Kaneki Yasuda

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus.

Thymocyte trafficking has an important role in thymic selection. Here we show that the Hippo homologue Mst1 is required for thymocyte migration and antigen recognition by LFA-1 and ICAM-1 within the medulla. Using two-photon imaging of thymic tissues, we found that highly motile mature thymocytes arrest and are activated in the vicinity of rare populations of Aire(+) ICAM-1(hi) medullary thymic epithelia in a negatively selecting environment. Notably, Mst1 deficiency or blocking the cell adhesion molecules LFA-1 and ICAM-1 results in inefficient migration and antigen recognition of CD4(+) thymocytes within the medulla. Consistent with these defects, thymocyte selection is impaired in Mst1(-/-) mice, which display T cell-dependent inflammatory infiltrates in multiple organs and develop autoantibodies. Our results suggest that Mst1 has a key role in regulating thymocyte self-antigen recognition in the medulla.

Enhanced cytotoxic T-cell function and inhibition of tumor progression by Mst1 deficiency

Mammalian ste‐20 like kinase Mst1 plays important roles during apoptosis, proliferation, cell polarity, and migration. Here, we report a novel role of Mst1 for cytotoxic T‐cell responses and tumor suppression. The defect of Mst1 caused decreased levels of FoxO, and promoted cytotoxicity in vitro. Mst1−/− cytotoxic T cells also exhibited enhanced T‐bet expression that was associated with elevated expression levels of IFNγ and granzyme B. Moreover, Mst1−/− cytotoxic T cells suppressed tumor growth in vivo. The data suggest that Mst1 inhibits cytotoxicity via T‐bet suppression by FoxO1 and FoxO3a. Thus, Mst1 is a potential therapeutic target for tumor immunotherapy.

NDR1-Dependent Regulation of Kindlin-3 Controls High-Affinity LFA-1 Binding and Immune Synapse Organization

ABSTRACT Antigen-specific adhesion between T cells and antigen-presenting cells (APC) during the formation of the immunological synapse (IS) is mediated by LFA-1 and ICAM-1. Here, LFA-1–ICAM-1 interactions were measured at the single-molecule level on supported lipid bilayers. High-affinity binding was detected at low frequencies in the inner peripheral supramolecular activation cluster (SMAC) zone that contained high levels of activated Rap1 and kindlin-3. Rap1 was essential for T cell attachment, whereas deficiencies of ste20-like kinases, Mst1/Mst2, diminished high-affinity binding and abrogated central SMAC (cSMAC) formation with mislocalized kindlin-3 and vesicle transport regulators involved in T cell receptor recycling/releasing machineries, resulting in impaired T cell-APC interactions. We found that NDR1 kinase, activated by the Rap1 signaling cascade through RAPL and Mst1/Mst2, associated with and recruited kindlin-3 to the IS, which was required for high-affinity LFA-1/ICAM-1 binding and cSMAC formation. Our findings reveal crucial roles for Rap1 signaling via NDR1 for recruitment of kindlin-3 and IS organization.

Intravesical Prostatic Protrusion as a Predicting Factor for the Adverse Clinical Outcome in Patients With Symptomatic Benign Prostatic Enlargement Treated With Dutasteride

OBJECTIVE To evaluate the role of intravesical prostatic protrusion (IPP) as a predictive factor for adverse clinical outcomes in patients treated with dutasteride for lower urinary tract symptoms secondary to benign prostatic enlargement (BPE). METHODS In total, 111 patients treated with dutasteride for symptomatic BPE were analyzed. Stepwise multivariate logistic regression was applied to evaluate predictors for acute urinary retention (AUR) or benign prostatic hyperplasia (BPH)-related surgery. We applied an IPP cutoff value of 10 mm. The clinical variables were assessed using univariate analysis. RESULTS Of 111 patients, 27 (24.3%) developed AUR or required surgical intervention. On multivariate analysis, IPP remained as the independent predictor for AUR and need for BPH-related surgery (odds ratio, 1.27; P < .001). Both international prostate symptom score and maximum urinary flow rate significantly improved in patients with low IPP (P  =  .03 and P  <  .001, respectively), but not in those with high IPP. No significant reduction was found in the degree of IPP despite the significant reduction in prostate volume after dutasteride treatment (P  =  .84 and P  <  .001, respectively). The 3-year cumulative incidence of AUR or BPH-related surgery in the low IPP group vs the high IPP group was 9.9% vs 71.5%, respectively (P  <  .001). CONCLUSION High IPP is associated with a higher risk of treatment resistance, AUR, or the need for prostatic surgery in patients receiving dutasteride treatment for symptomatic BPE. Dutasteride might not be effective for IPP reduction.

Introduction of an Enhanced Recovery after Surgery Protocol for Robot-Assisted Laparoscopic Radical Prostatectomy.

Introduction: No studies have shown whether the enhanced recovery after surgery (ERAS) protocol is superior to the conventional protocol after robot-assisted laparoscopic radical prostatectomy (RALP). We compared intestinal function and perioperative parameters of patients with prostate cancer after the ERAS and conventional protocols to determine the superior protocol for recovery of intestinal function. Material and Methods: A retrospective analysis of 198 consecutive patients who underwent RALP between August 2013 and June 2015 was conducted. Our study design included 2 cohorts. Patients underwent conventional care in one group (n = 123) and the ERAS protocol in the other group (n = 75). The primary outcome was the time to first defecation. Secondary outcomes were perioperative parameters and the complication rate. Results: The ERAS group showed a significantly shorter time to first defecation than did the conventional group (p = 0.006). Multivariate analysis showed that selection of the ERAS protocol was significantly associated with the number of days for first time to defecation. Conclusions: Successful application of an ERAS protocol was applied to our patients who underwent RALP and did not have major complications. The ERAS protocol included enhanced intestinal recovery. The ERAS group showed a significantly shorter time to first defecation than did the conventional group.

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Regulation of thymocyte trafficking plays an important role during thymic selection, but our understanding of the molecular mechanisms underlying these processes is limited. In this study, we demonstrated that class III semaphorin E (sema3e), a guidance molecule during neural and vascular development, directly inhibited Rap1 activation and LFA-1–dependent adhesion through the GTPase-activating protein activity of plexin D1. Sema3e inhibited Rap1 activation of thymocytes in response to chemokines and TCR stimulation, LFA-mediated adhesion, and T cell–APC interactions. Immunological synapse (IS) formation in mature thymocytes on supported lipid bilayers was also attenuated by sema3e. Impaired IS formation was associated with reduced Rap1 activation on the contact surface and cell periphery. Moreover, a significant increase of CD4+ thymocytes was detected in the medulla of mice with T cell lineage–specific deletion of plexin D1. Two-photon live imaging of thymic explants and slices revealed enhanced Rap1 activation and migration of CD69+ double-positive and single-positive cells with plexin D1 deficiency. Our results demonstrate that sema3e/plexin D1 modulates IS formation and Ag-scanning activities of thymocytes within thymic tissues.

Preoperative sexual status of Japanese localized prostate cancer patients: comparison of sexual activity and EPIC scores

Abstract Objective: This study aimed to evaluate the relationship between sexual activity and sexual function using questionnaires distributed to middle-aged Japanese patients with localized prostate cancer. Methods: A total of 145 patients who underwent radical prostatectomy were enrolled in the survey reported on herein. Sexual activity and sexual function were investigated via the Expanded Prostate Cancer Index Composite (EPIC) and an original self-reported questionnaire. Results: Of participants, 24.1% and 20.7% had sexual activity within a month period as investigated via the EPIC and original questionnaire, respectively. However, 29.7% of all those who reported sexual activity rate reported “about once every 2 months to a year,” as shown in the original questionnaire. Regarding sexual function as addressed through EPIC, no results within that questionnaire’s measure of sexual function showed significant differences among patients with a rate of actual sexual activity. Conclusions: The present survey showed that more than quarter of preoperative middle-aged Japanese prostate cancer patients surveyed had actual sexual activity, though not within the preceding 4 weeks. To precisely evaluate sexual function of middle-aged Japanese patients, it is necessary to consider actual sexual activity.

Influence of scars on body image consciousness with respect to gender following laparoendoscopic single-site versus conventional laparoscopic surgery

Abstract Objective: The aim of this study was to evaluate and compare the cosmetic outcomes of laparoscopic single-site surgery (LESS) and conventional laparoscopy (CL) in the treatment of ureteropelvic junction obstruction (UPJO) and urachal remnant removal. LESS is thought to produce better cosmetic results than CL; however, patients’ perception of their scars has not been assessed. This study compared the subjective body image and cosmesis ratings of patients who had undergone LESS or CL for UPJO and urachal remnant removal. Materials and methods: Fifty patients who underwent LESS or CL for UPJO or urachal remnant removal between June 2008 and June 2015 were included. Cosmetic outcomes were evaluated using the Body Image Questionnaire (BIQ) and Photo-Series Questionnaire (PSQ). Results: The body image and cosmetic scores were significantly higher for patients who underwent LESS than for those who underwent CL, for both pyeloplasty and urachal remnant removal (p < .05 each). When performed for either a pyeloplasty or urachal remnant removal, significantly greater BIQ and PSQ scores were observed in females after LESS compared to CL, but not in males. Conclusion: LESS for UPJO and urachal remnant removal has better self-reported body image and cosmesis ratings than CL. This trend is particularly strong in female patients.

Urinary l-type fatty acid-binding protein is a predictor of early renal function after partial nephrectomy

Abstract Purpose: Urinary biomarkers of renal injury urinary may identify loss of renal function following nephron-sparing surgery (NSS). This study was designed to evaluate whether urinary l-type fatty acid-binding protein (l-FABP) is an early biomarker of loss of renal function after NSS. Specifically, the kinetics of urinary l-FABP level after NSS and its correlation with factors related to ischemic renal injury were analyzed. Methods: This study prospectively evaluated 18 patients who underwent NSS between July and December 2014, including 12 who underwent laparoscopic and six who underwent robot-assisted partial nephrectomy. Urinary l-FABP concentrations were measured preoperatively and 1, 2, 3, 6, 12, 24, 48, and 72 h after renal artery declamping. Loss of renal function loss was calculated by comparing the effective renal plasma flow, as determined by 99mTc-mercaptoacetyltriglycine (MAG3) clearance, on the operated and normal sides. The decrease in estimated glomerular filtration rate from before surgery to six months after surgery was also measured. Results: Urinary l-FABP concentration peaked within 2 h of declamping, which may quantify nephron damage caused by ischemia. The decrease in MAG3 reduction ratio correlated with both the ischemia time and peak urinary l-FABP concentration. Peak urinary l-FABP concentration showed a significant correlation with MAG3 reduction ratio. Conclusions: l-FABP is a suitable urinary biomarker for predicting the extent of ischemic renal injury.