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PubMed1997

Expression of testis angiotensin-converting enzyme is mediated by a cyclic AMP responsive element.

Testis angiotensin-converting enzyme (testis ACE), an ACE isozyme that plays an important role in male fertility, is transcribed from a unique promotor active only in developing spermatids. In vitro analysis suggests the importance of a cyclic AMP response element (CRE)-like region within the testis ACE promoter, and similar DNA motifs are important in the expression of a variety of testis-specific genes. In the present study, we examined the effects of mutations in the CRE-like element on testis ACE promoter activity in vivo using transgenic mice. Disruption of this element reduced reporter gene expression to near background levels. In contrast, conversion of the CRE-like element to a consensus CRE-binding site resulted in high level expression of the reporter gene specifically in the testis. These experiments prove that the CRE-like element is essential for testis ACE promoter activity, although it does not appear to be responsible for its tissue specificity. These data provide insight into how a phenotypically differentiated tissue, ie, male gem cells, regulate tissue-specific gene expression.

Animals↗
PubMed1997

DNA repair capacity and cisplatin sensitivity of human testis tumour cells.

Metastatic testicular germ cell tumours can be cured using cisplatin-based combination chemotherapy. To investigate the role of DNA repair in cisplatin sensitivity, we measured the formation and removal of cisplatin adducts in the whole genome and in specific genomic regions in 3 testis and 3 bladder cancer cell lines. Following a 1 hr exposure to 50 microM cisplatin, the mean level of DNA platination was lower in the testis tumour cell lines. During a 72 hr post-treatment incubation period, the 3 bladder cell lines removed platinum from the overall genome, whereas 2 of the testis tumour cell lines showed relatively little reduction of DNA platination. The third testis tumour cell line, SuSa, showed an intermediate capacity to remove cisplatin. Cisplatin-induced damage and repair in selected regions of the actively transcribed N-ras gene and the inactive CD3delta gene were measured using quantitative PCR. The data were in agreement with those obtained with atomic absorption spectroscopy for the whole genome, showing that the bladder lines were repair-proficient: 2 of the testis tumour cell lines showed no repair, and the third testis line, SuSa, showed an intermediate level of repair in these 2 genes. Our findings confirm that reduced capacity to repair cisplatin-damaged DNA may contribute to the hypersensitivity of testis tumour cells to DNA-damaging agents.

Antineoplastic Agents↗
PubMedDate not supplied

Zyxin, axin, and Wiskott-Aldrich syndrome protein are adaptors that link the cadherin/catenin protein complex to the cytoskeleton at adherens junctions in the seminiferous epithelium of the rat testis.

During spermatogenesis, the movement of germ cells across the seminiferous epithelium is associated with extensive junction restructuring. Yet the underlying mechanism (or mechanisms) that regulates these events is largely unknown. If the molecular architecture of the cell-cell actin-based adherens junction (AJ), such as ectoplasmic specialization (ES) and tubulobulbar complex- two testis-specific AJ types, is known, many functional mechanistic studies can be designed. We thus undertook an investigation to study 3 adaptors in the seminiferous epithelium: zyxin, axin, and Wiskott-Aldrich syndrome protein (WASP). All 3 adaptors were shown to be products of Sertoli and germ cells. Zyxin was shown to be a stage-specific protein that was most prominent during stages V-VII and restricted mostly to pachytene spermatocytes, but it could also be detected at the site of basal and apical ectoplasmic specialization (ES). Zyxin, axin, and WASP were shown to be structurally linked to the N-cadherin/beta-catenin/alpha-actinin/actin complex but not to the nectin-3/afadin or the beta 1-integrin-mediated protein complexes. Interestingly, zyxin, axin, and WASP are also structurally linked to vimentin (an intermediate filament protein) and alpha-tubulin (the subunit of a microtubule), which suggests that they have a role (or roles) in the regulation of the dynamics of the desmosome-like junction and microtubule. These results illustrate that zyxin, axin, and WASP are adaptors in both AJs and intermediate filament-based desmosome-like junctions. This raises the possibility that classic cadherins are also associated with vimentin-based intermediate filaments via these adaptors in the testis. While virtually no N-cadherin was found to associate with vimentin in the seminiferous tubules, it did associate with vimentin when testis lysates were used. Interestingly, about 5% of the E-cadherin associated with vimentin in isolated seminiferous tubules, and about 50% of the E-cadherin in the testis used vimentin as its attachment site. These data suggest that cadherins in the testis, unlike those in other epithelia, use different attachment sites to anchor the cadherin/catenin complex to the cytoskeleton. The levels of zyxin, axin, and WASP were also assessed during AF-2364-mediated AJ disruption of the testis, which illustrated a time-dependent protein reduction that was similar to the trends observed in nectin-3 and afadin but was the opposite of those observed for N-cadherin and beta-catenin, which were induced. Collectively, these results illustrate that while these adaptors are structurally associated with the cadherin/catenin complex in the testis, they are regulated differently.

Adherens Junctions↗
PubMed2005

Urogenital nonunion--the case for laparoscopy for the impalpable testis.

A case of urogenital nonunion is presented to illustrate the importance of laparoscopy for the impalpable testis. A 4-year-old boy with an impalpable left testis underwent laparoscopy. This revealed not only the vas deferens entering the deep inguinal ring but also a small intraabdominal testis supplied by the testicular vessels. Exploration of the inguinal canal revealed the vas deferens terminating in a nubbin of tissue. Histology identified epididymal structures both adjacent to the testis and in the terminal nubbin of the vas deferens. This is an example of urogenital nonunion. Complete separation of the vas and testis with epididymal structures attached to each is very unusual, with only four other cases reported. Laparoscopy should be the initial procedure for impalpable testis. A blind-ending vas deferens found on exploration of the inguinal canal might be taken as evidence of the vanishing testis syndrome. However, this conclusion should not be drawn unless laparoscopy has demonstrated testicular vessels entering the internal inguinal ring.

Child, Preschool↗
PubMed1999

Laparoscopic classification and treatment of the impalpable testis.

Laparoscopic orchiopexy has gained popularity in recent years. However, the decision when to perform one-stage laparoscopic orchiopexy without division of the spermatic vessels versus initial ligation of the spermatic vessels followed later by orchiopexy is not clear. A new laparoscopic classification to facilitate decision-making during laparoscopy, according to the position of the impalpable testis and the relation of the spermatic vessels and vas deferens to the internal ring, with a management protocol based on this classification is presented. Over a 2-year period, a total of 37 boys with 52 impalpable gonads underwent a laparoscopic procedure. Four laparoscopic types of testis were noted: type I: no testis visualized; type II: a testis seen at the internal ring with the vas and vessels looping to the internal ring; type III: testis at the internal ring, with vas and vessels going to the testis directly; and type IV: intra-abdominal testis not related to the internal ring. Of the 52 gonads, 19 (36.5%) were type I, 13 (25%) type II, 6 (11.5%) type III, and 14 (27%) type IV. Thirty-three testes were followed up (mean follow-up 8 months); 3 showed atrophy (11%) and 4 were retracted at the scrotal neck after staged, laparoscopic-assisted orchiopexy (LAO). Laparoscopy is of great value for both diagnosis and management of impalpable testes. A classification based on laparoscopic findings will help in planning further surgical action, and LAO is a safe and effective form of operative management for impalpable testes.

Cryptorchidism↗
PubMed2005

Feminization of Japanese medaka (Oryzias latipes) exposed to 17beta-estradiol: formation of testis-ova and sex-transformation during early-ontogeny.

Gonad histological changes were examined in Japanese medaka exposed to 17beta-estradiol (E2) during early-life stages. Two experiments were conducted at different concentrations of E2 (33.5 and 140.6 ng/L, mean value of measurement) and larvae and juveniles were observed for histological changes in the gonad. Differentiation of ovary and testis in control fish was apparent 12 days post-hatch (dph). At 12 dph, normal testes were observed in male fish that had been exposed to 33.5 ng/L E2, but at 14 and 20 dph, testis-ova was recognized in male fish. Male fish exposed to 140.6 ng/L E2 had testis-ova at 12 dph and gradual transformation to ovary was observed in male fish until 20 dph. In both experiments, the ovarian tissue in testis of male fish exposed to E2 was frequently distributed along the central transverse axis of the gonad, expanding into the transverse axis. The results indicated that 17beta-estradiol can induce testis-ova in male medaka during the larval period and sex-transformation is more frequent at higher (140.6 ng/L) than lower concentrations (33.5 ng/L) of estradiol. The results also demonstrated that testis-ova first appear in the central area of the transverse axis of testis.

Animals↗
PubMed1999

Lack of carbachol response indicates the absence of cholinergic receptors in sacs associated with undescended testis.

BACKGROUND/PURPOSE: The mechanism of testicular descent remains controversial. The processus vaginalis (PV) contains smooth muscle and should have contractile activity that may contribute to descent. This study was designed to evaluate the smooth muscle of PVs associated with incomplete obliteration for spontaneous activities and responses to various stimuli, to determine if differences exist according to sex, diagnostic source, or location of the testis. MATERIALS: Peritoneal samples (n = 4); sacs from girls (n = 8) and boys with inguinal hernia (n = 12); and sacs from boys with hydrocele (n = 3), hydrocele of the cord (n = 2), or undescended testis (n = 7) were used for the current study. Tissues were attached to the isometric force displacement transducer in an organ bath containing mammalian Ringer's solution at 37 degrees C. Spontaneous mechanical activity and contractile responses of tissues to the electrical field stimulation, phenylephrine, carbachol, and serotonin were recorded. The values obtained from boys and girls with inguinal hernia and from boys with either undescended or descended testis were compared through Fisher's Exact test. RESULTS: There were no statistically significant differences in patient age between groups. Among the parameters studied, only the carbachol response of the sacs associated with undescended testis showed a significant difference compared with the others (P = .001). None of the sacs associated with undescended testis responded to carbachol, whereas all of the sacs from boys and girls with inguinal hernia responded to carbachol. CONCLUSIONS: Lack of carbachol response suggests the absence of cholinergic receptors within the sacs associated with undescended testis. The lack of cholinergic receptors may play a role in the failure of the process of testicular descent by hindering either PV elongation into the scrotum or a possible propulsive activity of the PV on the testis.

Carbachol↗
PubMed2001

Adult primary teratoma of the testis--report on 5 cases in clinical stage I disease.

OBJECTIVES: Testis pure teratoma accounts for 2.7% to 3% of all germ cell tumors in adult where it behaves as a malignant neoplasm. Pure teratoma of the testis presents in clinical stage I disease in 44% of the patients whose risk of having pathological stage II disease is 16.7% to 19.2%. Herein we report on 5 cases of adult pure teratoma of the testis presenting itself in clinical stage I disease. MATERIALS AND METHODS: From September 1976 to February 2000, 75 patients underwent orchidectomy for clinical stage I nonseminomatous germ cell cancer of the testis. Testis pure teratoma was detected in 5 patients (7%). Testis tumor markers were evaluated in all cases. Patients underwent imaging examination to detect the clinical stage of the disease. Treatment options after orchidectomy included retroperitoneal lymph node dissection (RPLND) in 4 patients and surveillance in 1. RESULTS: The average age of the patients was 31 years (range 24-45). The tumor was on the left sided in 3 cases (60%) and right in 2 (40%). Tumor average size was 3.2 cm (rang 1-6). Histopathology detected the following subtypes: mature teratoma in 3 cases (60%), immature teratoma in 1 (20%) and teratoma with malignant transformation in (20%). All patients were at clinical stage I disease. Germ cell cancer microscopic metastatic disease including embryonal carcinoma was detected in I dissected lymph node of 1/4 patients (25%). Average follow up was 166 months (range 93-249). All patients were alive and disease free and no relapses were detected during the follow up period. CONCLUSIONS: Primary pure teratoma of the testis does not respond to chemotherapy nor does it to radiation therapy. The disease treatment options after orchidectomy for patients with clinical stage I disease include RPLND or surveillance with their relative risks and benefits. RPLND is the chosen treatment because it is both staging and treating. A close a long term follow up is required since pure teratoma metastatic disease may clinically develop after more than 10 years.

Adult↗
PubMed2000

Cremaster muscles obtained from boys with an undescended testis show significant neurological changes.

OBJECTIVE: To compare cremaster muscles (CMs) obtained from boys with inguinal hernia, hydrocele or an undescended testis and those obtained from girls with inguinal hernia, thus defining the changes associated with each clinical condition. MATERIALS AND METHODS: CM samples were obtained from 26 boys and three girls with inguinal hernia, and 18 boys who had undergone surgery for an undescended testis (12) or hydrocele (six). The samples were frozen in isopentane cooled in liquid nitrogen and were processed for sectioning by cryostat. Sections (12 microm) were stained with a several histochemical stains. The presence of central nuclei, fibre splitting, basophilic fibres, fibre necrosis, inflammatory changes, small angular fibres, fibre hypertrophy, grouped atrophy, and endo- and perimysial fibrosis were evaluated. From each specimen, 200 fibres were also analysed morphometrically using a computerized image analysis system. RESULTS: Neurogenic changes were apparent in all the CMs from patients with an undescended testis but none of the samples obtained from girls showed any changes. While only two specimens of 26 from boys with inguinal hernia (8%) had evidence of neurological alterations, eight CM (31%) had general changes. The mean (SD) fibre diameters did not differ significantly among the groups with inguinal hernia, hydrocele and undescended testis, at 23. 0 (8.6), 24.4 (4.5) and 23.0 (10.5) microm, respectively. CONCLUSION: Cremasteric muscles associated with an inguinal hernia or an undescended testis differ; neurogenic changes were detected within all the CM of boys with an undescended testis. These changes in the CM may have influenced the location of the testis.

Child, Preschool↗
PubMed1991

Molecular cloning of a rat testis form of the inhibitor protein of cAMP-dependent protein kinase.

The form of inhibitor protein of the cAMP-dependent protein kinase (PKI) that has been most thoroughly studied is a protein purified from rabbit skeletal muscle. Beale et al. previously isolated a species of PKI from rat testis that appeared from its amino acid composition to be quite distinct from the rabbit skeletal muscle protein [Beale, E. G., Dedman, J. R. & Means, A. R. (1977) J. Biol. Chem. 252, 6322-6327]. The amino acid sequence of a form of rat testis PKI has now been determined both by sequencing overlapping peptide fragments for 95% of the protein and by the isolation of a cDNA clone containing the coding region for the 70-amino acid protein. The sequence of the 70-amino acid testis PKI displays a maximum of only 41% sequence identity with the previously sequenced 75-amino acid rabbit skeletal muscle PKI. However, the two forms have identical potency as inhibitors and the key amino acids of the pseudosubstrate site, shown to be critical for maximal inhibition with the rabbit skeletal muscle PKI, have been conserved in the testis protein. The rabbit skeletal muscle and rat testis PKIs most likely represent distinct isoforms. The nucleotide sequence of the rat testis PKI cDNA suggests that a second form of testis PKI, longer by 8 additional amino-terminal amino acids, might also be produced.

Amino Acid Sequence↗
PubMed2002

Adult nonpalpable testis: is laparoscopy always required?

Laparoscopy is widely used in the diagnosis and treatment of nonpalpable testes. Some nonpalpable testes are vanishing testes. In such cases, unnecessary laparoscopic interventions can be avoided by a careful selection of cases. Between 1996 and 2001, laparoscopic intervention was applied to 107 patients with nonpalpable testes. Of the cases, 23 were bilateral and 84 were unilateral. Patients were between 19 and 27 years of age (average age, 23 years). Diagnostic ultrasonography was performed in 44 of the 84 patients with nonpalpable testes. Dimensions of the scrotal testis were determined by the Prader orchiometer method. The dimensions of the opposite scrotal testis (of the scrotal nubbin) and the abdominal testis were compared with the dimensions of 20 normal, healthy individuals' scrotal testis (control group). Results were evaluated by the Mann-Whitney U test. During laparoscopy, 24 (28.5%) of the patients were found to have a vanishing testis. The vas deferens and the testicular blood vessels ended bluntly at the anterior edge of the interior inguinal ring in one patient, inside the inguinal canal in five patients, and in the scrotum in 18 patients. Among the 84 patients with nonpalpable testes, no testis was found in any of the 18 patients with palpable scrotal nubbins. The opposite scrotal testes were hypertrophic in 17 (70.8%) of 24 patients who had vanishing testis (P < .05), and they were hypertrophic in 22 (36%) of the 60 patients (P > .05) who had laparoscopically identified intraabdominal testes. We conclude that clinical and radiologic diagnosis is sufficient for adult patients with nonpalpable testicles and palpable scrotal nubbins and hypertrophic contralateral scrotal testes. Laparoscopic intervention should be applied to patients who do not have palpable scrotal nubbins.

Adult↗
PubMed2004

Juvenile granulosa cell tumor of the testis:: contemporary clinical management and pathological diagnosis.

PURPOSE: Juvenile granulosa cell tumor (JGCT) of the testis is a rarely diagnosed subset of testicular stromal tumors. Although this variant of testicular stromal tumor is predominantly a benign entity in prepubertal patients, limited experience precludes a complete understanding of its clinical presentation and pathological diagnosis. MATERIALS AND METHODS: We reviewed all cases of testicular tumors at Children's Hospital of Philadelphia between 1976 and 2002 in males younger than 18 years. We specifically reviewed our experience with JGCT in terms of presentation, surgical treatment and long-term outcome. We also reviewed the microscopic findings and histochemical techniques used to confirm the diagnosis. RESULTS: We identified 77 tumors during the defined interval, of which 3 (3.9%) were JGCTs. All 3 patients with JGCT were first noted to have a testis mass soon after birth. All presented with a firm, unilateral testicular mass. Ultrasonographic findings were consistent with a complex, multiseptated, hypoechoic mass. Two of the 3 patients underwent radical orchiectomy. Testis sparing mass excision was performed in 1 patient. Grossly the tumors were partially cystic masses. Histologically positive immunostaining with inhibin-alpha and negative staining for alpha-fetoprotein (AFP) reliably differentiated JGCTs from yolk sac tumors. At a mean followup of 8.5 years (range 5 to 14) no metastases or local tumor recurrences have been diagnosed. CONCLUSIONS: To our knowledge we report the first case of testis sparing enucleation of a JGCT with a 5-year recurrence-free followup. Testis sparing enucleation is now our procedure of choice for tumors in neonates and prepubertal children with serum AFP in the normal range for age. JGCT should be suspected in neonates presenting at birth with a complex, cystic mass of the testis. Positive immunostaining for inhibin-alpha and a lack of AFP staining have consistently corroborated the pathological diagnosis in our experience and they should be applied for pediatric testis tumors that may mimic yolk sac tumor pathology.

Adolescent↗
PubMed1988

Effect of unilateral cryptorchidism on the intertubular tissue of the adult rat testis: evidence for intracellular changes within the Leydig cells.

Adult male rats were made unilaterally cryptorchid for 1, 2 or 4 weeks, and the morphological response of the Leydig cells was then studied using morphometric assessment of total Leydig cell volume and number per testis in abdominal and scrotal testes. Serum hormone levels were measured and the steroidogenic properties of isolated Leydig cells were evaluated by in-vitro stimulation with hCG and interstitial fluid (IF) obtained from normal rat testes. Total Leydig cell volume and number per testis were not altered in abdominal vs scrotal testes, although the volume of the abdominal testis was 46, 29 and 21%, respectively, of the volume of the contralateral scrotal testis after 1, 2 and 4 weeks. This reduction was accompanied by significant (P less than 0.05) elevation of the serum levels of FSH and LH, although serum testosterone levels were unchanged from the normal range. Despite the lack of quantitative alterations in Leydig cell morphology, hCG- and IF-stimulated testosterone production was significantly (P less than 0.01) greater by abdominal Leydig cells when compared with scrotal Leydig cells derived from the same animals. Ultrastructural examination of Leydig cells in situ suggested an increase in volumetric density of mitochondria in abdominal Leydig cells. Together with the enhanced steroidogenic responses of these cells, these findings suggest that disruption of spermatogenesis in the cryptorchid testis is accompanied by intracellular activation of Leydig cells. Since these effects were not exhibited by Leydig cells from the scrotal testis it is concluded that local factors within the cryptorchid testis are responsible, at least in part, for regulation of Leydig cell activity.

Animals↗
PubMed1997

The role of laparoscopy in evaluation of the impalpable undescended testis.

BACKGROUND: The evaluation and management of the impalpable testis remains controversial. The authors' experience with laparoscopy for the treatment of this condition is reported here. METHODS: All children with impalpable testes underwent an examination under anaesthetic and if negative, a laparoscopy was performed to locate the testis. A prospective evaluation was undertaken to determine the success and morbidity of this approach. RESULTS: Thirty-six children (median age 2.5 years) underwent laparoscopy to localize 40 impalpable testes. In 32 patients with unilateral impalpable testis, 10 were intra-abdominal, nine were absent. In 13 patients, the vas and vessels entered the groin, and in 12 of these a small testis remnant was excised and in the other a normal-looking testis was brought down. In four patients with bilateral impalpable testes, one testis was absent, three testes were intra-abdominal and four were small testis remnants in the groin. The average laparoscopy time was 15 min, and 34 of 36 children were operated on as day-stay cases. One child had an omental hernia via a port site. CONCLUSION: Laparoscopy is safe and effective at localizing impalpable testes in children and can be performed as day-stay procedures in the majority of cases.

Adolescent↗
PubMed1985

Morphological and immunological observations in experimentally induced torsion of testis in rats.

In an experimentally established model of torsion of the testis, morphological and immunological observations were evaluated in 180 Wistar rats. Torsion of the testis were carried out to observe in animals the biological phenomenon that naturally occurs in man. The effect of the twisted testis on the contralateral testis was carefully checked. The morphological observations revealed serious damage to the seminiferous tubules in the contralateral testis. In four rats, persistent infertility was observed as an effect of torsion. The infertility was confirmed by total atrophy of seminiferous epithelium in testis section. The cell-binding ability of sera obtained from rats at different times after torsion were studied by cell-binding radioimmunoassay with different types of germinal cells. The presence of autoantibodies to epididymal spermatozoa was revealed in most cases, being a secondary effect of the thus-far unknown, nonspecific factors responsible for damage of the contralateral testis.

Age Factors↗
PubMed2004

Differential expression of divalent metal transporter DMT1 (Slc11a2) in the spermatogenic epithelium of the developing and adult rat testis.

Iron is essential for male fertility, and disruptions in iron balance lead to impairment of testicular function. The divalent metal transporter DMT1 is a key modulator of transferrin- and non-transferrin-bound iron homeostasis. As a first step in determining the role of DMT1 in the testis, we have characterized the pattern of DMT1 expression in the developing and adult rat testis. Northern blot analysis and RT-PCR of testis polyadenylated RNA revealed the presence of iron-responsive element (IRE) and non-IRE transcripts. Semiquantitative immunoblotting of immature and adult rat testis uncovered the expression of two distinct DMT1 protein species. Immunohistochemistry showed that DMT1 was widespread throughout each seminiferous tubule and was expressed in the intracellular compartment. In the adult rat testis, DMT1 was immunolocalized to both the Sertoli and germ cells. In contrast to the immature testis, expression was dependent on the stage of the spermatogenic cycle. DMT1 was not detected on any plasma membranes in either the developing or the adult testis, suggesting that DMT1 is not primarily responsible for translocating iron across this epithelium. Our data suggest an important role for DMT1 in intracellular iron handling during spermatogenesis and imply that germ cells have a need for a precisely targeted and timed supply of iron. We suggest that DMT1 may, as it does in other tissues, play a role in transporting iron between intracellular compartments and thus may play an important role in male fertility.

Age Factors↗
PubMed2005

Conditional expression of the CTCF-paralogous transcriptional factor BORIS in normal cells results in demethylation and derepression of MAGE-A1 and reactivation of other cancer-testis genes.

Brother of the Regulator of Imprinted Sites (BORIS) is a mammalian CTCF paralog with the same central 11Zn fingers (11ZF) that mediate specific interactions with varying approximately 50-bp target sites. Regulated in vivo occupancy of such sites may yield structurally and functionally distinct CTCF/DNA complexes involved in various aspects of gene regulation, including epigenetic control of gene imprinting and X chromosome inactivation. The latter functions are mediated by meCpG-sensitive 11ZF binding. Because CTCF is normally present in all somatic cells, whereas BORIS is active only in CTCF- and 5-methylcytosine-deficient adult male germ cells, switching DNA occupancy from CTCF to BORIS was suggested to regulate site specificity and timing of epigenetic reprogramming. In addition to 11ZF-binding paternal imprinting control regions, cancer-testis gene promoters also undergo remethylation during CTCF/BORIS switching in germ cells. Only promoters of cancer testis genes are normally silenced in all somatic cells but activated during spermatogenesis when demethylated in BORIS-positive germ cells and are found aberrantly derepressed in various tumors. We show here that BORIS is also expressed in multiple cancers and is thus itself a cancer-testis gene and that conditional expression of BORIS in normal fibroblasts activates cancer-testis genes selectively. We tested if replacement of CTCF by BORIS on regulatory DNA occurs in vivo on activation of a prototype cancer-testis gene, MAGE-A1. Transition from a hypermethylated/silenced to a hypomethylated/activated status induced in normal cells by 5-aza-2'-deoxycytidine (5-azadC) was mimicked by conditional input of BORIS and is associated with complete switching from CTCF to BORIS occupancy at a single 11ZF target. This site manifested a novel type of CTCF/BORIS 11ZF binding insensitive to CpG methylation. Whereas 5-azadC induction of BORIS takes only few hours, derepression of MAGE-A1 occurred 1 to 2 days later, suggesting that BORIS mediates cancer-testis gene activation by 5-azadC. Indeed, infection of normal fibroblasts with anti-BORIS short hairpin RNA retroviruses before treatment with 5-azadC blocked reactivation of MAGE-A1. We suggest that BORIS is likely tethering epigenetic machinery to a novel class of CTCF/BORIS 11ZF target sequences that mediate induction of cancer-testis genes.

Animals↗
PubMedDate not supplied

Leiomyosarcoma complicating chronic inflammation of the testis.

OBJECTIVE: To report on a case of leiomyosarcoma of the testis that appeared to have arisen from a background of chronic testicular inflammation. CLINICAL PRESENTATION: A 65-year-old man with a 15-year history of diabetes mellitus and low-grade discomfort and swelling in the right testis presented as an emergency with exacerbation of the pain and swelling of the testis. Repeated ultrasound examination of the testis in the past 5 years had suggested a chronic testicular inflammatory disorder. Ultrasound during the current emergency case admission revealed a normal left testis, but a large heterogeneous solid mass with a moderate intratesticular calcification in the right testis and the presence of a moderate hydrocele. Serum alpha-fetoprotein and beta-human chorionic gonadotropin were normal. A right radical orchidectomy was performed. Histopathology and immunohistochemistry revealed primary leiomyosarcoma of the right testis. There was no spermatic cord or venous involvement. One year after orchidectomy there was no sign of metastasis. CONCLUSION: Radical orchidectomy followed by surveillance appears to be the treatment of choice for this testicular leiomyosarcoma, which seemed to have run an indolent course compared to other testicular tumours.

Aged↗