Validation of continuous intraabdominal pressure measurement: feasibility and accuracy assessment using a capsular device in in-vivo studies.

BACKGROUND: Monitoring Intraabdominal Pressure (IAP) is essential in critical care, as elevated IAP can lead to severe complications, including Abdominal Compartment Syndrome (ACS). Advances in technology, such as digital capsules, have opened new avenues for measuring IAP non-invasively. This study assesses the feasibility and effectiveness of using a capsular device for IAP measurement in an animal model. METHOD: In our controlled experiment, we anesthetized pigs and simulated elevated IAP conditions by infusing CO2 into the peritoneal cavity. We compared IAP measurements obtained from three different methods: an intravesical catheter (IAPivp), a capsular device (IAPdot), and a direct peritoneal catheter (IAPdir). The data from these methods were analyzed to evaluate agreement and accuracy. RESULTS: The capsular sensor (IAPdot) provided continuous and accurate detection of IAP over 144 h, with a total of 53,065,487 measurement triplets recorded. The correlation coefficient (R²) between IAPdot and IAPdir was excellent at 0.9241, demonstrating high agreement. Similarly, IAPivp and IAPdir showed strong correlation with an R² of 0.9168. CONCLUSION: The use of capsular sensors for continuous and accurate assessment of IAP marks a significant advancement in the field of critical care monitoring. The high correlation between measurements from different locations and methods underscores the potential of capsular devices to transform clinical practices by providing reliable, non-invasive IAP monitoring.

A Pilot Study of Nephrogenic Probiotics to Further Improve an Already Stabilized Graft Function After Kidney Transplantation.

BACKGROUND: The majority of kidney recipients are a subset of chronic kidney disease. Our previous study demonstrated that the combination of Lactobacillus plantarum and Lactobacillus paracasei (Lm) had the highest clearance ability of uremic toxins and improved kidney function in a mouse model. This study aimed to evaluate Lm in improving graft function, effects on immunosuppressants, and safety in transplant recipients. METHODS: We retrospectively reviewed 24 patients. Twelve of them take Lm regularly; we compared the creatinine measurements and estimated glomerular filtration rate 3 months before and after Lm using a 2-tailed Wilcoxon matched-pairs signed-rank test while also evaluating the drug level of immunosuppressants and infection events. Other 12 patients who do not have Lm for evaluation of laboratory calibration and compared the proportion of improving creatinine using Fisher's exact test. RESULTS: The creatinine decreased by 0.06 mg/dL (P = .02), and the estimated glomerular filtration rate increased by 3.1 mL/min/1.73 m2 (P = .03) after Lm supplementation. This pilot study revealed the association of higher incidence (odds ratio 13.3, 95% CI 1.64-77.2, P = .01) of decreasing creatinine in transplant recipients using Lm. Furthermore, results showed a trend of higher trough levels of tacrolimus and sirolimus, which might provide a potential strategy for reducing the dosages of immunosuppressants. CONCLUSION: Our findings revealed an association between a higher incidence of decreasing creatinine in kidney transplant recipients using Lm, which may also provide a potential strategy for reducing the acquired dosages of immunosuppressants.

The p38-MITOGEN-ACTIVATED PROTEIN KINASE Signaling Pathway Is Involved in Leonurus artemisia Extract-Induced Inhibition of the Proliferation of Human Bladder Cancer BFTC-905 Cells via G1/G0 Arrest and Causes Apoptosis In Vitro.

Bladder cancer is a urothelial malignancy. Bladder cancer starts in the urothelial cells lining the inside of the bladder. The 5-year recurrence rate for bladder cancer ranges from 31% to 78%, and the progression rate is approximately 45%. To treat bladder cancer, intravesical drug therapy is often used. Leonurus artemisia extract (LaE) was obtained from medicinal samples of Chinese motherwort Scientific Chinese Medicine; L. artemisia has various biological effects. This study investigated the impact of LaE on human bladder cancer cells (the BFTC-905 cell line) and the molecular mechanism underlying apoptosis resulting from the activation of cell signal transduction pathways in bladder cancer cells. A cell counting kit-8 (CCK-8) assay was used to determine the effect of LaE on cell growth. The effect of LaE on migration ability was observed using a wound healing assay. The effects of LaE on the cell cycle, reactive oxygen species production, and apoptosis were investigated. Western blot analysis detected apoptosis-related and mitogen-activated protein kinase signaling pathway-related protein concentrations. At non-toxic concentrations, LaE inhibited the proliferation of BFTC-905 cells in a concentration-dependent manner, and the half-maximal inhibitory concentration (IC50) was 24.08172 µg/µL. LaE impaired the migration ability of BFTC-905 cells. LaE arrested the cell cycle in the G1 and G0 phases, increased reactive oxygen species production, and induced apoptosis. LaE increased Bax and p-ERK concentrations and decreased Bcl-2, cleaved caspase-3, and p-p38 concentrations. No differences in PARP, C-PARP, vimentin, e-cadherin, p-JNK, or TNF-alpha concentrations were observed. These results suggest that LaE inhibits the proliferation of human bladder cancer cells. Moreover, the mitogen-activated protein kinase signaling pathway is involved in the inhibition of the proliferation of BFTC-905 cells.

Clinical Determinants of Extraurinary Tract Recurrence and Survival after Radical Surgery for pT2 Upper Tract Urothelial Carcinoma.

BACKGROUND: Oncologic outcomes for pT2N0M0 upper tract urothelial carcinoma (UTUC) after nephroureterectomy are not well defined, with most previous studies focused on a heterogeneous population. Therefore, we aimed to investigate the clinical determinants of extraurinary tract recurrence and survival after radical surgery in patients with localized UTUC. METHODS: We retrospectively identified 476 patients with pT2N0M0 UTUC who underwent radical nephroureterectomy or ureterectomy between October 2002 and March 2022. To evaluate the prognostic impact, patients were divided into renal pelvic, ureteral, and both-region (renal pelvis plus synchronous ureter) groups based on tumor location. The outcomes included recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Associations were evaluated using multivariable Cox regression analyses for prognostic factors and Kaplan-Meier analyses for survival curves. RESULTS: The renal pelvic, ureteral, and both-region groups consisted of 151 (31.7%), 314 (66.0%), and 11 (2.3%) patients, respectively. Kaplan-Meier analyses comparing the three tumor types showed significant differences in 5-year RFS (83.6% vs. 73.6% vs. 52.5%, p = 0.013), CSS (88.6% vs. 80.7% vs. 51.0%, p = 0.011), and OS (83.4% vs. 70.1% vs. 45.6%, p = 0.002). Multivariable analyses showed that age >60 years, previous bladder cancer history, ureteral involvement (ureteral and both-regional groups), and positive surgical margins were significant negative prognostic factors for the studied outcomes. CONCLUSIONS: Patients with pT2 UTUC and presence of ureteral involvement had more frequent disease relapse. Subsequent adjuvant therapy regimens and close follow-up in patients with negative prognostic factors are warranted despite complete pathological removal of the tumor.

Case Report: Neoadjuvant immunotherapy with pembrolizumab alone for bilateral upper tract urothelial carcinoma is a feasible strategy for kidney sparing and avoidance of hemodialysis.

In Taiwan, the incidence of upper-tract urothelial carcinomas (UTUCs) is higher than in western countries (20%-31% vs. 5%-10%), as is bilateral disease. The standard management for high-grade UTUC is radical nephroureterectomy with bladder cuff excision and regional lymphadenectomy. The challenges in managing bilateral UTUCs are how to retain renal function and avoid permanent hemodialysis. We present two cases of developed bilateral high-grade renal pelvis urothelial carcinoma, cT3N0M0 stage III, that revealed excellent results in tumor regression after three cycles of half-dose pembrolizumab. One case received unilateral retroperitoneal laparoscopic nephroureterectomy with bladder cuff excision; thereafter, renal function has been good until now, and the remaining right kidney has been free of tumor recurrence in the 3 years of follow-up. The other patient, however, expired from an immune-related adverse event (irAE) 22 days after the third cycle of pembrolizumab, although tumor remission was evident also. Neoadjuvant pembrolizumab alone could be a potential strategy in positive of selected biomarkers for high-grade bilateral UTUC with remaining neglectable nephrotoxicity and may avoid permanent hemodialysis.

Pulmonary Embolism after Moderna Vaccination in Kidney Transplant Patients: Two Case Reports and Literature Review.

Currently, the coronavirus disease 2019 (COVID-19) pandemic is still an ongoing and constant medical issue, and with upcoming new variants, vaccinations and boosters remain important. The safety of vaccines in patients after kidney transplantation is an essential problem, with thrombosis being one of the severe side effects and vaccine-induced immune thrombotic thrombocytopenia (VITT) revealed as the most commonly reported syndrome for thromboembolic events following COVID-19 vaccination. Here, we present two cases of kidney transplantation developing pulmonary embolism post-Moderna vaccination within 30 days without thrombocytopenia. The first case was a 52-year-old man with history of type II diabetes, hypertension and hyperlipidemia who had had cadaveric kidney transplantation in September 2008, where right leg swelling with claudication occurred 23 days after the second Moderna vaccination. The second case was a 57-year-old man with history of type II diabetes and glaucoma who had had living-related kidney transplantation in April 2013 and then complained of exertional dyspnea 26 days after administration of the third Moderna vaccine. The advantages of vaccination even in immunocompromised patients far outweigh the disadvantages, although clinicians must understand the risks of deep-vein thrombosis or even pulmonary embolism for such patients, which might not occur after just the first vaccination.

Systematic Review of Diagnostic Sensors for Intra-Abdominal Pressure Monitoring.

Intra-abdominal pressure (IAP) is defined as the steady-state pressure within the abdominal cavity. Elevated IAP has been implicated in many medical complications. This article reviews the current state-of-the-art in innovative sensors for the measurement of IAP. A systematic review was conducted on studies on the development and application of IAP sensors. Publications from 2010 to 2021 were identified by performing structured searches in databases, review articles, and major textbooks. Sixteen studies were eligible for the final systematic review. Of the 16 articles that describe the measurement of IAP, there were 5 in vitro studies (31.3%), 7 in vivo studies (43.7%), and 4 human trials (25.0%). In addition, with the advancement of wireless communication technology, an increasing number of wireless sensing systems have been developed. Among the studies in this review, five presented wireless sensing systems (31.3%) to monitor IAP. In this systematic review, we present recent developments in different types of intra-abdominal pressure sensors and discuss their inherent advantages due to their small size, remote monitoring, and multiplexing.

Biodegradable Stent with mTOR Inhibitor-Eluting Reduces Progression of Ureteral Stricture.

In this study, we investigated the effect of mTOR inhibitor (mTORi) drug-eluting biodegradable stent (DE stent), a putative restenosis-inhibiting device for coronary artery, on thermal-injury-related ureteral stricture in rabbits. In vitro evaluation confirmed the dose-dependent effect of mTORi, i.e., rapamycin, on fibrotic markers in ureteral component cell lines. Upper ureteral fibrosis was induced by ureteral thermal injury in open surgery, which was followed by insertion of biodegradable stents, with or without rapamycin drug-eluting. Immunohistochemistry and Western blotting were performed 4 weeks after the operation to determine gross anatomy changes, collagen deposition, expression of epithelial-mesenchymal transition markers, including Smad, α-SMA, and SNAI 1. Ureteral thermal injury resulted in severe ipsilateral hydronephrosis. The levels of type III collagen, Smad, α-SMA, and SNAI 1 were increased 28 days after ureteral thermal injury. Treatment with mTORi-eluting biodegradable stents significantly attenuated thermal injury-induced urinary tract obstruction and reduced the level of fibrosis proteins, i.e., type III collagen. TGF-ß and EMT signaling pathway markers, Smad and SNAI 1, were significantly modified in DE stent-treated thermal-injury-related ureteral stricture rabbits. These results suggested that intra-ureteral administration of rapamycin by DE stent provides modification of fibrosis signaling pathway, and inhibiting mTOR may result in fibrotic process change.

Cyproterone acetate acts as a disruptor of the aryl hydrocarbon receptor.

Prostate cancer is a major cause of death in males. Cyproterone acetate (CPA), the steroidal anti-androgen for part of androgen deprivation therapy, may block the androgen-receptor interaction and then reduce serum testosterone through its weak anti-gonadotropic action. In addition to CPA inducing hepatitis, CPA is known to cause liver tumors in rats also. Aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and regulates multiple physiological functions. CYP1A1 is an AhR-targeted gene. We found that CPA induced CYP1A1 expression, transcriptional activity of the aryl hydrocarbon response element (AHRE), and the nuclear localization of AhR in mouse Hepa-1c1c7 cells. However, CPA suppressed CYP1A1 mRNA expression and the transcriptional activity of AHRE in human HepG2 and MCF7 cells, and also decreased AhR ligand-induced CYP1A1 protein expression and transcriptional activity of AHRE in HepG2 cells. In summary, CPA is an AhR agonist in mouse cells, but an AhR antagonist in human cells. Accordingly, CPA potentially plays a role as an endocrine disruptor of the AhR. This study helps us to understand why CPA induces acute hepatitis, gene mutation, and many other side effects. In addition, it may trigger further studies investigating the relationships between CPA, glucocorticoid receptor and castration-resistant prostate cancer in the future.

An Ingestible Electronics for Continuous and Real-Time Intraabdominal Pressure Monitoring.

Abdominal compartment syndrome can be treated through decompressive surgery if intraabdominal hypertension (IAH) can be detected in time. Treatment delays due to manual, conventional intravesical pressure (IVP) monitoring using a Foley catheter have been reported. In this work, we present an innovative gastrointestinal intraluminal pressure (GIP) measurement-based method to monitor and improve pressure-guided relief of intraabdominal pressure (IAP). A novel algorithm for detecting IAH in the gastrointestinal tract of a live porcine model is reported. A wireless pressure-sensing capsule (10 × 13 mm) was developed for absolute measurement. The IAP was estimated during artificial pneumoperitoneum. The pressure waveform-based measurements indicated that the wireless pressure sensor could be used to predict IAP. To enhance GIP monitoring for predicting IAH, the proposed continuous ingestible wireless electronics-based pressure waveform measurement device can be used as a complement to existing modalities. The use of the proposed pressure measurement and communication technology can help provide valuable data for digital health platforms.

Erectile Dysfunction After Surgical Treatment of Lung Cancer: Real-World Evidence.

BACKGROUND: Sexual problems are common in male lung cancer survivors. However, the development of erectile dysfunction (ED) in lung cancer patients after surgery has been rarely explored. In this study, we aimed to explore the incidence and risk factors of ED after lung cancer surgery. METHODS: From 2000 to 2012, 6025 and 24,100 male patients were included in each matched cohort of lung cancer and non-lung cancer patients, respectively. Poisson regression analysis was used to calculate the incidence rate ratio (IRR) and 95% confidence interval (CI). RESULTS: The incidence of ED was higher in the lung cancer cohort compared to the non-lung cancer cohort (38.47 vs 28.28 per 10,000 person-years) with an adjusted IRR (aIRR) of 1.34 (95% CI: 1.06-1.70, p=0.014) after the confounders were adjusted for. An increased incidence of ED was observed in the lung cancer cohort aged 40-54 years (aIRR: 5.44, 95% CI: 2.25-13.15, p<0.001), 55-64 years (aIRR: 3.62, 95% CI: 1.61-8.17, p=0.002) years, and anxiety (aIRR: 2.99, 95% CI: 1.81-4.94, p<0.001). In addition, a higher incidence of emergency room (ER) visits (aIRR: 2.19, 95% CI: 1.98-2.42, p<0.001) was observed in lung cancer patients with ED compared to those without ED. CONCLUSION: Our study results suggested that early surveillance and intervention of ED should be advocated in lung cancer patients after surgery.

Beneficial Effects of Inflammatory Cytokine-Targeting Aptamers in an Animal Model of Chronic Prostatitis.

Non-bacterial prostatitis is an inflammatory disease that is difficult to treat. Oligonucleotide aptamers are well known for their stability and flexibility in conjugating various inflammatory molecules. In this study, we investigated the effects of inflammatory cytokine-targeting aptamers (ICTA), putative neutralizers of TNF-alpha and IL-1 beta activation, on local carrageenan-induced prostate inflammation, allodynia, and hyperalgesia in rats. In vitro evaluation confirmed the binding capability of ICTA. Intraprostatic injection of carrageenan or control vehicle was performed in six-week-old rats, and ICTA (150 µg) or vehicle was administered in the prostate along with carrageenan injection. The von Frey filament test was performed to determine mechanical allodynia, and prostate inflammation was examined seven days after drug administration. Local carrageenan administration resulted in a reduction of the tactile threshold. The levels of mononuclear cell infiltration, pro-inflammatory cytokine interleukin-1 beta (b), caspase-1 (casp-1), and Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing proteins 1 and 3 (NALP1 and NALP3) in the prostate of rats were increased seven days after carrageenan injection. Treatment with ICTA significantly attenuated the carrageenan-induced hyperalgesia and reduced the elevated levels of proteins including TNF-a and IL-1b in the rats. Apoptosis markers, B-cell lymphoma 2-associated X protein (Bax) and caspase-3, were elevated in ICTA-treated Chronic pelvic pain syndrome (CPPS) rats. These results suggest that ICTA provides protection against local carrageenan-induced enhanced pain sensitivity, and that the neutralization of proinflammatory cytokines may result in inflammatory cell apoptosis.

The influence of smoking exposure and cessation on penile hemodynamics and corporal tissue in a rat model.

BACKGROUND: While epidemiological studies have clearly documented that smoking cessation significantly enhances sexual health, the underlying mechanism remains largely unknown. Thus, we wished to explore possible mechanisms by using a rat model of smoking-associated erectile dysfunction (ED). METHODS: Forty 8-week old male Sprague-Dawley rats were divided into 4 groups. Ten rats were exposed only to room air (N group). The remaining 30 rats were passively exposed to cigarette smoke over a 12-week period. At the end of 12 weeks, the smoking (S, n=10) group underwent immediate erectile function testing and were sacrificed. The remaining 20 rats were exposed to room air only for 4 (Q4W, n=10) or 8 (Q8W, n=10) weeks and then underwent erectile function testing and sacrifice. Erectile function was evaluated by measuring intracavernous pressure (ICP) and mean arterial pressure (MAP). After blood collection for serum testosterone determination, rats were sacrificed to obtain corporal tissue for immunohistochemistry. RESULTS: Mean ICP/MAP ratio was significantly lower in the S group compared to the N and Q8W groups (0.52±0.11, 0.94±0.05, and 0.94±0.12, respectively, P=0.0189). Smooth muscle/collagen ratio was also significantly lower in the S group compared to the N and Q8W groups (11.8±0.94, 17.5±1.82, and 16.4±0.60, respectively, P=0.0008). Oxidative stress and apoptotic indices were significantly higher in the S group compared to the N and Q8W groups. Neuronal and endothelial nitric oxide synthases were significantly less expressed in the S group compared to the N and Q8W groups. CONCLUSIONS: Smoking cessation is associated with partial recovery of penile hemodynamics in a rat model of smoking associated ED.

Feasibility of Using High-Contrast Grating as a Point-of-Care Sensor for Therapeutic Drug Monitoring of Immunosuppressants.

Point-of-care (POC) testing has demonstrated great transformative potential in personalized medicine. In particular, patients undergoing transplantation require POC testing to ensure appropriate serum immunosuppressant levels so as to maintain adequate graft function and survival. However, no suitable POC device for monitoring immunosuppressant levels is currently available. Exploiting the latest advances in metamaterials can lead to a breakthrough in POC testing. A high-contrast grating (HCG) biosensor is a low-cost, compact, simple-to-fabricate, and easy-to-operate structure. It is highly sensitive and robust in surface-based biomarker detection, which is favorable for the efficiency of a POC device. In this study, the feasibility of using an HCG as a POC sensor for therapeutic drug monitoring of immunosuppressants was evaluated. The detection efficiency of the most commonly prescribed immunosuppressive medication cyclosporine A by using this sensor was demonstrated to be comparable to those of conventional commercial kits, suggesting that the sensor has the potential to be used as a rapid detection and feedback platform for increasing drug compliance and improving new organ transplant survival.

Dietary Modification Is Associated with Normalization of Penile Hemodynamics in Rats Fed a High-Fat Diet.

BACKGROUND: Diet is associated with self-reported indices of sexual health. The mechanisms responsible for these changes remain poorly understood. AIM: To investigate the hemodynamic and histological impact of dietary change in a rat model of hyperlipidemia-associated erectile dysfunction. METHODS: 40 2-month old male Sprague-Dawley rats were divided into 4 groups. 10 rats were fed a diet of standard chow and served as negative controls (N group). The remaining 30 age-matched rats were divided at random into 3 groups: (i) high-fat diet for 5 months starting at age 5 months (H group); (ii) high-fat diet for 5 months starting at age 4 months followed by 1 month of standard chow (H+N1M group); and (iii) high-fat diet for 5 months starting at age 2 months followed by 3 months of standard chow (H+N3M group). All rats underwent erectile function testing and sacrifice at age 10 months. OUTCOMES: Intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured to evaluate erectile function. Blood samples were collected to measure serum testosterone and lipid levels, and penile tissue specimens were obtained for histological examination. RESULTS: Total body weight, low-density lipoprotein, and serum glucose were significantly higher in the H group compared with the N and H+N3M groups. Serum high-density lipoprotein level was significantly lower in the H group compared with the N and H+N3M groups. The mean ICP/MAP ratio was significantly lower in the H group compared with the N and H+N3M groups (0.33 ± 0.05 vs 0.79 ± 0.07 vs 0.73 ± 0.13; P < .05 for both). Markers for intracorporal neuronal nitric oxide synthase and endothelial cells were more weakly expressed in the H group compared with the N and H+N3M groups. There was no significant difference in smooth muscle content among the groups. Mean cavernosal oxidative stress and the apoptotic index were significantly higher in the H group compared with the N and H+N3M groups. No significant between-group differences were noted with respect to serum testosterone; the H group had significantly higher serum glucose and low-density lipoprotein levels, effects that were partially mitigated in the H +N1M and H+N3M groups. CLINICAL TRANSLATION: Administration of a healthy diet is associated with normalization of functional and histological penile defects associated with a high-fat diet. STRENGTHS & LIMITATIONS: Metabolic changes were clearly linked to functional improvements in penile blood flow. Differences between rat and human lipoprotein metabolism are a limitation of this study. CONCLUSION: Dietary changes may have positive effects on penile hemodynamics in a rat model of hyperlipidemia-associated erectile dysfunction. Huang Y-C, Ho D-R, Lin J-H, et al. Dietary Modification Is Associated with Normalization of Penile Hemodynamics in Rats Fed a High-Fat Diet. J Sex Med 2019;16:791-802.

Perioperative Complications and Mortality in Patients with Urothelial Carcinoma and End-Stage Renal Disease Undergoing One-Stage Complete Urinary Tract Extirpation.

BACKGROUND: Complete urinary tract extirpation (CUTE) is a complex procedure with substantial risk for perioperative complications. The association between clinical characteristics and the risk of major postoperative complications has not been systematically investigated. OBJECTIVE: The aim of this study was to analyze the incidence and risks for major perioperative complications after CUTE. METHODS: Respective chart review of 81 patients with urothelial carcinoma (UC) who were treated with one-stage CUTE between January 2004 and December 2015. Fisher's exact test with Chi square and two-tailed t test were used in categorical and continuous variables, respectively. Univariable and multivariable logistic regression models were used to evaluate the probability of major complications. RESULTS: In this population, 53 (65.4%) patients had Clavien grade 0-2 complications ('no major complications') and 28 (34.6%) patients had Clavien grade 3-5 complications ('major complications'). Compared with the major complications group, patients in the no major complications group were younger, had lower Charlson Comorbidity Index (CCI), higher preoperative serum albumin, and shorter duration of hospitalization (p < 0.05 for all). Major complications were more common in low-volume surgeons (p = 0.002). On multivariate logistic regression analyses, CCI ≥ 5 (odds ratio [OR] 6.25, 95% confidence interval [CI] 1.42-27.47; p = 0.015) and surgery by a provider who performed three or fewer cases during the study interval (OR 13.4, 95% CI 2.20-80.89; p = 0.005) were independent predictors for major complications. CONCLUSIONS: High CCI should alert providers to increased probability of major complications, and warrant vigilant management after CUTE. Surgeon volume was inversely related to major postoperative complications.

The Effects of Adipose-Derived Stem Cells in a Rat Model of Tobacco-Associated Erectile Dysfunction.

Tobacco use is associated with erectile dysfunction (ED) via a number of mechanisms including vascular injury and oxidative stress in corporal tissue. Adipose derived stem cells (ADSC) have been shown to ameliorate vascular/corporal injury and oxidative stress by releasing cytokines, growth factors and antioxidants. We assessed the therapeutic effects of intracavernous injection of ADSC in a rat model of tobacco-associated ED. Thirty male rats were used in this study. Ten rats exposed to room air only served as negative controls. The remaining 20 rats were passively exposed to cigarette smoke (CS) for 12 weeks. At the 12-week time point, ADSC were isolated from paragonadal fat in all rats. Amongst the 20 CS exposed rats, 10 each were assigned to one of the two following conditions: (i) injection of phosphate buffered saline (PBS) into the corpora cavernosa (CS+PBS); or (ii) injection of autologous ADSC in PBS into the corpora cavernosa (CS+ADSC). Negative control animals received PBS injection into the corpora cavernosa (normal rats [NR] + PBS). After injections all rats were returned to their previous air versus CS exposure state. Twenty-eight days after injection, all rats were placed in a metabolic cage for 24-hour urine collection to be testing for markers of oxidative stress. After 24-hour urine collection all 30 rats also underwent erectile function testing via intracavernous pressure (ICP) testing and were then sacrificed. Corporal tissues were obtained for histological assessment and Western blotting. Mean body weight was significantly lower in CS-exposed rats than in control animals. Mean ICP, ICP /mean arterial pressure ratio, serum nitric oxide level were significantly lower in the CS+PBS group compared to the NR+PBS and CS+ADSC groups. Urine markers for oxidative stress were significantly higher in the CS+PBS group compared to the NR+PBS and CS+ADSC groups. Mean expression of corporal nNOS and histological markers for endothelial and smooth muscle cells was significantly lower, and tissue apoptotic index significantly higher, in the CS+PBS group compared to the NR+PBS and CS+ADSC groups. Our findings confirm that chronic tobacco exposure causes ultrastructural damage to the corporal tissue and increases systemic oxidative stress states. Treatment with ADSC ameliorates these adverse effects and holds promise as a potential therapy for tobacco-related ED.

Chronic Cigarette Smoking Impairs Erectile Function through Increased Oxidative Stress and Apoptosis, Decreased nNOS, Endothelial and Smooth Muscle Contents in a Rat Model.

Cigarette use is an independent risk factor for the development of erectile dysfunction (ED). While the association between chronic smoking and ED is well established, the fundamental mechanism(s) of cigarette-related ED are incompletely understood, partly due to no reliable animal model of smoking-induced ED. The present study was designed to validate an in vivo rat model of chronic cigarette-induced ED. Forty 12-week old male Sprague-Dawley rats were divided into 4 groups. Ten rats served as control group and were exposed only to room air. The remaining 30 rats were passively exposed to cigarette smoke (CS) for 4 weeks (n = 10), 12 weeks (n = 10), and 24 weeks (n = 10). At the 24-week time point all rats were assessed with intracavernous pressure (ICP) during cavernous nerve electrostimulation. Blood and urine were collected to measure serum testosterone and oxidative stress, respectively. Corporal tissue was assessed by Western blot for neuronal nitric oxide synthase (nNOS). Penile tissues were subjected to immunohistochemistry for endothelial, smooth muscle, and apoptotic content. Mean arterial pressure (MAP) was significantly higher in 24-week cigarette exposed animals compared to the control animals. Mean ICP/MAP ratio and cavernosal smooth muscle/endothelial contents were significantly lower in the 12- and 24-week rats compared to control animals. Oxidative stress was significantly higher in the 24-week cigarette exposed group compared to control animals. Mean nNOS expression was significantly lower, and apoptotic index significantly higher, in CS-exposed animals compared to control animals. These findings indicate that the rat model exposure to CS increases apoptosis and oxidative stress and decreases nNOS, endothelial and smooth muscle contents, and ICP in a dose dependent fashion. The rat model is a useful tool for further study of the molecular and cellular mechanisms of CS-related ED.

The Efficacy of Postoperative Adjuvant Chemotherapy for Patients with pT3N0M0 Upper Tract Urothelial Carcinoma.

PURPOSE: Nephroureterectomy with bladder cuff excision may not be sufficient as monotherapy for patients with pT3N0M0 upper tract urothelial carcinoma. The efficacy of postoperative adjuvant chemotherapy in this setting remains controversial. We evaluated the efficacy of adjuvant chemotherapy for patients with pT3N0M0 upper tract urothelial carcinoma in overall, cancer specific and recurrence-free survival. MATERIALS AND METHODS: We retrospectively reviewed records on 171 consecutive patients with pT3N0M0 upper tract urothelial carcinoma treated with radical nephroureterectomy between 2004 and 2014 at 2 branches of the same institution. Postoperative adjuvant chemotherapy was gemcitabine/cisplatin or cisplatin/fluorouracil/leucovorin. Overall, cancer specific and recurrence-free survival rates were estimated using the Kaplan-Meier method. The values of prognostic factors were evaluated by Cox regression analysis. RESULTS: Postoperative adjuvant chemotherapy was administered in 60 patients vs nonadjuvant therapy in 111 patients. Median followup was 35.8 months. Between the adjuvant and nonadjuvant treatment groups there were statistically significant differences in 5-year cancer specific (80.5% vs 57.6%, p = 0.010) and recurrence-free (74.4% vs 52.9%, p = 0.026) survival rates. Although there was no statistically significant difference in overall survival (71.9% vs 49.0%, p = 0.072), there was a trend of better overall survival in the patients who received postoperative chemotherapy. On multivariable analysis age (p = 0.018), tumor location (p = 0.003) and adjuvant chemotherapy (p = 0.001) were predictors of cancer specific survival. CONCLUSIONS: Adjuvant chemotherapy improves cancer specific and recurrence-free survival in patients with pT3N0M0 upper tract urothelial carcinoma after radical nephroureterectomy.

AKT mediates actinomycin D-induced p53 expression.

At high cytotoxic concentrations, actinomycin D (ActD) blocks transcription, decreasing levels of MDM2 and thus causing p53 stabilization. At low cytostatic concentrations, ActD causes ribosomal stress, which decreases MDM2 activity, resulting in p53 stabilization and activation. ActD can thus be used for p53-based cyclotherapy. We analyzed pathways mediating ActD-induced p53 expression. Inhibitors (LY294002, wortmannin, and deguelin) of phosphatidylinositol 3-kinases (PI3K) and AKT, but not inhibitors of MEK1/2, JNK, and p38-MAPK abolished the ActD-induced p53 expression in diverse cell types. RNA interference further supported these results. When AKT was downregulated by small hairpin RNA-AKTs, ActD-induced p53 expression was significantly decreased. ActD caused AKT phosphorylation at Ser473, indicating full activation of AKT. The potential for cancer therapy is discussed.