Autophagy and mitophagy in cancer metabolic remodelling.

Metabolic reprogramming in tumours is now recognized as a hallmark of cancer, participating both in tumour growth and cancer progression. Cancer cells develop global metabolic adaptations allowing them to survive in the low oxygen and nutrient tumour microenvironment. Among these metabolic adaptations, cancer cells use glycolysis but also mitochondrial oxidations to produce ATP and building blocks needed for their high proliferation rate. Another particular adaptation of cancer cell metabolism is the use of autophagy and specific forms of autophagy like mitophagy to recycle intracellular components in condition of metabolic stress or during anticancer treatments. The plasticity of cancer cell metabolism is a major limitation of anticancer treatments and could participate to therapy resistances. The aim of this review is to report recent advances in the understanding of the relationship between tumour metabolism and autophagy/mitophagy in order to propose new therapeutic strategies.

Epididymal-testicular fusion anomalies in cryptorchidism are associated with proximal location of the undescended testis and with a widely patent processus vaginalis.

Past studies documented the presence of epididymal/testicular fusion anomalies and persistence of a patent processus vaginalis in a small case-series of cryptorchid and/or hydrocele patients. The primary aim of this study was to determine the prevalence of the epididymal/testicular anomalies in a series of more than 1000 cryptorchid patients compared with controls. Secondary aims were: (i) to investigate the association between the cryptorchidism and the patency of p. vaginalis; and (ii) to correlate the epididymal/testicular fusion anomalies with the position of the testis and with the patency of the p. vaginalis. The clinical and surgical data of 1002 cryptorchid patients and 230 controls were retrospectively retrieved and analysed. Epididymal/testicular fusion anomalies were classified as: (i) normal anatomy; (ii) minor anomalies; and (iii) major anomalies. Statistical analysis was performed using the Student's t-test and Chi-square tests. The prevalence of the epididymal/testicular fusion anomalies was higher in the cryptorchid group compared with that of the control group (minor and major anomalies in cryptorchids vs. controls, respectively: 42.2 vs. 5.6% and 9.3 vs. 1.6%, P < 0.0001). Moreover, we documented a correlation of these anomalies with a more proximal localization of the testis (minor and major anomalies in proximal vs. distal location of the testis, respectively: 62.5 vs. 34.8% and 19.1 vs. 6.3%, P < 0.0001) and with the persistence of a widely patent p. vaginalis (minor and major anomalies in widely patent p. vaginalis vs. narrow duct, respectively: 51.7 vs. 42.2 and 11.9% vs. 7.8%, P < 0.001). In conclusion, the epididymal/testicular fusion anomalies were strongly associated with cryptorchidism and the persistence of a widely patent peritoneal vaginal duct. Although it remains unclear whether these anomalies cause non-descent of the testis or, conversely, result from the cryptorchidism or from the persistence of a widely patent duct, our data re-enforce this association.

Blockade of CaV3 calcium channels and induction of G0/G1 cell cycle arrest in colon cancer cells by gossypol.

BACKGROUND AND PURPOSE: Gastrointestinal tumours overexpress voltage-gated calcium (CaV3) channels (CaV3.1, 3.2 and 3.3). CaV3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits CaV3 currents. A systematic study was performed on gossypol blocking mechanism on CaV3 channels and its potential anticancer effects in colon cancer cells, which express CaV3 isoforms. EXPERIMENTAL APPROACH: Transcripts for CaV3 proteins were analysed in gastrointestinal cancers using public repositories and in human colorectal cancer cell lines HCT116, SW480 and SW620. The gossypol blocking mechanism on CaV3 channels was investigated by combining heterologous expression systems and patch-clamp experiments. The anti-tumoural properties of gossypol were estimated by cell proliferation, viability and cell cycle assays. Ca2+ dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca2+ indicators. KEY RESULTS: High levels of CaV3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of CaV3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of CaV3 channels. Gossypol and CaV3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G0/G1 and G2/M phases, respectively. CaV3 channels underlie the vectorial Ca2+ uptake by endoplasmic reticulum in colorectal cancer cells. CONCLUSION AND IMPLICATIONS: Gossypol differentially blocked CaV3 channel and its anticancer activity was correlated with high levels of CaV3.1 and CaV3.2 in colorectal cancer cells. The CaV3 regulates cell proliferation and Ca2+ dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.

Varicocele: To Treat or Not to Treat?

Varicocele treatment in infertility still remains controversial. It is clear, in fact, that in many patients, varicocele has no impact on fertility. Recent scientific evidence demonstrated that varicocele treatment is beneficial in improving semen parameters and pregnancy rate when an appropriate selection of patients is made. The purpose of treating varicocele in adults is mainly to improve current fertility status. On the other hand, the goal of treatment in adolescents is to prevent testicular injury and maintain testicular function for future fertility. Hence, the key to the success of varicocele treatment seems to be a correct indication. The aim of this study is to review and summarize current evidence in managing varicocele treatment focusing on the controversies regarding surgical indications in adolescent and adult patients, and in other specific situations such as azoospermia, bilateral or subclinical varicocele, and prior to ART.

Maternal exposures to endocrine disrupting chemicals and hypospadias in offspring.

BACKGROUND: Prenatal exposures to endocrine-disrupting chemicals (EDCs) are suspected risk factors in the etiology of hypospadias. The aim of this case-control study was to test the hypothesis of an association between maternal environmental exposures to EDCs and hypospadias in the offspring. METHODS: Detailed questionnaire data on occupational and dietary exposures to EDCs in the perinatal period were collected from 80 mothers with hypospadiac infants and from 80 mothers with healthy controls within 24 months of childbirth. Maternal exposure to selected EDCs was also ascertained by measuring the concentration of dichlorodiphenyldichloroethylene, hexachlorobenzene, and several polychlorinated biphenyl congeners in the serum of primiparous mothers of 37 cases and 21 controls. RESULTS: The risk to bear an hypospadiac infant was associated with perinatal maternal occupational exposures to EDCs evaluated by a job-exposure matrix: jobs with exposure to one class of EDCs (odds ratios [OR](crude), 2.83; 95% confidence intervals [CI], 1.32-6.07; OR(adjusted), 2.44; 95% CI, 1.06-5.61) and jobs with exposure to more than one group of EDCs (OR(crude), 4.27; 95% CI, 1.43-12.78; OR(adjusted), 4.11; 95%CI, 1.34-12.59). Increase in risk was also found among mothers consuming a diet rich in fish or shellfish (OR(crude), 3.41; 95% CI, 1.42-8.23; OR(adjusted), 2.73; 95%CI, 1.09-6.82). Serum hexachlorobenzene concentration above the median of all subjects was significantly associated with the risk of hypospadias (OR(adjusted), 5.50; 95% CI, 1.24-24.31). CONCLUSIONS: This study, although based on a limited number of cases, for the first time provides evidence of an association between maternal exposure to EDCs, in particular elevated plasma hexachlorobenzene concentration, and the development of hypospadias in the offspring.

Snodgrass urethroplasty: grafting the incised plate--10 years later.

PURPOSE: We report our retrospective, nonrandomized, single center experience with modified tubularized incised urethral plate repair, consisting of grafting the incised urethral plate before tubularization, as first introduced 10 years ago. Indications, technical points and results are described. MATERIALS AND METHODS: From 1997 to 2007 at our unit 1,095 cases of hypospadias were treated, including 75% primary and 25% repeat cases. Of primary cases 18 (8%) of those suitable for tubularized incised urethral plate were instead selected for a grafted tubularized incised urethral plate. All 18 patients were characterized anatomically by a small glans, a flat urethral groove and a long spongiosum defect. Of repeat cases 83 were suitable for a tubularized incised urethral plate, of which 44 (53%) were selected for the modified procedure. Grafted tubularized incised urethral plate surgery consisted of an extended longitudinal incision of the urethral plate distal beyond the neomeatal line associated with scar excision in repeat cases. The resulting urethral plate defect was then lined with a graft. RESULTS: Mean followup was 36 months (range 4 to 122). Complications were noted in 8 repeat cases (13% overall), representing 18% of this subgroup. CONCLUSIONS: Case selection is a crucial factor that influences the quality of tubularized incised urethral plate results. However, in most repeat cases scarring may lead to an increased complication rate after tubularized incised urethral plate surgery. The grafted modification has the advantage of extending indications for the tubularized incised urethral plate to cases in which another surgical procedure would be necessary. To our knowledge we present the first series of primary and repeat cases.

Complete Scrotal Agenesis: New Surgical Approach Using Self-inflating Tissue Expander.

Complete agenesis of the scrotum is an extremely rare entity: to date, only 8 cases have been reported. The authors describe 1 case carrying a heterozygous genomic variant in exon 17 of the MAP3K1 gene, whose surgical treatment included osmotic prosthesis implant to achieve reconstruction of a new scrotum. By constant and gradual expansion, self-inflating prothesis avoids patient discomfort and facilitates orchiopexy.

Carnitine deficiency induces a short QT syndrome.

BACKGROUND: Short QT syndrome is associated with an increased risk of cardiac arrhythmias and unexpected sudden death. Until now, only mutations in genes encoding the cardiac potassium and calcium channels have been implicated in early T-wave repolarization. OBJECTIVE: The purpose of this study was to confirm a relationship between a short QT syndrome and carnitine deficiency. METHODS: We report 3 patients affected by primary systemic carnitine deficiency and an associated short QT syndrome. Ventricular fibrillation during early adulthood was the initial symptom in 1 case. To confirm the relationship between carnitine, short QT syndrome, and arrhythmias, we used a mouse model of carnitine deficiency induced by long-term subcutaneous perfusion of MET88. RESULTS: MET88-treated mice developed cardiac hypertrophy associated with a remodeling of the mitochondrial network. The continuous monitoring of electrocardiograms confirmed a shortening of the QT interval, which was negatively correlated with the plasma carnitine concentration. As in humans, such alterations coincided with the genesis of ventricular premature beats and ventricular tachycardia and fibrillation. CONCLUSION: Altogether, these results suggest that long-chain fatty acid metabolism influence the morphology and the electrical function of the heart.

Long-chain acylcarnitines regulate the hERG channel.

BACKGROUND AND PURPOSE: In some pathological conditions carnitine concentration is high while in others it is low. In both cases,cardiac arrhythmias can occur and lead to sudden cardiac death. It has been proposed that in ischaemia, acylcarnitine (acyl-CAR), but not carnitine, is involved in arrhythmias through modulation of ionic currents. We studied the effects of acyl-CARs on hERG, K(IR)2.1 and K(v)7.1/minK channels (channels responsible for I(KR), I(K1) and I(KS) respectively). EXPERIMENTAL APPROACH: HEK293 cells stably expressing hERG, K(IR)2.1 or Kv7.1/minK were studied using the patch clamp technique. Free carnitine (CAR) and acyl-CAR derivatives from medium- (C8 and C10) and long-chain (C16 and C18:1) fatty acids were applied intra- and extracellularly at different concentrations. For studies on hERG, C16 and C18:1 free fatty acid were also used. KEY RESULTS: Extracellular long-chain (LCAC), but not medium-chain, acyl-CAR,induced an increase of I(hERG) amplitude associated with a dose-dependent speeding of deactivation kinetics. They had no effect on K(IR)2.1 or Kv7.1/minK currents.Computer simulations of these effects were consistent with changes in action potential profile. CONCLUSIONS AND APPLICATIONS: Extracellular LCAC tonically regulates I(hERG) amplitude and kinetics under physiological conditions. This modulation may contribute to the changes in action potential duration that precede cardiac arrhythmias in ischaemia, diabetes and primary systemic carnitine deficiency.

Scafoid megalourethra--a reliable surgical approach.

Congenital megalourethra is a very rare malformation, which has 2 anatomical variants, scafoid and fusiform. The etiology of this malformation is still a matter of discussion. A surgical approach is proposed here, which has been successfully used in the case of a boy affected by scafoid megalourethra.

Simplifying the surgical approach to glanular and coronal hypospadias: longitudinal urethral incision and glanuloplasty.

OBJECTIVE: Meatal advancement with glanuloplasty incorporated (MAGPI) is an appropriate approach for most glanular and coronal hypospadias. The very low incidence of complications with this technique (i.e., fistulas, meatal regression and stenosis) makes MAGPI very competitive if compared with other approaches proposed for similar anatomical defects. In certain cases, however, the MAGPI approach has led to an unsatisfactory neo meatus; instead of a natural slit-like appearance, the meatus can look too rounded and puckered. METHODS: The last 84 patients referred to our unit with indications suitable for MAGPI (mean age 39 months) were operated on using a novel approach: the glanuloplasty was associated with a simple deep urethral plate incision, extending along the urethral channel, and left unsutured. RESULTS: At minimum follow up of 12 months two meatal regressions to mid glans were recorded. No meatal stenosis was seen in this series. CONCLUSION: This approach allowed us to achieve a conical glans with a natural looking meatus, avoiding urethral sutures.

Herlyn-Werner-Wunderlich syndrome: uterus didelphys, blind hemivagina and ipsilateral renal agenesis. Sonographic and MR findings in 11 cases.

BACKGROUND: Uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis is a rare entity, sometimes referred to as Herlyn-Werner-Wunderlich syndrome (HWW). It usually presents after menarche with progressive pelvic pain, sometimes with regular menses, and a palpable mass due to hemihaematocolpos. The diagnosis is generally made only if the suspicion of this genitourinary syndrome is raised. OBJECTIVE: To highlight the imaging diagnostic clues in this rare condition. MATERIALS AND METHODS: We report on 11 adolescents with this condition. RESULTS: Sonography mostly allowed the correct diagnosis by showing uterovaginal duplication, haematocolpos or haematometrocolpos, and the absence of the ipsilateral kidney. MRI provided more detailed information regarding uterine morphology, the continuity with each vaginal channel (obstructed and nonobstructed), and the bloody nature of the contents. CONCLUSION: Early and accurate diagnosis of this syndrome is important so that adequate and prompt surgical therapy (excision of the vaginal septum) can provide relief of pain and prevent further complications. It is also advisable to look for an obstructed Müllerian system whenever a multicystic dysplastic kidney or the absence of a kidney is discovered in a fetus, or girl postnatally.

Surgical approach to the congenital megaprepuce.

The megaprepuce (MP) is a very rare malformation of unknown aetiology, with anatomical findings similar to those observed in the congenital buried penis (BP). The aspect of this entity and the symptoms are rather typical: the penis is totally buried and before micturition an evident pubic and scrotal swelling denounces the urine collection in an abnormal preputial cavity surrounding the entire shaft. Early surgery is recommended, in order to deal with functional and cosmetic aspects. The very diminutive phallus is the most important cause of family anxiety. The authors present six infants, aged 5, 12, 13, 18, 20 and 43 months, operated upon for MP. The surgical approach consisted in the complete exteriorization of the shaft with section of the penile ligament, the restoring of the pubo-penile and peno-scrotal angles and the tailoring of the cutaneous cylinder. No intra- or postoperative complications were observed. Late functional and cosmetic results were judged satisfactory by both parents and surgeons. The surgical approach to BP is not simply transferable to the correction of MP. The cosmetic arrangement of the shaft skin is the more difficult step of the MP correction in order to avoid postoperative complications and an unsatisfied cosmetic appearance.

Polyorchidism and torsion. A lesson from 2 cases.

Two cases of polyorchidism with 2 left scrotal testes are referred. In both patients, the segmented gonads showed a "bell clapper" deformity. In the first patient, the contralateral gonad also presented a large mesorchium and absence of scrotal ligament, whereas in the second case, the right gonad was firmly adhered to the tunica vaginalis because of a previous appendix testis torsion. Orchidopexy of all testes, judged at risk for torsion, was performed. Contrary to what is recommended by recent literature, we consider scrotal exploration and testis fixation mandatory of the contralateral, apparently normal gonad as well, even in the absence of clinical and ultrasound signs of associated abnormalities or complications.

Cystic dysplasia of the rete testis: report of two cases and review of the literature.

Cystic dysplasia of the rete testis (CDT) is a rare congenital defect, characterized by multiple irregular cystic spaces in the mediastinum of the testis that may involve the whole gonad. A review of the literature has shown 32 reported cases, the majority of which were associated with ipsilateral renal malformations (agenesis/cystic dysplasia). Pathogenesis may be attributed to an early insult involving mesonephric duct development. Although treatment is surgical, when feasible, a conservative or nonoperative approach is suggested. Here we report two cases, one in a 3-year-old boy and one in a 10-day-old newborn. Concomitant cystic dysplasia of ipsilateral kidney was present in the former patient, while CDT was the solitary finding in the latter patient. Orchiectomy was performed in both patients, for extensive gonad involvement in the older boy and for suspected gonad torsion in the newborn patient.