Anti-Metastatic Effects of Standardized Polysaccharide Fraction from Diospyros kaki Leaves via GSK3ß/ß-Catenin and JNK Inactivation in Human Colon Cancer Cells.

A polysaccharide fraction from Diospyros kaki (PLE0) leaves was previously reported to possess immunostimulatory, anti-osteoporotic, and TGF-ß1-induced epithelial-mesenchymal transition inhibitory activities. Although a few beneficial effects against colon cancer metastasis have been reported, we aimed to investigate the anti-metastatic activity of PLE0 and its underlying molecular mechanisms in HT-29 and HCT-116 human colon cancer cells. We conducted a wound-healing assay, invasion assay, qRT-PCR analysis, western blot analysis, gelatin zymography, luciferase assay, and small interfering RNA gene silencing in colon cancer cells. PLE0 concentration-dependently inhibited metastasis by suppressing cell migration and invasion. The suppression of N-cadherin and vimentin expression as well as upregulation of E-cadherin through the reduction of p-GSK3ß and ß-catenin levels resulted in the outcome of this effect. PLE0 also suppressed the expression and enzymatic activity of matrix metalloproteinases (MMP)-2 and MMP-9, while simultaneously increasing the protein and mRNA levels of the tissue inhibitor of metalloproteinases (TIMP-1). Furthermore, signaling data disclosed that PLE0 suppressed the transcriptional activity and phosphorylation of p65 (a subunit of NF-κB), as well as the phosphorylation of c-Jun and c-Fos (subunits of AP-1) pathway. PLE0 markedly suppressed JNK phosphorylation, and JNK knockdown significantly restored PLE0-regulated MMP-2/-9 and TIMP-1 expression. Collectively, our data indicate that PLE0 exerts an anti-metastatic effect in human colon cancer cells by inhibiting epithelial-mesenchymal transition and MMP-2/9 via downregulation of GSK3ß/ß-catenin and JNK signaling.

Comparison of Short-Term Outcomes and Safety Profiles between Androgen Deprivation Therapy+Abiraterone/Prednisone and Androgen Deprivation Therapy+Docetaxel in Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: This study aimed to compare the short-term outcomes and safety profiles of androgen-deprivation therapy (ADT)+abiraterone/prednisone with those of ADT+docetaxel in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC). MATERIALS AND METHODS: A web-based database system was established to collect prospective cohort data for patients with mHSPC in Korea. From May 2019 to November 2022, 928 patients with mHSPC from 15 institutions were enrolled. Among these patients, data from 122 patients who received ADT+abiraterone/prednisone or ADT+docetaxel as the primary systemic treatment for mHSPC were collected. The patients were divided into two groups: ADT+abiraterone/prednisone group (n=102) and ADT+docetaxel group (n=20). We compared the demographic characteristics, medical histories, baseline cancer status, initial laboratory tests, metastatic burden, oncological outcomes for mHSPC, progression after mHSPC treatment, adverse effects, follow-up, and survival data between the two groups. RESULTS: No significant differences in the demographic characteristics, medical histories, metastatic burden, and baseline cancer status were observed between the two groups. The ADT+abiraterone/prednisone group had a lower prostate-specific antigen (PSA) progression rate (7.8% vs. 30.0%; p=0.011) and lower systemic treatment discontinuation rate (22.5% vs. 45.0%; p=0.037). No significant differences in adverse effects, oncological outcomes, and total follow-up period were observed between the two groups. CONCLUSIONS: ADT+abiraterone/prednisone had lower PSA progression and systemic treatment discontinuation rates than ADT+docetaxel. In conclusion, further studies involving larger, double-blinded randomized trials with extended follow-up periods are necessary.

Single-port Mini-Pfannenstiel Robotic Pyeloplasty: Establishing a Non-narcotic Pathway Along With a Same-day Discharge Protocol.

OBJECTIVE: To analyze the feasibility of a same day discharge protocol following single-port (SP) robotic pyeloplasty. MATERIALS AND METHODS: From a single institution series, 23 patients (12 multi-port, 11 SP) who underwent primary robotic dismembered pyeloplasty between February 2018 and March 2021 were analyzed. The association between baseline and perioperative characteristics with functional outcome was analyzed using, chi-square, Fisher's exact, Mann Whitney U and t tests. RESULTS: All SP cases were completed using the mini Pfannenstiel incision without the need for conversion or additional ports. Baseline characteristics were comparable. No intraoperative complications were seen. Only 1 patient in the SP group had a Clavien II complication. All patients in the multi-port group had a drain placed, whereas drain was not placed in the SP group. Length of stay was shorter in the SP group (11.4 vs 42.6 hours, P <.001). Although visual analog pain score was comparable at discharge (P = .633), the SP group had lower opioid usage (morphine milligram equivalent) in the hospital (P <.001) and a lower rate of opioid prescription during discharge (18.2% vs 91.7% P <.001). At a median follow-up of 8 months, no patients had flank pain and all patients had good kidney drainage on follow-up images. CONCLUSION: Single-port robotic dismembered pyeloplasty through a mini-Pfannenstiel access allows a same-day discharge protocol with minimal opiate use.

Predictive factors of postoperative complications and hospital readmission after implementation of the single-port robotic platform: A single-center and single-surgeon experience.

OBJECTIVES: To measure the incidence, and identify potential risk factors of conversion, postoperative complication and readmission for patients treated with urological robotic single-port surgery. METHODS: All consecutive urological surgery procedures carried out with the single-port robotic platform by the same surgeon in a single institution between September 2018 and March 2020 were included in this retrospective analysis. Demographic data, main perioperative outcomes and information related to the surgical technique were gathered and analyzed. A logistic regression model was used to assess predictive factors for any grade and high-grade (e.g. Clavien grade ≥3) postoperative complications, as well as predictive factors for readmission. RESULTS: Analysis included 221 patients, of whom 194 (88%) underwent pelvic surgery and 27 (12.2%) underwent upper urinary tract surgery. Only one patient was converted to open surgery in the entire cohort. A total of 40 patients (18.1%) experienced postoperative complications, with grade ≥3 postoperative complications in 7.6% of the entire cohort. On multivariable analysis, the factors significantly associated with the risk of postoperative complication of any grade were diabetes (P < 0.001), perineal approach (P < 0.01) and postoperative pain management with opioids (P = 0.01). Only diabetes (P = 0.03) predicted a grade ≥3 complication. Overall, 17 patients (7.7%) were readmitted during the 3 months after surgery. A body mass index >30 kg/m2 was the only identified predictor of readmission (P = 0.01). CONCLUSION: A wide range of pelvic, extraperitoneal and upper-tract urological procedures can be carried out using the robotic single-port platform with a minimal conversion rate and low complication or readmission rate.

Robot-assisted Radical Prostatectomy Using Single-port Perineal Approach: Technique and Single-surgeon Matched-paired Comparative Outcomes.

BACKGROUND: Radical perineal prostatectomy (RPP) has been revived with the advent of single-port (SP) robotic surgery. However, its interest and precise role need to be evaluated and better defined. OBJECTIVE: To describe in detail the technique of SP-RPP and compare initial perioperative outcomes with those of multiport robot-assisted transperitoneal radical prostatectomy (MP-RARP). DESIGN, SETTING, AND PARTICIPANTS: From October 2018 to June 2020, perioperative data of 26 consecutive patients who underwent SP-RPP for localized prostate cancer (PCa) in a single institution were prospectively entered into an institutional review board-approved database. Data of 86 consecutive patients treated from September 2017 to September 2018 with MP-RARP by the same surgeon, before the beginning of the SP experience, were used as comparators. SURGICAL PROCEDURE: SP-RPP was performed using the SP robotic platform (Intuitive Surgical, Sunnyvale, CA, USA) according to the technique described in the supplementary video. MEASUREMENTS: Demographics, and intra- and postoperative data were analyzed in a matched-paired design with a 1:1 ratio on the following factors: age at surgery, prostate-specific antigen level, preoperative Gleason score, and history of abdominal surgery. RESULTS AND LIMITATIONS: After matching, baseline characteristics were comparable except for the rate of prior laparotomy, which was higher in the SP-RPP group (52% vs 8%, p < 0.001). In the SP-RPP group, 84% of the patients had a high risk and an unfavorable intermediate risk of positive surgical margins (PSMs) versus 57% in the MP-RARP group (p = 0.03). While the rate of nonlimited PSMs (ie, >3 mm) was higher in the SP-RPP group (38.5% vs 7.7%, p < 0.01), the number of patients with biochemical recurrence at 1 yr was comparable between SP-RPP and MP-RARP (1 vs 3, p = 0.3). CONCLUSIONS: SP-RPP is a complex procedure for patients with a complex surgical history and high-risk localized PCa with limited alternative therapeutic options. PATIENT SUMMARY: Our study suggests that patients with high-risk localized prostate cancer and limited treatment options due to a complex abdominal surgical history (ie, frozen pelvis) may be suitable candidates for single-port radical perineal prostatectomy.

Predictive factors for opioid-free management after robotic radical prostatectomy: the value of the SP® robotic platform.

BACKGROUND: The aim of this study was to evaluate perioperative factors associated with opioid-free management after robotic radical prostatectomy in a single institution. METHODS: From January 2019 to January 2020, data from patients who underwent robotic radical prostatectomy was retrospectively entered in a preapproved IRB database. Data were analyzed according to the postoperative opioid administration in hospital and/or after discharge. Robotic radical prostatectomy was performed using either the standard multi-port Da Vinci Si robotic platform with a transperitoneal approach (MP-RALP) or the novel DaVinci SP® robotic platform (Intuitive Surgical, Inc., Sunnyvale, CA, USA) with an extraperitoneal approach (SP-EPP). Patients undergoing minimally invasive surgery were included in the "enhanced recovery after surgery" (ERAS) protocol regardless of the surgery approach. RESULTS: During the study period, 210 patients matched the selection criteria. Of those, 158(75%) patients received opioids during the hospital stay or after discharge and 52(25%) patients never received opioids. SP-EPP surgical approach and shorter LOS were predictors of never receiving opioids (Odds Ratio [OR]=4.97, (95% CI 1.81-14.77, P=0.002 and OR=0.56, CI 95% 0.35-0.86, P=0.011, respectively). SP-EPP surgical approach was increasing the odds of remaining opioid free whether in-hospital or after discharge (OR= 11.97, 95% CI 4.8-32, P<0.0001 and OR=11.6, 95% CI 4.6-31, P<0.0001, respectively). Finally, a high BMI increased the odds of receiving opioid in hospital or after discharge (OR=0.89, 95% CI 0.82-0.96, P=0.003 and OR=0.89, 95% CI 0.82-0.96, P=0.002, respectively). CONCLUSIONS: In this series, after robotic radical prostatectomy the use of a less invasive approach (SP-EPP), a shorter LOS and a lower BMI, were predictive of opioid-free status.

Pure Single-site Robot-assisted Radical Prostatectomy Using Single-port Versus Multiport Robotic Radical Prostatectomy: A Single-institution Comparative Study.

BACKGROUND: Pure single-site robot-assisted extraperitoneal prostatectomy (EPP) using a single-port (SP) robotic platform has been shown to be feasible and safe in previous descriptive studies. OBJECTIVE: To compare the perioperative outcomes of patients undergoing SP-EPP versus conventional multiport (MP) transperitoneal robot-assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS: From January 2019 to January 2020, data of 100 consecutive patients who underwent SP-EPP performed by the same surgeon and 110 consecutive patients who underwent MP-RARP by three surgeons from the same institution were prospectively collected. INTERVENTION: All SP-EPPs were performed in a pure single-site fashion without Trendelenburg. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demographic characteristics as well as intra- and postoperative data of patients in both groups were analyzed. Quantitative data were described in terms of median and quartiles. RESULTS AND LIMITATIONS: After SP-EPP, the rate of patients discharged the same day was nine times higher than that after MP-RARP (p < 0.001), and the median length of postoperative hospital stay was significantly shorter: 4.3 h (interquartile range [IQR] 3.3-17.4) versus 26.1 h (IQR 21.5-44.8). The rate of opioid use in the hospital and after discharge in the SP group was at least half that in the MP group (respectively, 32% vs 64%, p < 0.001, and 35% vs 87%, p < 0.001). The overall positive surgical margin rate as well as continence rate at 12 mo (85% vs 88%, p = 0.97) and the prostate-specific antigen relapse-free survival (p = 0.09) were statistically comparable between the SP and MP groups. CONCLUSIONS: Pure single-site SP-EPP was associated with a shorter length of stay as well as a decreased need for postoperative pain medication and narcotic administration in comparison with conventional transperitoneal multiport prostatectomy, with comparable postoperative complications and readmission rate. PATIENT SUMMARY: Surgical treatment of localized prostate cancer using a single-port robotic platform allows for a shorter hospital stay, less pain, and less opioid use than conventional robotic surgery without more morbidity. TAKE HOME MESSAGE: Pure single-site single-port extraperitoneal prostatectomy was associated with a shorter length of stay as well as a decreased need for postoperative pain medication and narcotic administration in comparison with conventional transperitoneal multiport prostatectomy, with comparable postoperative complication and readmission rate.

Single-institution Cost Comparison: Single-port Versus Multiport Robotic Prostatectomy.

BACKGROUND: In the era of efficient value-based health care, each surgical innovation should be proven to be cost-effective for the patient and the hospital administration. OBJECTIVE: To compare the costs associated with robot-assisted prostatectomy using a single-port (SP) or multiport (MP) robotic platform. DESIGN, SETTING, AND PARTICIPANTS: Costs for surgical care for consecutive patients with localized prostate cancer treated from November 2018 to November 2019 were itemized and evaluated. INTERVENTION: Patients were treated using either the SP (n = 78) or MP (n = 97) platform. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demographics, perioperative data, and costs for surgical care of patients in both groups were analyzed. RESULTS AND LIMITATION: The mean cost for prostatectomy was comparable between SP ($13 512 ± $1615) and MP ($13 284 ± $1360; p = 0.32). The main cost differences between the groups were the cost of hospitalization, which was lower in the SP group (p < 0.001), offset by the cost of disposables in the operating room, which was higher in the SP group (p < 0.001). The mean length of stay was significantly shorter in the SP group (9.84 ± 11.3 vs 35.5 ± 29.1 h; p < 0.001) and the proportion of patients discharged home on the day of surgery was higher in the SP group (70% vs 5%; p < 0.001). The main limitation of this study is its retrospective design. CONCLUSIONS: Overall, the costs for SP and MP prostatectomy are comparable. The higher SP cost for consumable surgical materials is offset by the lower cost associated with hospitalization, which was largely due to a shorter hospital stay after SP surgery. PATIENT SUMMARY: In this report, we found that implementation of the new single-port robotic platform for radical prostatectomy was not associated with higher surgical care costs compared to conventional multiport surgery.

Floating docking technique: a simple modification to improve the working space of the instruments during single-port robotic surgery.

OBJECTIVE: To compare the range of motion and ergonomic characteristics of single-port robotic instruments in the setting of the "floating" versus "flat" docking technique using the GelPOINT® system. MATERIAL AND METHODS: The basic principle of the floating docking technique resides in the GelSeal cap and trocar (s) being 8 cm off the skin level with the Alexis® acting as a conduit between the trocar (s) and the body while preserving insufflation. In the setting of a dry lab study, we measured the range of motion of one robotic instrument with the "floating" and the "flat" docking technique in two different situations depending on whether the distance between the incision and the target was more or less than 10 cm. RESULTS: The minimum required distances between the target and the tip of the cannula for activation of the wrist and elbow were 5 and 10 cm, respectively. When the target was near to the cannula (i.e., less than 10 cm), the floating technique was associated with a significant increase in the range of motion of the instrument in all directions. The working space volume of the instrument was increased by more than 390% (from 101 to 497 cm3) when the surgeon switched from flat (standard) to the floating technique in the setting of a target close (i.e., less than 10 cm) to the cannula CONCLUSION: The floating docking technique is a simple and effective way to increase the working surgical space, especially in confined and narrow surgical fields with a target closer than 10 cm from the skin.

Outpatient Extraperitoneal Single-Port Robotic Radical Prostatectomy.

OBJECTIVE: To assess the safety and feasibility of extraperitoneal single-port robotic assisted laparoscopic radical prostatectomy using the da Vinci SP robotic platform for same-day surgery. METHODS: Extraperitoneal single-port robotic prostatectomy (ESRP) using the da Vinci SP platform was performed on 60 patients with clinically localized prostate cancer and no prior definitive therapy. An enhanced recovery protocol was used in the perioperative period and minimal to no opiates were used in these patients. Preoperative, perioperative, and postoperative data were collected in a prospectively maintained institutional review board approved database and evaluated in a retrospective fashion. RESULTS: Mean operative time was 198 minutes and mean estimated blood loss was 179 mL. No patients required blood transfusion and there were no intraoperative complications. Pain at discharge was 0-1 in 37% of patients. Forty-five patients (75%) were discharged home the day of surgery, including patients with all surgical start times. When excluding patients that were planned for an overnight stay preoperatively or patients whose surgery finished after 6 PM, 88% of patients were discharged home the day of surgery and 96% were discharged within 24 hours of surgery. Median length of stay was 4.2 hours. Fourty-eight percent of patients required 0-1 pads at 30 days postoperatively in patients with 30 day follow data (n = 58) and 76% of patients reported requiring 0-1 pads per day by 90 days postoperatively (n = 37). CONCLUSION: ESRP using the da Vinci SP platform can be performed safely and reproducibly as a same-day outpatient surgery with minimal to no opiate use, excellent pain control, and acceptable short term functional and oncological outcomes.

Single-Port Robot-Assisted Dismembered Pyeloplasty With Mini-Pfannenstiel or Peri-Umbilical Access: Initial Experience in a Single Center.

OBJECTIVE: To assess the feasibility and describe the surgical technique for single-port robotic-assisted laparoscopic pyeloplasty using the new da Vinci SP surgical platform (Intuitive Surgical Inc., Sunnyvale, CA), and to describe the approach through a mini-pfannenstiel incision. METHODS: Data from a prospectively maintained single-institution database on all patients undergoing single-port robotic-assisted pyeloplasty between November 2018 and November 2019 were reviewed. Pyeloplasty was performed with the da Vinci SP system through a pure single site approach (except for the first patient). The initial procedures were performed through a midline incision and the technique evolved to a mini-pfannenstiel incision. Patient demographics, intraoperative data, post-operative data and surgical outcomes were collected. RESULTS: Overall, 10 patients were included and underwent the procedure without intraoperative complications or conversion to an alternate approach. The patients' ages ranged between 11 and 75 years. Mean operative time was 166 minutes (interquartile range [IQR] 146-181) and EBL was minimal. Pfannenstiel incision was performed for 6 patients and 4 patients had a vertical midline incision. The only complication recorded was a postoperative urinary tract infection treated with antibiotics. The median postoperative hospital stay was 21 hours (7-24). Postoperative pain management after discharge was managed exclusively with non-opioid medication. Overall success rate defined as the absence of pain and renal obstruction on post-operative imaging at 3 months after surgery was 100%. CONCLUSION: Single-port robotic-assisted laparoscopic pyeloplasty is a safe and feasible procedure through a mini-pfannenstiel incision.

Predictors Associated with a Prolonged Hospital Stay After Single-Port Extraperitoneal Robotic Radical Prostatectomy: A Comparative Analysis of Outpatient Versus Inpatient Care.

Purpose: To compare the perioperative characteristics of patients receiving outpatient vs inpatient care and to define predictors of inpatient care after single-port extraperitoneal robotic radical prostatectomy (RRP). Patients and Methods: Data on 120 patients who underwent single-port extraperitoneal RRP were collected and categorized into two groups: Group I (n = 98) included patients who received outpatient care (i.e. discharged on postoperative day 0) and Group II (n = 22) comprised patients with inpatient care. Demographics and perioperative data were recorded and analyzed between the two groups. Multivariable binary logistic regression was used to determine factors associated with inpatient care. Results: Most patients (98/120: 81.7%) were discharged in few hours (median: 4.1 hours) after surgery (outpatient care: Group I [n = 98]), whereas others (Group II [n = 22]) received inpatient care (median hospital stay: 25.4 hours); p < 0.00001. Most patients with inpatient care (13/22, 59.1%) were among the first initial 40 cases, whereas 37 out of last 40 patients received outpatient care (p = 0.005). Operative time was significantly shorter in patients with outpatient prostatectomy (p = 0.015). The amount of narcotics per patient (if administered) was also significantly greater in Group II (p = 0.006). With regression analysis, having medical comorbidities (odds ratio [OR]: 3.41 95% confidence interval [CI]: 2.05-5.64; p = 0.014), a longer operative time (OR: 1.15 95% CI: 1.10-1.28, p = 0.017), as well as a higher dose of administered narcotics after operation (OR: 1.31 95% CI: 1.08-1.61, p = 0.005) were significant predictors of inpatient care after single-port extraperitoneal RRP. Conclusion: A safe transition to outpatient care is feasible in patients undergoing single-port extraperitoneal RRP. In addition to associated medical comorbidities, a longer operative time and the amount of received narcotic after procedure were the most significant predictors of prolong hospital stay after single-port extraperitoneal RRP. These later modifiable predictors can be optimized with improvement of surgical techniques, intraoperative and postoperative pain management protocols through quality improvement initiatives.

Single-Port Robotic Urological Surgery Using Purpose-Built Single-Port Surgical System: Single-Institutional Experience With the First 100 Cases.

OBJECTIVES: To present a comprehensive report regarding our experience with single-port robotic surgery in our first 100 consecutive patients. We describe the diversity of procedures that can be performed with this platform as well as the challenges and complications we had with the application of this novel technology. METHODS: Between September 2018 and August 2019, data on 100 patients who underwent single-port robotic surgery were consecutively collected. Preoperative, intraoperative and early postoperative outcomes after various urologic procedures were recorded and analyzed. RESULTS: During the study period, 100 patients (age [range] 35-84 years; 88 [88%] Male) underwent various single-port robotic surgeries for different indications (Retroperitoneal [n = 14], Pelvic surgeries [n = 86]). Transperitoneal (n = 37), extraperitoneal (n = 53) and transvesical (n = 10) approaches have been used to access the target organs. Of these procedures, 73 (73%) were for different oncological indications: Radical prostatectomy (n = 60), Partial nephrectomy (n = 6), Retroperitoneal lymph node dissection (n = 1) and Radical cystectomy with intracorporeal diversion (n = 6). Surgery was successfully completed in all but 1 patient, in whom the surgery was converted to open surgery due to dense adhesions and failure to progress. Grades II-III postoperative complications were detected in (n = 9) patients. CONCLUSION: The purpose-built single-port robotic platform can be safely incorporated into the minimally invasive armamentarium. A wide range of pelvic and retroperitoneal urological procedures can be done with different approaches using this platform. Randomized trials with adequate sample size and postoperative follow up period is advisable for further evaluation of the outcomes and to determine the added value of this emerging technology.

Novel Rhodanine Derivative, 5-[4-(4-Fluorophenoxy) phenyl]methylene-3-{4-[3-(4-methylpiperazin-1-yl) propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride, Induces Apoptosis via Mitochondria Dysfunction and Endoplasmic Reticulum Stress in Human Colon Cancer Cells.

We previously reported that 5-[4-(4-fluorophenoxy) phenyl] methylene-3-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride (KSK05104) has potent, selective and metabolically stable IKKß inhibitory activities. However, the apoptosis-inducing of KSK05104 and its underlying mechanism have not yet been elucidated in human colon cancer cells. We show that KSK05104 triggered apoptosis, as indicated by externalization of Annexin V-targeted phosphatidylserine residues in HT-29 and HCT-116 cells. KSK05104 induced the activation of caspase-8, -9, and -3, and the cleavage of poly (ADP ribose) polymerase-1 (PARP-1). KSK05104-induced apoptosis was significantly suppressed by pretreatment with z-VAD-fmk (a broad caspase inhibitor). KSK05104 also induced release of cytochrome c (Cyt c), apoptosis inducing factor (AIF), and endonuclease G (Endo G) by damaging mitochondria, resulting in caspase-dependent and -independent apoptotic cell death. KSK05104 triggered endoplasmic reticulum (ER) stress and changed the intracellular calcium level ([Ca2+]i). Interestingly, treatment with KSK05104 activated not only ER stress marker proteins including inositol-requiring enzyme 1-alpha (IRE-1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), but also µ-calpain, and caspase-12 in a time-dependent manner. KSK05104-induced apoptosis substantially decreased in the presence of BAPTA/AM (an intracellular calcium chelator). Taken together, these results suggest that mitochondrial dysfunction and ER stress contribute to KSK05104-induced apoptosis in human colon cancer cells.

Efficacy and Safety of Tadalafil 5 mg Once Daily for the Treatment of Erectile Dysfunction After Robot-Assisted Laparoscopic Radical Prostatectomy: A 2-Year Follow-Up.

BACKGROUND: Although nerve-sparing robot-assisted radical prostatectomy (NS-RALP) is performed, a large number of patients still experience erectile dysfunction (ED) after surgery. AIM: To evaluate the efficacy and safety of tadalafil 5 mg once daily (OaD) in ED treatment over 2 years and investigate the cause of vascular ED after NS-RARP. METHODS: We retrospectively evaluated 95 men who underwent NS-RARP and had a penile rehabilitation treatment with tadalafil 5 mg OaD. They were classified into 3 groups: tadalafil 5 mg OaD for 2 years (group I), tadalafil 5 mg OaD for 1 year (group II), and no tadalafil (group III). All patients in group I underwent penile color duplex ultrasound to evaluate the cause of vascular ED. OUTCOMES: Patients were surveyed using the abridged 5-item International Index of Erectile Function (IIEF-5). RESULTS: Statistically significant improvements were observed in group I for all IIEF-5 domain scores (P = .000). There was no statistically significant difference in recovery of erectile function (EF) the 2-year follow-up between groups I and II. Sub-analysis based on NS status showed no difference in recovery of EF. However, group I showed better trends in EF improvement. Those with venogenic ED had poor responses compared with those with arteriogenic ED or unremarkable findings with tadalafil 5-mg OaD treatment (14.2% vs 55.0% vs 53.3%). The overall side effects included hot flushing in 9.5%, headache in 7.1%, and dizziness in 2.3% of patients. CLINICAL IMPLICATIONS: Long-term usage of tadalafil 5 mg OaD after RARP can be an effective option for penile rehabilitation. STRENGTHS AND LIMITATIONS: The present study is a retrospective study with a relatively small sample. CONCLUSIONS: Although the responses of patients with venogenic ED were limited compared with those with arteriogenic ED, tadalafil 5-mg OaD treatment was well tolerated and significantly improved EF up to 2 years after NS-RARP. Kim S, Sung GT. Efficacy and Safety of Tadalafil 5 mg Once Daily for the Treatment of Erectile Dysfunction After Robot-Assisted Laparoscopic Radical Prostatectomy: A 2-Year Follow-Up. Sex Med 2018;6:108-114.

6-(3,4-Dihydro-1H-isoquinoline-2-yl)-N-(6-methoxypyridine-2-yl) nicotinamide-26 (DIMN-26) decreases cell proliferation by induction of apoptosis and downregulation of androgen receptor signaling in human prostate cancer cells.

Previously, we reported that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl) nicotinamide (DIMN) analogues inhibited the growth of prostate cancer cells as an anti-androgenic compound. In the present study, we evaluated cytotoxic effects of these DIMN derivatives and found that DIMN-26 most potently inhibited the proliferation of the LNCap-LN3 androgen-dependent and DU145 androgen-independent prostate cancer cells through induction of G2/M phase cell cycle arrest and subsequent apoptosis. The G2/M phase arrest was found due to increases in the activation of cdc2 (also known as cyclin-dependent kinase 1, CDK1)/cyclin B1 complex. DIMN-26 also induced apoptosis in LNCap-LN3 and DU145 prostate cancer cells through activation of caspase-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase-1 (PARP-1). In addition, DIMN-26 caused the dephosphorylation and mitochondrial accumulation of Bad protein and induced the loss of mitochondria membrane potential, consequently releasing cytochrome c into the cytosol of the cell. Furthermore, overexpression of AKT protein significantly reduced DIMN-26-induced PARP-1 cleavage and p-Bad decrease and cdc2 activation. In addition, DIMN-26 inhibited the 5α-dihydrotestosterone (DHT)-induced cell growth and proliferation and nuclear translocation and transcriptional activities of androgen receptor (AR) in LNCap-LN3 prostate cancer cells. Consistent with these findings, DIMN-26 significantly inhibited the DHT-induced expression of AR-response genes (ARGs), such as prostate-specific antigen (PSA), AR, ß2-microglobulin (B2M), selenoprotein P (SEPP1), and ste20-related proline-alanine-rich kinase (SPAK) in LNCap-LN3 prostate cancer cells. Taken together, these results suggest that DIMN-26 plays a therapeutic role not only in induction of G2/M arrest and apoptosis but also in suppression of androgen receptor signaling in androgen-dependent and androgen-independent prostate cancer cells.

Effect of biomimetic shear stress on intracellular uptake and cell-killing efficiency of doxorubicin in a free and liposomal formulation.

Shear stress could be considered in the context of cellular uptake and cell-killing efficiency. Thus, mimicking the dynamic characteristics of in vivo environment is important in targeted drug delivery. We investigated the intracellular uptake and cell-killing efficiency of doxorubicin (DOX) in a free and liposomal form (Doxil(®)) under biomimetic shear stress to mimic in vivo environment. In this dynamic environment, cells demonstrated significantly higher fluorescence intensity than that of the static environment, and fluorescence microscopy images indicated increased intracellular uptake of DOX in the presence of fluidic shear stress. In cells treated with free DOX and liposomal Doxil(®), cell-killing efficiency was affected by shear stress. Taken together, shear stress, affecting drug uptake and cell-killing efficiency, is important in intracellular drug targeting.

Dielectrophoretic manipulation of the mixture of isotropic and nematic liquid.

In various applications involving liquid crystals, the manipulation of the nanoscale molecular assembly and microscale director alignment is highly useful. Here we show that a nematic-isotropic mixture, a unique bi-liquid system, has potential for the fabrication of microstructures having an ordered phase within a disordered phase, or vice versa. The volume expansion and shrinkage, migration, splitting, mergence and elongation of one phase within the other are easily accomplished via thermal treatment and dielectrophoretic manipulation. This is particularly achievable when one phase is suspended in the middle. In that case, a highly biased ordered-phase preference of surfaces, that is, the nematic-philic nature of a polyimide layer and the nematic-phobic nature of a self-assembled monolayer of chlorosilane derivatives, is used. Further, by combining this approach with photopolymerization, the patterned microstructure is solidified as a patterned polymer film having both isotropic and anisotropic molecular arrangements simultaneously, or as a template with a morphological variation.

Effect of rectal enema on intrafraction prostate movement during image-guided radiotherapy.

INTRODUCTION: Rectal volume and movement are major factors that influence prostate location. The aim of this study was to assess the effect of a rectal enema on intrafraction prostate motion. METHODS: The data from 12 patients with localised prostate cancer were analysed. Each patient underwent image-guided radiotherapy (RT), receiving a total dose of 70 Gy in 28 fractions. Rectal enemas were administered to all of the patients before each RT fraction. The location of the prostate was determined by implanting three fiducial markers under the guidance of transrectal ultrasound. Each patient underwent preparation for IGRT twice before an RT fraction and in the middle of the fraction. The intrafraction displacement of the prostate was calculated by comparing fiducial marker locations before and in the middle of an RT fraction. RESULTS: The rectal enemas were well tolerated by patients. The mean intrafraction prostate movement in 336 RT fractions was 1.11 ± 0.77 mm (range 0.08-7.20 mm). Intrafraction motions of 1, 2 and 3 mm were observed in 56.0%, 89.0% and 97.6% of all RT fractions, respectively. The intrafraction movements on supero-inferior and anteroposterior axes were larger than on the right-to-left axes (P < 0.05). The CTV-to-PTV margin necessary to allow for movement, calculated using the van Herk formula (2.5Σ + 0.7σ), was 1.50 mm. CONCLUSIONS: A daily rectal enema before each RT fraction was tolerable and yielded little intrafraction prostate displacement. We think the use of rectal enemas is a feasible method to reduce prostate movement during RT.

Anti-inflammatory effects of 7-hydroxyl-1-methylindole-3-acetonitrile, a synthetic arvelexin derivative, on the macrophages through destabilizing mPGES-1 mRNA and suppressing NF-κB activation.

We previously demonstrated that 7-hydroxyl-1-methylindole-3-acetonitrile (7-HMIA), a synthesized analog of arvelexin, showed the strong inhibitory effects on LPS-induced NO and PGE2 production in macrophages. In this study, we focused on elucidating the anti-inflammatory properties of 7-HMIA and the mechanisms involved using in vitro and in vivo experimental models. In LPS-induced RAW 264.7 macrophages, 7-HMIA significantly inhibited the release of proinflammatory mediators such as prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). We also found that 7-HMIA suppressed PGE2 production not by inhibiting cyclooxygenase-2 (COX-2) expression or activity, but rather by suppressing the mRNA stability of microsomal prostaglandin E synthase (mPGES-1). Furthermore, 7-HMIA mediated attenuation of inducible NO synthase (iNOS), TNF-α, and IL-6 was closely associated with suppression of transcriptional activities of nuclear factor-kappa B (NF-κB), by decreasing p65 nuclear translocation and Akt phosphorylation. Animal studies revealed that 7-HMIA potently suppressed the carrageenan-induced paw edema and myeloperoxidase (MPO) activity in paw tissues. Taken together, our data indicated that the molecular basis for the anti-inflammatory properties of 7-HMIA involved the inhibition of mRNA stability of mPGES-1 and PI3K/Akt-mediated NF-κB pathways.