINAL ARTICLES Top

Deficiency of the transcription factor PLAG1 results in aberrant coiling and morphology of the epididymis p. 342
Joanne Wong, Almas R Juma, Stephanie C Tran, Jemma G Gasperoni, Sylvia V H Grommen, Bert De Groef
DOI:10.4103/aja.aja_87_19  PMID:31464202
Mice deficient in the transcription factor pleomorphic adenoma gene 1 (PLAG1) exhibit reproductive issues that are characterized, in part, by decreased progressive sperm motility in the male. However, the underlying cause of this impairment is unknown. As epididymal transit is critical for sperm maturation and motility, the morphology of the epididymis of Plag1-deficient mice was investigated and the spatial expression patterns of PLAG1 protein and mRNA were identified. Using X-gal staining and in situ hybridization, PLAG1 was shown to be widely expressed in both the epithelium and stroma in all regions of the mouse epididymis. Interestingly, the X-gal staining pattern was markedly different in the cauda, where it could be suggestive of PLAG1 secretion into the epididymal lumen. At all ages investigated, the morphology of epididymides from Plag1 knockout (KO) mice was aberrant; the tubule failed to elongate and coil, particularly in the corpus and cauda, and the cauda was malformed, lacking its usual bulbous shape. Moreover, the epididymides from Plag1 KO mice were significantly reduced in size relative to body weight. In 20% of Plag1-deficient mice, the left testicle and epididymis were lacking. The impaired morphogenesis of the epididymal tubule is likely to be a major contributing factor to the fertility problems observed in male Plag1-deficient mice. These results also establish PLAG1 as an important regulator of male reproduction, not only through its involvement in testicular sperm production, but also via its role in the development and function of the epididymis.
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Use of testicular sperm in couples with SCSA-defined high sperm DNA fragmentation and failed intracytoplasmic sperm injection using ejaculated sperm p. 348
Mohannad Alharbi, Fadl Hamouche, Simon Phillips, Jacques Isaac Kadoch, Armand Zini
DOI:10.4103/aja.aja_99_19  PMID:31571640
Sperm DNA fragmentation (SDF) has been linked with male infertility, and previous studies suggest that SDF can have negative influence on pregnancy outcomes with assisted reproduction. We performed a retrospective review of consecutive couples with a high SDF level that had intracytoplasmic sperm injection (ICSI) using testicular sperm (T-ICSI). We compared the T-ICSI outcomes to that of two control groups: 87 couples with failed first ICSI cycle and who had a second ICSI cycle using ejaculated sperm (Ej-ICSI), and 48 consecutive couples with high sperm chromatin structure assay (SCSA)-defined SDF (>15%) that underwent an ICSI cycle using ejaculated sperm after one or more failed ICSI cycles (Ej-ICSI-high SDF). The mean number of oocytes that were retrieved and the total number of embryos were not different among the three groups. The mean number of transferred embryos in the T-ICSI group was higher than the Ej-ICSI group but not significantly different than the Ej-ICSI-high SDF group (1.4, 1.2, and 1.3, respectively, P < 0.05). Clinical pregnancy rate in the T-ICSI group was not significantly different than the Ej-ICSI and Ej-ICSI-high SDF groups (48.6%, 48.2%, and 38.7%, respectively, P > 0.05). No significant difference was found in live birth rate when comparing T-ICSI to Ej-ICSI and Ej-ICSI-high SDF groups. The results suggest that pregnancy outcomes and live birth rates with T-ICSI are not significantly superior to Ej-ICSI in patients with an elevated SCSA-defined sperm DNA fragmentation and prior ICSI failure(s).
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Testicular volume and clinical correlates of hypothalamic–pituitary–testicular function: A cross-sectional study in obese men p. 354
Mark Ng Tang Fui, Rudolf Hoermann, Gary Wittert, Mathis Grossmann
DOI:10.4103/aja.aja_96_19  PMID:31535628
The aim of this study was to determine whether testicular volume is correlated with clinical and biochemical markers of hypothalamic–pituitary–testicular (HPT) axis function. This was a cross-sectional substudy of a larger randomized controlled trial including obese men, body mass index (BMI) ≥30 kg m−2, with a total testosterone level <12 nmol l−1. Testicular volume was measured by orchidometer, testosterone by liquid chromatography/tandem mass spectrometry, and body composition by dual-energy X-ray absorptiometry. Men completed the Aging Males' Symptoms (AMS) score, International Index of Erectile Function-5 (IIEF-5), physical function, and handgrip dynamometer testing. Eighty-nine men participated with a median (interquartile range [IQR]) age of 53.1 (47.6, 59.2) years, BMI of 37.0 (34.6, 40.5) kg m−2, and a total testosterone of 7.0 (6.1, 7.9) nmol l−1. Median testicular volume was 18 (IQR: 10, 20) ml. Testicular volume was negatively correlated with BMI (τ = −0.1952, P = 0.010) and total fat mass (τ = −0.2115, P = 0.005) independent of age and testosterone. When BMI, testosterone, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were present in a multivariable model, only BMI (-0.38 ml change in testicular volume per 1 kg m-2BMI; 95% CI: −0.74, −0.02; P = 0.04) and LH (-0.92 ml change in testicular volume per 1 IU l-1 LH; 95% CI: −1.75, −0.095; P = 0.03) remained independent significant predictors of testicular volume. Testicular volume was positively correlated with IIEF-5 (τ = 0.2092, P = 0.021), but not related to handgrip strength, physical function tests, or AMS. In obese men, testicular volume is inversely and independently associated with measures of adiposity, but not with most clinical or biochemical markers of HPT axis action. From a clinical perspective, this suggests that obesity might compromise the reliability of reduced testicular volume as a sign of androgen deficiency in men.
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A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility p. 360
Francesco Del Giudice, Gian Maria Busetto, Ettore De Berardinis, Isabella Sperduti, Matteo Ferro, Martina Maggi, Martin S Gross, Alessandro Sciarra, Michael L Eisenberg
DOI:10.4103/aja.aja_101_19  PMID:31621654
Aromatase activity has commonly been associated with male infertility characterized by testicular dysfunction with low serum testosterone and/or testosterone to estradiol ratio. In this subset of patients, and particularly in those with hypogonadism, elevated levels of circulating estradiol may establish a negative feedback on the hypothalamic–pituitary–testicular axis by suppressing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production and impaired spermatogenesis. Hormonal manipulation via different agents such as selective estrogen modulators or aromatase inhibitors to increase endogenous testosterone production and improve spermatogenesis in the setting of infertility is an off-label option for treatment. We carried out a systematic review and meta-analysis of the literature of the past 30 years in order to evaluate the benefits of the use of aromatase inhibitors in the medical management of infertile/hypoandrogenic males. Overall, eight original articles were included and critically evaluated. Either steroidal (Testolactone) or nonsteroidal (Anastrozole and Letrozole) aromatase inhibitors were found to statistically improve all the evaluated hormonal and seminal outcomes with a safe tolerability profile. While the evidence is promising, future prospective randomized placebo-controlled multicenter trials are necessary to better define the efficacy of these medications.
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Y chromosome microdeletion screening using a new molecular diagnostic method in 1030 Japanese males with infertility p. 368
Masashi Iijima, Kazuyoshi Shigehara, Hideki Igarashi, Koichi Kyono, Yasuo Suzuki, Yuji Tsuji, Yoshitomo Kobori, Hideyuki Kobayashi, Atsushi Mizokami
DOI:10.4103/aja.aja_97_19  PMID:31603142
The azoospermia factor (AZF) region is important for spermatogenesis, and deletions within these regions are a common cause of oligozoospermia and azoospermia. Although several studies have reported this cause, the present research, to the best of our knowledge, is the first large-scale study assessing this factor in Japan. In this study, 1030 male patients with infertility who were examined for Y chromosome microdeletion using the polymerase chain reaction-reverse sequence-specific oligonucleotide (PCR-rSSO) method, a newly developed method for Y chromosome microdeletion screening, were included. The study enrolled 250 patients with severe oligospermia and 717 patients with azoospermia. Among the 1030 patients, 4, 4, 10, and 52 had AZFa, AZFb, AZFb+c, and AZFc deletions, respectively. The sperm recovery rate (SRR) of microdissection testicular sperm extraction in patients with AZFc deletions was significantly higher than that in those without AZF deletions (60.0% vs 28.7%, P = 0.04). In patients with gr/gr deletion, SRR was 18.7%, which was lower than that in those without gr/gr deletion, but was not statistically significant. In conclusion, our study showed that the frequency of Y chromosome microdeletion in male patients in Japan was similar to that reported in patients from other countries, and SRR was higher in patients with AZFc deletion.
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Prevalence of and risk factors for erectile dysfunction in young nondiabetic obese men: results from a regional study p. 372
María Molina-Vega, Maite Asenjo-Plaza, María José Banderas-Donaire, María Dolores Hernández-Ollero, Silvia Rodríguez-Moreno, Juan J Álvarez-Millán, Pablo Cabezas-Sanchez, Fernando Cardona-Díaz, Juan Alcaide-Torres, Lourdes Garrido-Sánchez, Daniel Castellano-Castillo, Francisco J Tinahones, José C Fernández-García
DOI:10.4103/aja.aja_106_19  PMID:31603141
Erectile dysfunction (ED), a condition closely related to cardiovascular morbidity and mortality, is frequently associated with obesity. In this study, we aimed to determine the prevalence of ED and evaluate the associated risk factors in a cohort of 254 young (18–49 years) nondiabetic obese (body mass index [BMI] ≥ 30 kg m−2) men from primary care. Erectile function (International Index of Erectile Function [IIEF-5] questionnaire), quality of life (Aging Males' Symptoms [AMS scale]), and body composition analysis (Tanita MC-180MA) were determined. Total testosterone was determined using high-performance liquid chromatography–mass spectrometry. Multivariate logistic regression analysis was used to study the factors associated with ED. ED prevalence was 42.1%. Subjects with ED presented higher BMI, waist circumference, number of components of the metabolic syndrome, AMS score, insulin resistance, and a more unfavorable body composition than those without ED. Multivariate logistic regression analysis showed that a pathological AMS score (odds ratio [OR]: 4.238, P < 0.001), degree of obesity (BMI ≥ 40 kg m−2, OR: 2.602, P = 0.005, compared with BMI 30–34.9 kg m−2), high-density lipoprotein (HDL)-cholesterol levels (OR: 0.956, P = 0.004), and age (OR: 1.047, P = 0.016) were factors independently associated with ED. In conclusion, we demonstrate that, in a primary care-based cohort of nondiabetic young obese men, ED affected >40% of subjects. A pathological AMS score, the degree of obesity, and age were positively associated with ED, while elevated HDL-cholesterol levels were inversely associated with the odds of presenting ED. Further prospective studies are needed to evaluate the long-term consequences of ED in this population.
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Efficacy and safety of low-intensity shockwave therapy plus tadalafil 5 mg once daily in men with type 2 diabetes mellitus and erectile dysfunction: a matched-pair comparison study p. 379
Paolo Verze, Marco Capece, Massimiliano Creta, Roberto La Rocca, Francesco Persico, Lorenzo Spirito, Antonio Cardi, Vincenzo Mirone
DOI:10.4103/aja.aja_121_19  PMID:31696836
Low-intensity extracorporeal shockwave therapy (LiESWT) represents a promising treatment for patients with erectile dysfunction (ED). We investigated the efficacy of LiESWT combined with tadalafil 5 mg once daily in men with type 2 diabetes mellitus (T2DM) and ED and compared LiESWT protocols administering different number of shockwaves. We performed a retrospective matched-pair comparison using data from a prospectively maintained database. Seventy-eight patients who received tadalafil 5 mg once daily for 12 weeks + LiESWT performed with an electrohydraulic source for 3 weeks (Group A) were matched 1:1 to patients who received tadalafil 5 mg once daily alone for 12 weeks (Group B). A subgroup analysis was performed according to the number of shockwaves delivered during each session (1500, 1800, and 2400 in subgroup A1, A2, and A3, respectively). The mean International Index of Erectile Function-5 (IIEF-5) score variations with respect to baseline recorded at 4, 12, and 24 weeks after the end of the treatment were investigated as treatment outcomes. The mean IIEF-5 scores significantly improved in all groups and subgroups at 4-week follow-up without intergroup differences. At 12- and 24-week follow-up, the mean IIEF-5 improvement was significantly higher among patients in the A3 subgroup (+5.0 ± 2.1 [P < 0.001] and +4.7 ± 2.3 [P < 0.001], respectively). The combined approach with tadalafil 5 mg once daily and LiESWT with a protocol involving 2400 shockwaves provides significant advantages in terms of IIEF-5 improvement and durability compared to tadalafil 5 mg once daily alone in patients with T2DM and ED.
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The role of radical prostatectomy and definitive external beam radiotherapy in combined treatment for high-risk prostate cancer: a systematic review and meta-analysis p. 383
Xu Cheng, Zhi-Hui Wang, Mou Peng, Zhi-Chao Huang, Lu Yi, Yi-Jian Li, Lei Yi, Wen-Zhi Luo, Jia-Wen Chen, Yin-Huai Wang
DOI:10.4103/aja.aja_111_19  PMID:31603140
The first-line treatment options for high-risk prostate cancer (PCa) are definitive external beam radiotherapy (EBRT) with or without androgen deprivation therapy (ADT) and radical prostatectomy (RP) with or without adjuvant therapies. However, few randomized trials have compared the survival outcomes of these two treatments. To systematically evaluate the survival outcomes of high-risk PCa patients treated with EBRT- or RP-based therapy, a comprehensive and up-to-date meta-analysis was performed. A systematic online search was conducted for randomized or observational studies that investigated biochemical relapse-free survival (bRFS), cancer-specific survival (CSS), and/or overall survival (OS), in relation to the use of RP or EBRT in patients with high-risk PCa. The summary hazard ratios (HRs) were estimated under the random effects models. We identified heterogeneity between studies using Q tests and measured it using I2 statistics. We evaluated publication bias using funnel plots and Egger's regression asymmetry tests. Seventeen studies (including one randomized controlled trial [RCT]) of low risk of bias were selected and up to 9504 patients were pooled. When comparing EBRT-based treatment with RP-based treatment, the pooled HRs for bRFS, CSS, and OS were 0.40 (95% confidence interval [CI]: 0.24–0.67), 1.36 (95% CI: 0.94–1.97), and 1.39 (95% CI: 1.18–1.62), respectively. Better OS for RP-based treatment and better bRFS for EBRT-based treatment have been identified, and there was no significant difference in CSS between the two treatments. RP-based treatment is recommended for high-risk PCa patients who value long-term survival, and EBRT-based treatment might be a promising alternative for elderly patients.
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Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients p. 390
Ming Hao, Min Nie, Bing-Qing Yu, Yin-Jie Gao, Xi Wang, Wan-Lu Ma, Qi-Bin Huang, Rui Zhang, Jiang-Feng Mao, Xue-Yan Wu
DOI:10.4103/aja.aja_88_19  PMID:31464203
Partial congenital hypogonadotropic hypogonadism (PCHH) is caused by an insufficiency in, but not a complete lack of, gonadotropin secretion. This leads to reduced testosterone production, mild testicular enlargement, and partial pubertal development. No studies have shown the productivity of spermatogenesis in patients with PCHH. We compared the outcomes of gonadotropin-induced spermatogenesis between patients with PCHH and those with complete congenital hypogonadotropic hypogonadism (CCHH). This retrospective study included 587 patients with CHH who were treated in Peking Union Medical College Hospital (Beijing, China) from January 2008 to September 2016. A total of 465 cases were excluded from data analysis for testosterone or gonadotropin-releasing hormone treatment, cryptorchidism, poor compliance, or incomplete medical data. We defined male patients with PCHH as those with a testicular volume of ≥4 ml and patients with a testicular volume of <4 ml as CCHH. A total of 122 compliant, noncryptorchid patients with PCHH or CCHH received combined human chorionic gonadotropin and human menopausal gonadotropin and were monitored for 24 months. Testicular size, serum luteinizing hormone levels, follicle-stimulating hormone levels, serum total testosterone levels, and sperm count were recorded at each visit. After gonadotropin therapy, patients with PCHH had a higher spermatogenesis rate (92.3%) than did patients with CCHH (74.7%). During 24-month combined gonadotropin treatment, the PCHH group took significantly less time to begin producing sperm compared with the CCHH group (median time: 11.7 vs 17.8 months, P < 0.05). In conclusion, after combined gonadotropin treatment, patients with PCHH have a higher spermatogenesis success rate and sperm concentrations and require shorter treatment periods for sperm production.
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Establishing the lower limits of total serum testosterone among Chinese proven fertile men who received treatment of assisted reproductive technology p. 396
Hui-Yu Xu, Hui Jiang, Guo-Shuang Feng, Ying Feng, Yong Han, Wen-Hao Tang, Hong-Xian Zhang, Feng-Hua Chen, Hong-Xia Zhang, De-Feng Liu, Rong Li, Jie Qiao
DOI:10.4103/aja.aja_100_19  PMID:31571639
Testosterone (T) plays a crucial role in spermatogenesis because extremely low levels of intratesticular T lead to correspondingly low serum levels of total T (tT), severe disorders of spermatogenesis, and male sterility. However, there is little consensus on the lower limits of serum tT in proven fertile men undergoing assisted reproductive technology treatments in Chinese or other Asian populations. We aimed to establish the reference range of serum tT based on a population of 868 fertile Chinese men undergoing in vitro fertilization or intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) treatments. We defined a fertile man as having had a live baby with his partner as recorded in our IVF registration system. The lower limits of serum tT were established using a Siemens IMMULITE 2000 chemiluminescent system. The 1st, 2.5th, and 5th percentiles and their 95% confidence intervals (CIs) were 3.6 (95% CI: 2.7–4.1) nmol l−1, 4.3 (95% CI: 4.1–5.0) nmol l−1, and 5.6 (95% CI: 4.8–5.8) nmol l−1, respectively. Using the linear correlation of serum tT between the Siemens platform and a liquid chromatography–tandem mass spectrometry platform, the calculated lower limits of serum tT were also established for fertile Chinese men undergoing IVF/ICSI-ET treatments, which will benefit the clinical diagnosis and treatment of male infertility during such procedures.
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Distribution of DNA damage in the human sperm nucleus: implications of the architecture of the sperm head p. 401
Silvia González-Rojo, Cristina Fernández-Díez, Marta Lombó, María Paz Herráez
DOI:10.4103/aja.aja_26_19  PMID:31210149
The sperm nucleus is prone to sustain DNA damage before and after ejaculation. Distribution of the damage is not homogeneous, and the factors determining differential sensitivity among nuclear regions have not yet been characterized. Human sperm chromatin contains three structural domains, two of which are considered the most susceptible to DNA damage: the histone bound domain, harboring developmental related genes, and the domain associated with nuclear matrix proteins. Using a quantitative polymerase chain reaction (qPCR) approach, we analyzed the number of lesions in genes homeobox A3 (HOXA3), homeobox B5 (HOXB 5), sex-determining region Y (SRY)-box 2 (SOX2), β-GLOBIN, rDNA 18S, and rDNA 28S in human sperm after ultraviolet irradiation (400 μW cm−2, 10 min), H2O2treatment (250 mmol l−1, 20 min), and cryopreservation, which showed differential susceptibility to genetic damage. Differential vulnerability is dependent on the genotoxic agent and independent of the sperm nuclear proteins to which the chromatin is bound and of accessibility to the transcription machinery. Immunodetection of 8-hydroxy-2'-deoxyguanosine (8-OHdG) showed that the highest level of oxidation was observed after H2O2treatment. The distribution of oxidative lesions also differed depending on the genotoxic agent. 8-OHdG did not colocalize either with histone 3 (H3) or with type IIα + β topoisomerase (TOPO IIα + β) after H2O2treatment but matched perfectly with peroxiredoxin 6 (PRDX6), which is involved in H2O2metabolism. Our study reveals that the characteristics of the sperm head domains are responsible for access of the genotoxicants and cause differential degree of damage to nuclear areas, whereas chromatin packaging has a very limited relevance. The histone-enriched genes analyzed cannot be used as biomarkers of oxidative DNA damage.
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Effect of probucol on autophagy and apoptosis in the penile tissue of streptozotocin-induced diabetic rats p. 409
Ke-Qin Zhang, Tao Tian, Liang-Liang Hu, Hao-Ran Wang, Qiang Fu
DOI:10.4103/aja.aja_89_19  PMID:31464204
Autophagy and apoptosis have been regarded as important processes in the development of diabetic erectile dysfunction (DMED). Probucol is considered to have anti-apoptotic effects, but its relationship with autophagy has not been reported. The aim of this study was to investigate the effects and mechanisms of probucol on erectile function. Thirty Sprague–Dawley (SD) male rats (12 weeks old) were fasted for 12 h. Twenty SD rats were injected with a single intraperitoneal injection of 60 mg kg−1 streptozotocin (STZ). Ten rats were given vehicle only and used as a sham group. After 72 h, 20 STZ-treated rats with random blood glucose concentrations consistently greater than 16.7 mmol l−1 were used as successfully established diabetic rats. The diabetic rats were divided randomly into two groups and treated with a daily gavage of probucol at a dose of 0 or 500 mg kg−1 for 12 weeks. After treatment, the intracavernous pressure (ICP) was used to measure erectile function upon electrical stimulation of the cavernous nerve. After euthanasia, penile tissue was examined using immunohistochemistry and Western blot to assess the protein levels of B-cell lymphoma-2 (Bcl-2), BCL2-associated X (Bax), microtubule-associated protein light chain 3-II (LC3-II), mammalian target of rapamycin (mTOR), and sequestosome 1 (P62). Caspase-3 activity was measured to determine apoptosis using a caspase-3 assay kit. After 12 weeks of treatment, the erectile function of the probucol group was significantly better than that of the DM group (P < 0.05). Bax and LC3-II protein expression and caspase-3 activity were significantly lower in the probucol group than those in the DM group (all P < 0.05), while Bcl-2, mTOR, and P62 protein expression levels were significantly higher than those in the DM group (all P < 0.05). We demonstrated that probucol inhibited apoptosis and autophagy in STZ-induced diabetic rats.
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Mkrn2 deficiency induces teratozoospermia and male infertility through p53/PERP-mediated apoptosis in testis p. 414
Ying-Chen Qian, Yun-Xia Xie, Chao-Shan Wang, Zhu-Mei Shi, Cheng-Fei Jiang, Yun-Yi Tang, Xu Qian, Lin Wang, Bing-Hua Jiang
DOI:10.4103/aja.aja_76_19  PMID:31489847
The apoptosis that occurs in the immature testis under physiological conditions is necessary for male germ cell development, whereas improper activation of apoptosis can impair spermatogenesis and cause defects in reproduction. We previously demonstrated that in mice, the makorin-2 (Mkrn 2) gene is expressed exclusively in the testis and its deletion leads to male infertility. To understand the potential molecular mechanism, in this study, we found that levels of apoptosis in the testis were abnormally high in the absence of Mkrn 2. To identify specific gene(s) involved, we performed digital gene expression profiling (DGE) and pathway analysis via gene set enrichment analysis (GSEA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and we found that MKRN2 inhibits p53 apoptosis effector related to PMP22 (PERP) expression and that levels of the protein in sperm samples have an inverse correlation with infertility levels. GSEA additionally indicated that PERP is a negative regulator of spermatogenesis and that its ectopic expression induces male infertility. Further, Gene Expression Omnibus (GEO) dataset analysis showed that p53, upstream of PERP, was upregulated in oligoasthenoteratozoospermia (OAT). These observations suggest that Mkrn 2 is crucial for protecting germ cells from excessive apoptosis and implicate Mkrn 2-based suppression of the p53/PERP signaling pathway in spermatogenesis and male fertility.
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Upregulation of erythropoietin and erythropoietin receptor in castration-resistant progression of prostate cancer p. 422
Chen Ye, Guang-Hua Chen, Xin Chen, Sheng-Fei Qin, Min-Feng Shi, Tie Zhou
DOI:10.4103/aja.aja_80_19  PMID:31417010
Hypoxia-induced erythropoietin signaling plays an important role in tumor growth and invasion. In the present study, we investigated the contribution of erythropoietin signaling pathway to castration-resistant prostate cancer and the development of a neuroendocrine phenotype. Immunohistochemical staining showed that the erythropoietin and erythropoietin receptor scores in castration-resistant prostate cancer and androgen-dependent prostate cancer were 7.55 versus 4.5 and 7.45 versus 5.9,respectively (P < 0.001). Furthermore, a cell proliferation assay was conducted, and the differential expression of erythropoietin and erythropoietin receptor in LNCaP cells and hypoxia-induced LNCaP cells was evaluated using western blot and quantitative real-time PCR. The proliferation capacity of hypoxia-induced LNCaP cells was similar in cultures of both fetal bovine serum and charcoal-stripped fetal bovine serum, suggesting that LNCaP cells acquired hypoxia-induced androgen-independent growth. After 2 weeks of hypoxic culture, LNCaP cells showed a neuroendocrine cell change and increased expression of neuron-specific enolase, erythropoietin, and erythropoietin receptor; knockdown of erythropoietin receptor reversed the hypoxia-induced upregulation of neuron-specific enolase in the LNCaP cells. In conclusion, the concurrent upregulation of erythropoietin and erythropoietin receptor in castration-resistant prostate cancer suggests that the erythropoietin/erythropoietin receptor autocrine loop plays an important role in the progression of castration resistance and is responsible for the development of a neuroendocrine phenotype.
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Clinical and oncologic findings of extraprostatic extension on needle biopsy in de novo metastatic prostate cancer p. 427
Jun-Ru Chen, Jin-Ge Zhao, Sha Zhu, Meng-Ni Zhang, Ni Chen, Jian-Dong Liu, Guang-Xi Sun, Peng-Fei Shen, Hao Zeng
DOI:10.4103/aja.aja_77_19  PMID:31424026
This study aimed to explore the clinical and oncologic findings in patients with de novo metastatic prostate cancer (mPCa) and extraprostatic extension (EPE) on biopsy. We retrospectively evaluated data on 630 patients with de novo mPCa between January 2009 and December 2017 in the West China Hospital (Chengdu, China), including evaluating the relationships between EPE and other variables and the association of EPE with survival outcomes by the Chi-square test, Kaplan–Meier curves, and the Cox proportional-hazards model. EPE was found in 70/630 patients, making a prevalence of 11.1%. The presence of EPE on biopsy was associated with higher Gleason scores and higher incidence of neuroendocrine differentiation (NED), intraductal carcinoma of the prostate (IDC-P), and perineural invasion (PNI). Compared with those without EPE, patients with EPE had shorter castration-resistant prostate cancer-free survival (CFS; median: 14.1 vs 17.1 months, P = 0.015) and overall survival (OS; median: 43.7 vs 68.3 months, P = 0.032). According to multivariate analysis, EPE was not an independent predictor for survival. Subgroup analyses demonstrated that patients with favorable characteristics, including negative NED or IDC-P status, Eastern Cooperative Oncology Group (ECOG) score <2, and prostate-specific antigen (PSA) <50 ng ml−1, had worse prognoses if EPE was detected. In patients with PSA <50 ng ml−1, EPE was a negative independent predictor for OS (hazard ratio [HR]: 4.239, 95% confidence interval [CI]: 1.218–14.756, P = 0.023). EPE was strongly associated with other aggressive clinicopathological features and poorer CFS and OS. These data suggest that EPE may be an indicator of poor prognosis, particularly in patients, otherwise considered likely to have favorable survival outcomes.
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Initial experience with a novel method for cognitive transperineal magnetic resonance imaging-targeted prostate biopsy p. 432
Hai-Feng Wang, Rui Chen, Bi-Ming He, Min Qu, Yan Wang, Heng-Zhi Lin, Qing-Song Yang, Xu Gao, Ying-Hao Sun
DOI:10.4103/aja.aja_83_19  PMID:31464205
A cognitive magnetic resonance imaging (MRI)-targeted prostate biopsy conducted by an experienced clinician enhances the detection rate of (high-grade) prostate cancer; however, this method is less successful in the hands of inexperienced surgeons. Therefore, an alternative method of conducting a cognitive MRI-targeted biopsy that can be successfully performed by the inexperienced clinicians should be developed. Ninety-six males suspected of prostate cancer were analyzed using systematic biopsy and cognitive MRI-targeted biopsy based on our novel three-dimensional matrix positioning method. Typically, the core principle of the latter procedure was to put the MRI and ultrasound images into the same virtual coordinate system. Afterward, the targeted biopsy was transformed to target a coordinate for the suspected lesion in the MRI. Subsequently, patients were assessed for the presence/absence of prostate cancer or high-grade prostate cancer. According to our results, the overall detection rate of prostate cancer was 70.8% (68/96), and the detection rate of high-grade prostate cancer was 56.3% (54/96). Specifically, the detection rate of prostate cancer by systematic biopsy was 54.2% (52/96) and that by targeted biopsy was 59.4% (57/96; P = 0.560). Clearly, the combined application of targeted biopsy could remarkably increase the detection rates of prostate cancer (P = 0.025) and high-grade prostate cancer (P = 0.009). Taken together, the findings of this study suggest that the combination of systematic biopsy with our three-dimensional matrix positioning-driven cognitive-targeted biopsy is superior to systematic biopsy in detecting prostate cancer and high-grade prostate cancer.
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LETTERS TO THE EDITOR Top

Single-center experience with radium-223 in patients with castration-resistant prostate cancer and bone metastases p. 437
Anil Kapoor, Nathan C Wong, Yuding Wang, Som Mukherjee, Sebastien Hotte, Ian Dayes, Himu Lukka
DOI:10.4103/aja.aja_66_19  PMID:31535625
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COMMENTARY Top

When to pull the trigger in nonazoospermic infertile men undergoing intracytoplasmic sperm injection? p. 439
Sandro C Esteves, Sheena EM Lewis
DOI:10.4103/aja.aja_4_20  PMID:32167076
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