Shou-Hung Tang

Ketamine-associated bladder dysfunction

Objective:  To assess the impact of ketamine abuse on genitourinary tract dysfunction.

The HDAC Inhibitor LBH589 Induces ERK-Dependent Prometaphase Arrest in Prostate Cancer via HDAC6 Inactivation and Down-Regulation

Histone deacetylase inhibitors (HDACIs) have potent anti-cancer activity in a variety of cancer models. Understanding the molecular mechanisms involved in the therapeutic responsiveness of HDACI is needed before its clinical application. This study aimed to determine if a potent HDACI, LBH589 (Panobinostat), had differential therapeutic responsiveness towards LNCaP and PC-3 prostate cancer (PCa) cells. The former showed prometaphase arrest with subsequent apoptosis upon LBH589 treatment, while the latter was less sensitive and had late G2 arrest. The LBH589 treatment down-regulated HDAC6 and sustained ERK activation, and contributed to prometaphase arrest. Mechanistically, LBH589 inhibited HDAC6 activity, caused its dissociation from protein phosphatase PP1α, and increased 14-3-3ζ acetylation. Acetylated 14-3-3ζ released its mask effect on serine 259 of c-Raf and serine 216 of Cdc25C subsequent to de-phosphorylation by PP1α, which contributed to ERK activation. Enhanced ERK activity by LBH589 further down-regulated HDAC6 protein levels and sustained ERK activation by free-forward regulation. The sustained Cdc25C and ERK activation resulted in early M-phase (prometaphase) arrest and subsequent apoptosis in the most sensitive LNCaP cells but not in PC-3 cells. This study provides pre-clinical evidence that HDAC6 may serve as a sensitive therapeutic target in the treatment of prostate cancer with HDACI LBH589 for clinical translation. This study also posits a novel mechanism of HDAC6 participation in regulating the c-Raf-PP1-ERK signaling pathway and contributing to M phase cell-cycle transition.

Emodin modulates epigenetic modifications and suppresses bladder carcinoma cell growth.

The deregulation of epigenetics was involved in early and subsequent carcinogenic events. Reversing cancer epigenetics to restore a normal epigenetic condition could be a rational approach for cancer treatment and specialized prevention. In the present study, we found that the expression levels of two epigenetic markers, histone H3K27 trimethylation (H3K27me3), was low but histone H3S10 phosphorylation (pH3Ser10) was high in human bladder cancer tissues, which showed opposite expression patterns in their normal counterparts. Thus, we investigated whether a natural product, emodin, has the ability to reverse these two epigenetic modifications and inhibit bladder cancer cell growth. Emodin significantly inhibited the cell growth of four bladder cancer cell lines in a dose‐ and time‐dependent manner. Emodin treatment did not induce specific cell cycle arrest, but it altered epigenetic modifications. Emodin treatment resulted in the suppression of pH3Ser10 and increased H3K27me3, contributing to gene silencing in bladder cancer cells. Microarray analysis demonstrated that oncogenic genes including fatty acid binding protein 4 (FABP4) and fibroblast growth factor binding protein 1 (HBP17), RGS4, tissue inhibitor of metalloproteinase 3 (TIMP3), WNT5b, URB, and collagen, type VIII, alpha 1 (COL8A1) responsible for proliferation, survival, inflammation, and carcinogenesis were significantly repressed by emodin. The ChIP assays also showed that emodin increased H3K27me3 but decreased pH3Ser10 modifications on the promoters of repressed genes, which indicate that emodin reverses the cancer epigenetics towards normal epigenetic situations. In conclusion, our work demonstrates the significant anti‐neoplastic activity of emodin on bladder cancer cells and elucidates the novel mechanisms of emodin‐mediated epigenetic modulation of target genes. Our study warrants further investigation of emodin as an effective therapeutic or preventive agent for bladder cancer.

Testicular Microlithiasis in Taiwanese Men

Testicular microlithiasis (TM) is an unusual ultrasonographic manifestation in testicular parenchyma. Limited information is available about TM in Taiwanese men. We performed a retrospective analysis to investigate the characteristics of TM and its association with testicular cancer and infertility in Taiwan. Male patients who had received scrotal ultrasonography because of scrotal symptoms or infertility between January 2000 and December 2003 were recruited. The incidence of TM was 7.6%. Both testicular microlithiasis and testicular cancer occurred chiefly in the third decade. Patients with TM exhibit a higher chance of testicular cancer (6% vs. 0.9%). No local field effect between TM and testicular cancer was observed. Testicular microlithiasis severity is not positively correlated with sperm quality and sterility. Forty-eight patients (32%) were available at follow-up. No patient developed a testicular tumor or elevated tumor markers (AFP, ß-hCG) during follow-up. We suggest monthly self-examination, annual scrotal ultrasonography and tumor markers screening between the age of 20 and 30 years of patients with TM.

Association between lower urinary tract symptoms and sexual dysfunction in Taiwanese men

The study investigated the association between lower urinary tract symptoms (LUTS) and sexual dysfunction in ageing men. It was a cross‐sectional study in an unselected consecutive sample of 398 men aged >40 years attending a urology clinic. LUTS and sexual function were assessed by validated symptom scales, including the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function‐5 (IIEF‐5). Clinically the severity of total and obstructive IPSS showed no significant correlation with age, but irritative IPSS is statistically correlated with age (P < 0.05). The prevalence of moderate to severe ED (IIEF‐5 < 12) was significantly associated with LUTS severity (P < 0.05) and the severity of IIEF‐5 correlated significantly with age (P < 0.01). A consistent inverse correlation was found between IIEF‐5 and IPSS severity across the age groups, with the strongest effect within aged 60 to 69 years (r = −0.286, P < 0.01). The irritative IPSS showed a significant correlation with IIEF‐5 severity across all age groups. These results reveal a significant correlation between LUTS and the severity of ED, especially on the irritative domain.

Renal infarction secondary to ketamine abuse

Renal infarction is an uncommon condition that resulted from inadequate perfusion of the kidney and is easily missed diagnosed due to its nonspecific clinical presentations. Major risk factors for renal infarction are atrial fibrillation, previous embolism, and ischemic and valvular heart disease. Progressive decrease in renal function or even death can occur if renal infarction is not diagnosed accurately and promptly. Ketamine abuse may cause variable urinary tract injury. However, renal infarction caused by ketamine abuse has never been reported. To our knowledge, this is the first documented case of renal infarction following nasal insufflation of ketamine.

Remote Recurrence Of Malignant Pheochromycytoma 14 Years After Primary Operation

The reported incidence of recurrent pheochromocytoma is 4.6% to 6.5%.1 Recurrence of pheochromocytoma more than 10 years after initial treatment is rare. We present a case of recurrent pheochromocytoma with malignant change 14 years after primary surgery. CASE REPORT A 72-year-old female had undergone left total adrenalectomy 14 years previously for adrenal pheochromocytoma. She had initially presented with frequent episodes of faintness and abdominal pain during periods of emotional stress. It is noteworthy that there were no classic signs or symptoms of pheochromocytoma, such as headache, palpitation, diaphoresis or hypertension, at initial presentation. Postoperatively followup abdominal ultrasonograms had consistently been negative. At presentation the patient reported discomfort at the previous lumbar incision several months in duration. Biochemical analyses, including 24-hour urinary vanillylmandelic acid and metanephrines, were within normal limits. Abdominal ultrasonography revealed a circumscribed 3.6 cm. hypoechoic lesion in the left suprarenal region. Computerized tomography and magnetic resonance imaging further demonstrated the mass to be highly suspicious for pheochromocytoma, which was later confirmed on ultrasound guided biopsy (see figure). A marked transient increase in blood pressure was noted at exploration. Pathological findings confirmed the presence of recurrent pheochromocytoma with additional muscular invasion, which indicated malignant change. The patient subsequently received external beam radiation therapy started on postoperative day 7. DISCUSSION

Ipsilateral Synchronous Neoplasms of Kidney Presenting as Acute Pyelonephritis and Bladder Metastasis

Ipsilateral multiple synchronous primary renal neoplasms is an uncommon presentation, and only a few cases have been reported in published studies. We report the case of a 57-year-old woman with acute pyelonephritis as the initial presentation, in whom conservative treatment had no effect. Surgical intervention revealed the presence of concomitant renal cell carcinoma, collecting duct carcinoma, and urothelial carcinoma (transitional cell carcinoma) of the kidney. Metastatic renal cell carcinoma to the bladder, liver, and lung subsequently developed. Deceptive inflammatory presentations can occur in aggressive synchronous renal malignancies. Recognition of this rare disease entity could prevent delays in diagnosis and treatment.

Novel Cancer Therapeutics with Allosteric Modulation of The Mitochondrial C-Raf/DAPK Complex by Raf Inhibitor Combination Therapy

Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf(S338)) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK(S308)), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF(C-Raf-/-) or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPK(S308), this drug-target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf(S338) and pDAPK(S308) translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK(S308) to DAPK. PP2A then dissociated from the C-Raf-DAPK complex and induced profound cancer cell death. Increased pDAPK(S308) modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK(S308) may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation.

Short-Term Result of Renal Transplantation Using Extracorporeal Membrane Oxygenation–Supported Brain-Dead Donors

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is now widely used to maintain hemodynamic stability after traumatic events among medical centers. It remains unclear whether renal transplantation using ECMO-supported donors carries poorer outcomes. METHODS From February 2010 to March 2013, we performed 9 renal transplantations (6 females and 3 males) from 5 ECMO-supported donors. Demographic data and clinical outcomes were retrospectively analyzed through medical chart review. RESULTS The mean follow-up period was 15 ± 9 months (range: 8-37). Eight of the 9 grafts remained functioning within the follow-up period. One (11.1%) graft loss was noted after repeated acute rejection. Acute rejection occurred in 3/9 (33%) of cases. Delayed graft function was also observed in 3/9 (33%) of cases. CONCLUSION Renal transplantation using ECMO-supported brain-dead donors was not associated with an unacceptably high rate of graft loss in this short-term follow-up. It might be an alternative way to expand donor pools.