This Month in Investigative Urology

Article Outline

• DLEC1 is Critical Tumor Suppressor for Renal Cell Carcinoma
• Red Blood Cell Membrane Fragments Promote Calcium Oxalate Monohydrate Crystals
• Minced Urothelium for Creation of Epithelialized Subcutaneous Conduits
• α2-Adrenoceptor Blockade and Urethral Continence
• Effects of Cyclosporine A on the Contralateral Testis After Ipsilateral Torsion/Detorsion
• Copyright

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DLEC1 is Critical Tumor Suppressor for Renal Cell Carcinoma 

Identification of tumor suppressor genes silenced by promoter CpG methylation may not only uncover mechanisms of renal cell carcinoma (RCC) tumorigenesis, but may also identify new epigenetic biomarkers for early cancer detection. DLEC1 (Deleted in Lung and Esophageal Cancer) is located at 3p22.3, a critical tumor suppressor gene locus for RCC. Zhang et al (page 731) from China examined the expression and methylation of DLEC1 in 9 RCC cell lines and 81 primary tumors. The relationship between DLEC1 methylation and clinicopathological features of RCC was also analyzed.

DLEC1 methylation and down-regulation were detected in all RCC cell lines. Treatment with 5-aza-2'-deoxycytidine and/or trichostatin A reversed the methylation and restored DLEC1 expression, indicating that methylation directly mediates its silencing. Aberrant methylation was further detected in 31% (25 of 81) of primary tumors vs only 2% (1 of 53) of nonmalignant renal tissues. DLEC1 methylation status was significantly associated with TNM classification and RCC grade/stage. Ectopic expression of DLEC1 in silenced RCC cells resulted in substantial inhibition of tumor cell clonogenicity. The authors conclude that DLEC1 is frequently down-regulated by CpG methylation and exhibits tumor inhibitory function in RCC. Inactivation of DLEC1 may increase the malignant potential of renal cancer, and tumor specific methylation of DLEC1 might serve as a biomarker for early detection and prognosis.

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Red Blood Cell Membrane Fragments Promote Calcium Oxalate Monohydrate Crystals 

Urinary organic macromolecules, such as glycoproteins, carbohydrates and membrane phospholipids, can have an important role in calcium oxalate (CaOx) kidney stone formation. Chutipongtanate and Thongboonkerd (page 743) from Bangkok, Thailand examined the effects of red blood cell (RBC) membrane fragments on CaOx monohydrate (COM) and CaOx dihydrate (COD) crystal growth and aggregation. COM and COD crystals were treated with RBC membrane fragments or intact RBCs obtained from a healthy donor, and phase-contrast microscopic examination was performed to evaluate crystal morphology and aggregation.

RBC membrane fragments had significant promoting activity on COM crystal growth (approximately 75%) and aggregation (approximately 2.5-fold) vs controls. Approximately 50% of COM crystals were adhered by RBC membrane fragments. Intact RBCs had no significant effects on COM crystal growth and aggregation but transformed COM to COD crystals. However, RBC membrane fragments and intact RBCs had no effect on COD crystals. The authors conclude that RBC membrane fragments are a promoting factor for COM crystal growth and aggregation, indicating that they may be involved in CaOx kidney stone formation.

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Minced Urothelium for Creation of Epithelialized Subcutaneous Conduits 

Pediatric urological reconstruction can be hampered by a shortage of appropriate tissue, especially when severe congenital malformations, secondary operations or aplasia of the affected organ are involved. Fossum et al (page 757) from Boston, Massachusetts and Stockholm, Sweden used the patient body as an in vivo incubator for cell expansion and tissue regeneration to create 3-dimensional subcutaneous conduits lined with an inner layer of autologous urothelial mucosa. They performed laparotomy and excision of a fifth of the urinary bladder in 5 female Yorkshire pigs. The detrusor muscle was mechanically removed and the bladder mucosa minced to obtain small particles, which were then attached to the outer surface of latex tubes with a thin layer of fibrin glue. The tubes were placed in the subcutaneous tissue of the abdominal wall of the original donor, with tubes lacking particles serving as controls.

Biopsies were taken 1, 2, 3 and 4 weeks after transplantation. At 1 week particles were still present in the granulation tissue. At 2 weeks the epithelium was differentiated with transitional uroepithelium facing the lumen. No epithelium was detected around control tubes. The authors conclude that this novel approach to urothelium transplantation may allow successful formation of a bladder conduit or neourethra.

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α2-Adrenoceptor Blockade and Urethral Continence 

Duloxetine, a dual reuptake inhibitor preventing the depletion of serotonin and norepinephrine at neuronal synapses, significantly reduces urine loss and improves quality of life in women with stress urinary incontinence (SUI). However, the side effects of therapeutic doses can be problematic and duloxetine is not currently approved by the Food and Drug Administration for the treatment of SUI. Kitta et al (page 762) from Pittsburgh, Pennsylvania studied whether α2-adrenoceptor (AR) antagonists (idazoxan or yohimbine) reduced the dose requirements of duloxetine in normal female rats and rats with SUI induced by vaginal distension (VD).

In all rats low dose duloxetine did not alter the amplitude of urethral pressure during sneezing but urethral baseline pressure increased significantly. However, low dose duloxetine with α2-AR antagonists significantly increased the amplitude of urethral pressure during sneezing. After low dose duloxetine administration all 7 VD rats had fluid leakage during sneezing. However, after low dose duloxetine and idazoxan fluid leakage disappeared in 2 of 7 VD rats and sneeze induced leak point pressure significantly increased in the remainder. The authors conclude that combination therapy with α2-AR antagonists may effectively reinforce the clinical efficacy of serotonin morepinephrine reuptake inhibitors in the treatment of SUI.

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Effects of Cyclosporine A on the Contralateral Testis After Ipsilateral Torsion/Detorsion 

Prior experimental studies on the prevention of testicular damage following testicular torsion mostly used agents that prevent immunological or ischemia/reperfusion injury. However, the degree of injury to the contralateral testis induced by these 2 mechanisms may be different during puberty and adulthood because the formation of the blood-testis barrier is incomplete during puberty. Jeong et al (page 790) from Seoul, Korea compared the preventive effects of cyclosporine A combined with prednisolone and melatonin on the damage to the contralateral testis after ipsilateral testicular torsion/detorsion in pubertal and adult Sprague-Dawley® rats. Preventive effects of cyclosporine A combined with prednisolone were observed only in pubertal rats, whereas preventive effects of melatonin were observed in pubertal and adult rats. The authors conclude that the damage to the contralateral testis induced by an immunological mechanism may be more significant during puberty than adulthood.