Ayman Mahdy

Acid Ceramidase Upregulation in Prostate Cancer Cells Confers Resistance to Radiation: AC Inhibition, a Potential Radiosensitizer

Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

The Functional Effects of Acid Ceramidase Overexpression in Prostate Cancer Progression and Resistance to Chemotherapy

Among the many processes regulating cell death, ceramide signaling is a vital component. We previously determined that acid ceramidase (AC) is upregulated in 60% of primary prostate cancer (PCa) tissues, suggesting that AC may play a role in tumor development. In order to determine the significance of AC elevation, stable clones of DU145 cells with AC over-expression (AC-EGFP) were generated. Compared to controls (EGFP), AC-EGFP cells exhibited enhanced cell proliferation and migration. Subcutaneous injection of AC-EGFP cells into Nu/Nu mice resulted in larger tumor volumes compared to EGFP controls. Moreover, using the MTS viability assay, AC-EGFP cells were more resistant to cell death induced by doxorubicin, cisplatin, etoposide, gemcitabine or C6-ceramide. Conversely, knock down of AC using siRNA, sensitized AC-EGFP cells to these drugs. In addition, mass spectroscopic analysis of sphingolipids indicated that long chain ceramide levels were decreased in AC-EGFP cells treated with either doxorubicin or etoposide. In conclusion, this study implicates AC as a critical regulator of PCa progression by affecting not only tumor cell proliferation and migration but also responses to drug therapy, suggesting AC as a potential therapeutic target in advanced PCa.

New insights on the use of desipramine as an inhibitor for acid ceramidase

Treatment of different cancer cell lines with desipramine induced a time‐ and dose‐dependent downregulation of acid ceramidase. Desipramines effect on acid ceramidase appeared specific for amphiphilic agents (desipramine, chlorpromazine, and chloroquine) but not other lysomotropic agents such as ammonium chloride and bafilomycin A1, and was not transcriptionally regulated. The cathepsin B/L inhibitor, CA074ME, but not the cathepsin D inhibitor, pepstatin A, blocked desipramines effect on acid ceramidase. Desipramine led to a more pronounced downregulation of sphingosine compared to ceramide suggesting acid ceramidase inhibition is important to desipramines mechanism of action. This study reveals a new mechanism of action for desipramine.

Acid ceramidase inhibition: a novel target for cancer therapy

During the last decade, sphingolipid deregulation, namely the balance between the pro-apoptotic molecule ceramide and the anti-apoptotic sphingolipid sphingosine-1-phosphate, has emerged as an important factor in cancer pathology and resistance to therapy. Thus, our research has been focused on developing drugs that are able to restore normal sphingolipid balance, precisely through increasing the levels of ceramide and decreasing sphingosine-1-phosphate. Particularly, inhibition of the ceramide metabolizing enzyme acid ceramidase, whose over-expression in cancer cells has been implicated in resistance to treatment, is proving to be an efficient and promising strategy. In this review, we consider our recent work with acid ceramidase inhibitors, in combination with radiation or gene therapy as a sensitizer that enhance cancer therapy.

Recurrent Stress Urinary Incontinence After Dislodged Screws in Patient With Bone-Anchored Suburethral Sling

This is the first reported case of recurrent stress urinary incontinence secondary to dislodged bone-anchoring screws. A 71-year-old man who had undergone successful bone-anchored sling placement for post-prostatectomy incontinence, presented with recurrent stress urinary incontinence after a bout of coughing. Pelvic radiography revealed three screws had been dislodged. The mesh was left in place, with replacement of the dislodged screws and the addition of one extra screw. The findings of this case suggest that dislodged screws can be a possible cause of sling failure. Preoperative bone scanning and postoperative pelvic radiography should be a part of the routine workup for patients with bone-anchored slings.

Successful Treatment of Stent Knot in the Proximal Ureter Using Ureteroscopy and Holmium Laser

Knotted ureteral stent is rare yet tedious complication that might represent a treatment challenge to the endourologist. Only twelve cases of knotted stent have been reported. Different management options have been reported, including simple traction, ureteroscopy, percutaneous removal, and open surgery. In this paper, we present the successful untying of the knot using ureteroscopy with holmium laser.

Clean Intermittent Catheterization in the Elderly

Clean intermittent catheterization (CIC) has become the gold standard for bladder management in a host of neurologic and non-neurologic disease states causing urinary retention. While CIC has been extensively studied, there has been limited research in applying CIC to the elderly population. In this review paper, we evaluate the lessons learned about the feasibility, complications, and obstacles to compliance associated with CIC and apply them to an elderly population. With the use of improved teaching methods, devices to assist with passing the catheter, and ongoing education and follow-up, we believe that CIC can be a viable option for bladder management in elderly patients with urinary retention.

The outcome of transobturator anterior vaginal wall prolapse repair using porcine dermis graft: intermediate term follow-up

INTRODUCTION AND HYPOTHESIS We evaluated the anatomical success and complications of Perigee® with porcine dermis Graft in the repair of anterior vaginal wall prolapse (AVWP) MATERIALS AND METHODS: After Institutional Review Board (IRB) approval, the charts of all patients who underwent AVWP repair using the Perigee/InteXen® kit from July 2005 to July 2009 were reviewed. Patients who had less than 6-month follow-up were excluded. Preoperative data including patient age, previous AVWP repairs, hysterectomy status, preoperative dyspareunia and pertinent physical findings were collected and recorded. Postoperative success was defined as anatomical stage 0 or I using the Pelvic Organ Prolapse Quantification (POP-Q) scoring system. Graft related complications were also recorded. RESULTS Out of 89 patients, 69 completed at least 6-month follow-up. Median follow-up was 13 (6-48) months. Seventeen patients (25%) had previous AVWP repair and 32 (46%) had previous hysterectomy. Preoperatively, AVWP stage II was found in 9 (13%), stage III in 27 (39%) and stage IV in 33 (48%) patients. Anatomic success was found in 48 (69%) patients, with 23 (33%) having stage 0 and 25 (36%) stage I AVWP. Intraoperative complications included incidental cystotomy in one patient and bladder perforation in one. Postoperative complications included vaginal exposure and dyspareunia in one case, wound dehiscence in one and tenderness over the graft arm with dyspareunia in one. CONCLUSIONS The use of porcine dermis in AVWP repair is safe with minimal graft related complications; however, anatomical success is lower than that reported with the use of synthetic grafts.

Objective cure of urinary retention following laparoscopic hysterectomy for a large uterine fibroid

Acute urinary retention (AUR) in women is not uncommon. Many reports have been published discussing the possible theories and pathogeneses of this condition. AUR induced by uterine fibroid is a rare entity that has been mentioned only in case reports. All the reported cases focused mainly on the different approaches for fibroid management. In this study, we present a 52-year-old female with recurrent episodes of urinary retention that was related to periods of menstruation. Pelvic magnetic resonance imaging revealed a markedly enlarged uterus with multiple fibroids. The patient had laparoscopic hysterectomy with postoperative resolution of patient’s symptoms and improved uroflow studies. This is the first article that proves the cure of AUR following hysterectomy using an objective tool.

Nephrogenic Adenoma in a Urethral Diverticulum

Nephrogenic adenoma (NA) is a rare benign metaplastic lesion of the urothelial tract that arises as a response to injury and chronic inflammation. Although the most common site for NA is the bladder, it can occur in any part of urinary tract lined by urothelium. NA can mimic minor variants of urothelial cancer, clear cell adenocarcinoma, and prostate adenocarcinoma, making a combination of histologic examination and immunohistochemistry essential for diagnosis. We hereby report a rare case of nephrogenic adenoma arising in a urethral diverticulum.