Transient receptor potential canonical 4 (TRPC4) channel is a nonselective calcium-permeable cation channels. In intestinal smooth muscle cells, TRPC4 currents contribute more than 80% to muscarinic cationic current (mIcat). With its inward-rectifying current-voltage relationship and high calcium permeability, TRPC4 channels permit calcium influx once the channel is opened by muscarinic receptor stimulation. Polyamines are known to inhibit nonselective cation channels that mediate the generation of mIcat. Moreover, it is reported that TRPC4 channels are blocked by the intracellular spermine through electrostatic interaction with glutamate residues (E728, E729). Here, we investigated the correlation between the magnitude of channel inactivation by spermine and the magnitude of channel conductance. We also found additional spermine binding sites in TRPC4. We evaluated channel activity with electrophysiological recordings and revalidated structural significance based on Cryo-EM structure, which was resolved recently. We found that there is no correlation between magnitude of inhibitory action of spermine and magnitude of maximum current of the channel. In intracellular region, TRPC4 attracts spermine at channel periphery by reducing access resistance, and acidic residues contribute to blocking action of intracellular spermine; channel periphery, E649; cytosolic space, D629, D649, and E687.
Amino Acids ; Binding Sites ; Calcium ; Cytosol ; Glutamic Acid ; Myocytes, Smooth Muscle ; Permeability ; Polyamines ; Receptors, Muscarinic ; Spermine ; Transient Receptor Potential Channels

PURPOSE: To predict the malignant potential of prostate cancer (PCa) according to prostate-specific antigen velocity (PSAV), PSA density (PSAD), free/total PSA ratio (%fPSA), and digital rectal examination (DRE). MATERIALS AND METHODS: From January 2009 to December 2012, 548 adult male patients were diagnosed with PCa by prostate biopsy at four hospitals in Korea. We retrospectively analyzed 155 adult male patients with an initial PSA level < or =10 ng/mL and whose PSA levels had been checked more than two times at least 6 months before they had been diagnosed with PCa, with test intervals of more than 3 months. Patients with a urinary tract infection, and patients who had previously undergone cystoscopy or surgery of the prostate were excluded. We separated patients into two groups according to Gleason sum [Gleason sum < or =7 (n=134) or Gleason sum > or =8 (n=21)] and the presence of extracapsular invasion [organ confined (n=129) or extracapsular invasion (n=26)]. Differences between the groups were compared. RESULTS: The group with a Gleason sum > or =8 or extracapsular invasion of PCa showed high PSAV and significantly lower %fPSA. There were no significant differences in PSAD and the presence of an abnormality on DRE between two groups. CONCLUSION: In PCa patients treated with other therapies besides prostatectomy, a high PSA velocity and a low %fPSA may predict high grade PCa with a Gleason sum > or =8 or the presence of extracapsular invasion.
Adult ; Aged ; Biopsy, Needle ; Digital Rectal Examination ; Humans ; Kinetics ; Male ; Middle Aged ; Neoplasm Grading ; Predictive Value of Tests ; Prognosis ; Prostate/*pathology ; Prostate-Specific Antigen/*blood ; Prostatectomy ; Prostatic Neoplasms/*pathology/surgery ; Republic of Korea ; Retrospective Studies ; Tumor Burden

PURPOSE: Up to 10% of recurrences develop beyond 5 years after curative treatment of localized renal cell carcinoma (RCC). Clinicopathologic features were evaluated to determine which factors are associated with late recurrence. MATERIALS AND METHODS: A total of 753 patients were diagnosed with localized RCC from January 2000 to June 2008. We enrolled 225 patients who were treated surgically and had a minimal recurrence-free survival of 60 months. Patients who had recurrence beyond 5 years after nephrectomy were defined as the late recurrence group and the remaining patients as the recurrence-free group. Multivariate logistic regression analyses and the Cox proportional hazard model were used for determination of features associated with late recurrence. RESULTS: In multivariate analyses, age older than 60 (p=0.030), Fuhrman grade > or = 3 (p=0.042), and pT stage > or = pT2 (p=0.010) showed statistical association with late recurrence. The Cox proportional hazard model showed significant differences in recurrence-free survival when we classified the patients based on pT2 (p=0.007) and on patient age > or = 60 years (p=0.039). CONCLUSION: Patient age greater than 60 years, Fuhrman grade > or = 3, and tumor stage > or = pT2 are independent risk factors of recurrence more than 5 years after surgery in patients with RCC. Therefore, close lifelong follow-up is recommended for patients with these risk factors.
Carcinoma, Renal Cell* ; Humans ; Kidney ; Logistic Models ; Multivariate Analysis ; Nephrectomy ; Proportional Hazards Models ; Recurrence ; Risk Factors

PURPOSE: The purpose of this study was to compare health-related quality of life (HRQoL) of disease-free prostate (PC), kidney (KC), and bladder cancer (BC) survivors with that of the general population. MATERIALS AND METHODS: Our study included 331 urological cancer (UC) survivors (114 PC, 108 KC, and 109 BC) aged ≥ 50 years disease-free for at least 1 year after surgery. The control group included 1,177 subjects without a history of cancer. The HRQoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30, the Duke-UNC Functional Social Support Questionnaire, and the Patient Health Questionnaire-9. RESULTS: There was no significant difference between the groups in terms of any of the functioning sub-scales and symptoms, except significantly lower social functioning observed in BC survivors than that observed in KC survivors. Although the three groups of UC survivors showed essentially similar functioning sub-scales and symptoms when compared to the general population, PC and BC survivors showed significantly lower social functioning and a lower appetite than that observed in controls. KC survivors showed lower physical functioning, as well as higher pain and dyspnea. Although all three groups of UC survivors reported higher financial difficulties, they also reported higher perceived social support than that reported by the non-cancer control group. No statistically significant difference was observed in terms of depressive symptoms between each group of UC survivors and the general population. CONCLUSION: Disease-free survivors of the three major types of UCs showed generally similar HRQoL compared to the general population, as well as compared to each other.
Appetite ; Depression* ; Dyspnea ; Humans ; Kidney Neoplasms ; Kidney* ; Prostate* ; Prostatic Neoplasms ; Quality of Life* ; Survivors* ; Urinary Bladder Neoplasms* ; Urinary Bladder* ; Urologic Neoplasms

PURPOSE: Health-related quality of life (HRQOL) information related to radical prostatectomy (RP) is valuable for prostate cancer (PC) patients needing to make treatment decisions. We aimed to investigate HRQOL change in PC patients who underwent three types of RP (open, laparoscopic, or robotic) and compared their HRQOL with that of general population. MATERIALS AND METHODS: Patients were prospectively recruited between October 2014 and December 2015. European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) and PC-specific module (PR25) were administered before surgery (baseline) and at postoperative 3 and 12 months. At each time point, HRQOL was compared, and a difference of 10 out of 0-100 scale was considered clinically significant. RESULTS: Among 258 screened patients, 209 (41 open, 63 laparoscopic, and 105 robotic surgeries) were included. Compared to baseline, physical, emotional, and cognitive functioning improved at 12 months. Role functioning worsened at 3 months, but recovered to baseline at 12 months. Pain, insomnia, diarrhea, and financial difficulties also significantly improved at 12 months. Most PR25 scales excluding bowel symptoms deteriorated at 3 months. Urinary symptoms and incontinence aid recovered at 12 months, whereas sexual activity and sexual function remained poor at 12 months. Clinically meaningful differences in HRQOL were not observed according to RP modalities. Compared to the general population, physical and role functioning were significantly lower at 3 months, but recovered by 12 months. Social functioning did not recover. CONCLUSION: Most HRQOL domains showed recovery within 12 months after RP, excluding sexual functioning and social functioning. Our findings may guide patients considering surgical treatment for PC.
Cohort Studies ; Diarrhea ; Humans ; Prospective Studies ; Prostate ; Prostatectomy ; Prostatic Neoplasms ; Quality of Life ; Sexual Behavior ; Sleep Initiation and Maintenance Disorders ; Weights and Measures

The transient receptor potential canonical (TRPC) 5 channel, known as a nonselective cation channel, has a crucial role in calcium influx. TRPC5 has been reported to be activated by muscarinic receptor activation and extracellular pH change and inhibited by the protein kinase C pathway. Recent studies have also suggested that TRPC5 is extracellularly activated by englerin A (EA), but the mechanism remains unclear. The purpose of this study is to identify the EA-interaction sites in TRPC5 and thereby clarify the mechanism of TRPC5 activation. TRPC5 channels are over-expressed in human embryonic kidney (HEK293) cells. TRPC5 mutants were generated by site-directed mutagenesis. The whole-cell patch-clamp configuration was used to record TRPC5 currents. Western analysis was also performed to observe the expression of TRPC5 mutants. To identify the EA-interaction site in TRPC5, we first generated pore mutants. When screening the mutants with EA, we observed the EA-induced current increases of TRPC5 abolished in K554N, H594N, and E598Q mutants. The current increases of other mutants were reduced in different levels. We also examined the functional intactness of the mutants that had no effect by EA with TRPC5 agonists, such as carbachol or GTPγS. Our results suggest that the three residues, Lys-554, His-594, and Glu-598, in TRPC5 might be responsible for direct interaction with EA, inducing the channel activation. We also suggest that although other pore residues are not critical, they could partly contribute to the EA-induced channel activation.
Calcium ; Carbachol ; Humans ; Hydrogen-Ion Concentration ; Ion Channels ; Kidney ; Mass Screening ; Mutagenesis, Site-Directed ; Mutant Proteins ; Protein Kinase C ; Receptors, Muscarinic