Longitudinal change in castration-resistant prostate cancer biomarker AST/ALT ratio reflects tumor progression.

We investigated whether aspartate transaminase (AST)-to-alanine aminotransferase (ALT) ratio and its change during the course of treatment in castration-resistant prostate cancer (CRPC) patients is associated with tumor condition and lethality. Clinical data from 130 CRPC patients were retrospectively evaluated. AST/ALT ratios at the time of prostate cancer (PC) diagnosis, androgen deprivation therapy (ADT), CRPC diagnosis, and the final follow-up examination after CRPC treatment were calculated for each. The prognostic capabilities of the AST/ALT ratio for overall survival (OS) were analyzed by use of the Kaplan-Meier method and Cox hazard models. The median AST/ALT ratio at PC diagnosis was 1.517 and the optimal value predicting lethality defined by the receiver operating curve was 1.467. The AST/ALT ratio decreased once during ADT and then elevated in a stepwise manner with cancer progression. In surviving patients, the median AST/ALT ratio at the time of PC diagnosis was 1.423, which did not change longitudinally, whereas that in patients later deceased was significantly higher (1.620) and further elevated after CRPC diagnosis. Kaplan-Meier curves indicated significantly worse OS in patients with an AST/ALT ratio ≥ 1.467, which was confirmed by multivariate analysis. These findings indicate AST/ALT ratio as a prognostic biomarker for CRPC with longitudinal changes reflecting tumor progression.

Urine pH and imaging findings of prostate useful predictors of prolonged duration of hematospermia.

Background: Few investigations regarding hematospermia duration have been reported thus far. The aim of this study was to identify clinical factors associated with the duration of hematospermia. Methods: Clinical data of 198 patients with hematospermia treated at Toho University Omori Medical Center from 2007 to 2022 were retrospectively evaluated. To identify independent predictors of hematospermia duration, uni- and multivariate Cox analyses were performed. Receiver operating characteristic analysis, Kaplan-Meier survival curves, and propensity score matching were applied for statistical evaluations. Results: Multivariate analysis of all 198 patients showed urine pH (UpH) level and any abnormal imaging finding of the prostate to be independent predictors of hematospermia duration. Based on the receiver-operating curve of UpH level for hematospermia improvement, the patients were divided into two groups using a threshold of 6.0 (Low-UpH 5.0-6.0, n=128; High-UpH 7.0-9.0, n=70). Kaplan-Meier curves indicated that patients in the High-UpH group or with any abnormal imaging finding had a higher rate of hematospermia persistence (both P<0.05). Even after matching between the groups classified by UpH (n=60 each), multivariate analysis showed that UpH level (hazard ratio 0.75, 95% CI: 0.61-0.92; P=0.006) and any abnormal imaging finding (hazard ratio 1.55, 95% CI: 1.04-2.31; P=0.033) were independent predictors of hematospermia duration. In Kaplan-Meier analysis findings of matched cohorts, High-UpH and presence of any abnormal imaging findings remained significantly correlated with higher rate of hematospermia persistence, while further stratification using a combination of these two factors identified a stepwise reduction in that rate (P=0.019). In addition, the proportion of patients with these two factors present simultaneously was significantly higher in the group with hematospermia for two months or more, and especially with a duration of greater than six months, than in the group with a duration of less than two months. Conclusions: Although further research is needed, both UpH level and imaging findings of the prostate are considered useful biomarkers for predicting prolonged hematospermia.

Successful treatment of ejaculation pain with silodosin in patient with Zinner syndrome: a case report.

Background: Zinner syndrome is a rare congenital anomaly featuring a unilateral seminal vesicle cyst and ipsilateral renal agenesis. While the majority of affected patients are asymptomatic and followed with conservative management, others have symptoms such as micturition, ejaculatory difficulties, and/or pain, thus may require treatment. These patients often undergo an invasive procedure as first-line treatment, such as transurethral resection of the ejaculatory duct, or aspiration and drainage, which reduces pressure within the seminal vesicle cyst, or surgical resection of the seminal vesicle. Reported here is a patient with ejaculation pain and pelvic discomfort associated with Zinner syndrome who was successfully treated in a non-invasive manner with silodosin, an α1-adrenoceptor antagonist. Case Description: A 37-year-old Japanese male had ejaculation pain and pelvic discomfort associated with Zinner syndrome. Two months of treatment with silodosin, an α1-blocker, resulted in complete pain relief. Thereafter, conservative management with regular follow-up examinations has been conducted for five years, without recurrence of ejaculation pain or other symptoms associated with Zinner syndrome. Conclusions: This is the first known published case report of a patient with Zinner syndrome treated with silodosin who was completely relieved from ejaculation pain. The effect of α1-adrenoceptor antagonists to inhibit seminal vesicle contraction, as well as cause relaxation of smooth muscles of the urethra and prostate may contribute to reduce pain associated with ejaculation. We concluded that silodosin treatment should be attempted in affected patients before considering surgical treatment.

Combination of C-reactive protein/albumin ratio and time to castration resistance enhances prediction of prognosis for patients with metastatic castration-resistant prostate cancer.

Objective: This study aimed to identify the prediction accuracy of the combination of C-reactive protein (CRP) albumin ratio (CAR) and time to castration resistance (TTCR) for overall survival (OS) following development of metastatic castration-resistant prostate cancer (mCRPC). Methods: Clinical data from 98 mCRPC patients treated at our institution from 2009 to 2021 were retrospectively evaluated. Optimal cutoff values for CAR and TTCR to predict lethality were generated by use of a receiver operating curve and Youden's index. The Kaplan-Meier method and Cox proportional hazard regression models for OS were used to analyze the prognostic capabilities of CAR and TTCR. Multiple multivariate Cox models were then constructed based on univariate analysis and their accuracy was validated using the concordance index. Results: The optimal cutoff values for CAR at the time of mCRPC diagnosis and TTCR were 0.48 and 12 months, respectively. Kaplan-Meier curves indicated that patients with CAR >0.48 or TTCR <12 months had a significantly worse OS (both p < 0.005). Univariate analysis also identified age, hemoglobin, CRP, and performance status as candidate prognostic factors. Furthermore, a multivariate analysis model incorporating those factors and excluding CRP showed CAR and TTCR to be independent prognostic factors. This model had better prognostic accuracy as compared with that containing CRP instead of CAR. The results showed effective stratification of mCRPC patients in terms of OS based on CAR and TTCR (p < 0.0001). Conclusion: Although further investigation is required, CAR and TTCR used in combination may more accurately predict mCRPC patient prognosis.

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie's Disease.

Peyronie's disease (PD) is a benign condition caused by plaque formation on the tunica albuginea of the penis. It is associated with penile pain, curvature, and shortening, and contributes to erectile dysfunction, which worsens patient quality of life. In recent years, research into understanding of the detailed mechanisms and risk factors involved in the development of PD has been increasing. In this review, the pathological mechanisms and several closely related signaling pathways, including TGF-ß, WNT/ß-catenin, Hedgehog, YAP/TAZ, MAPK, ROCK, and PI3K/AKT, are described. Findings regarding cross-talk among these pathways are then discussed to elucidate the complicated cascade behind tunica albuginea fibrosis. Finally, various risk factors including the genes involved in the development of PD are presented and their association with the disease summarized. The purpose of this review is to provide a better understanding regarding the involvement of risk factors in the molecular mechanisms associated with PD pathogenesis, as well as to provide insight into disease prevention and novel therapeutic interventions.

[A Study of Factors Affecting Febrile Urinary Tract Infection Following Ureterorenoscopic Lithotripsy].

Febrile urinary tract infection (f-UTI) is a common complication after ureterorenoscopic lithotripsy (URSL) but is sometimes lethal. In this article, we analyzed the factors of post URSL f-UTI. We retrospectively evaluated the association between the development of f-UTI and patients, stones, and perioperative factors in 695 cases in which URSL was performed at our institution from September 2015 to 2018. Seventy-six of the 695 patients (10.9%) had postoperative f-UTI. Elderly (p＝0.013), female (p＝0.02), and hypertension (p＝0.001) patients had significantly higher rates of f-UTI. Renal stone (p＝0.001) cases showed significantly higher rates of f-UTI. Preoperative urine positive culture (p＝0.045), preoperative f-UTI (p＜0.001), URSL procedure using flexible ureteroscopy (p＝0.048), non-stone-free (p＝0.006), long operation time (p＝0.011), preoperative urinary stent insertion due to preoperative f-UTI (p＜0.001), were factors associated with post-operative f-UTI. Multivariate analysis revealed that hypertension (OR＝2.08, p＝0.008) and preoperative f-UTI (OR＝3.739, p＝0.033) were independent factors of postoperative f-UTI. Patients with hypertension or preoperative f-UTI should be managed more carefully during the perioperative period, suspecting that they are more likely to develop postoperative f-UTI.

Significant inverse association of testosterone level with penile deformity severity in Japanese males with Peyronie's disease.

OBJECTIVES: We evaluated the relationship between penile curvature and testosterone in Peyronie's disease patients treated in Japan. METHODS: Data were obtained from 109 patients with Peyronie's disease treated with surgery at our hospital between April 2004 and December 2019. Penile deformity assessment was based on findings of a rigid erection induced by intracavernosal injection. Low total testosterone level was defined as <300 ng/dl. Patients were divided into two groups according to curvature severity (I, <60°; II ≥60°), then clinical factors including total testosterone were compared. Uni- and multivariate logistic regression analyses were performed to identify factors predicting severe penile deformity (≥60°). RESULTS: For all patients, mean total testosterone was 469 ng/dl and median curvature was 50°, with a significant inverse correlation found between curvature and testosterone level (p < 0.0001). Group I and II patients numbered 55 and 54, respectively. Mean total testosterone for Group II was 397 ng/dl, significantly lower than Group I (539 ng/dl). Median curvature in 15 patients with a low testosterone level was 80°, significantly higher than those with a normal testosterone range (50°). Univariable and multivariable logistic regression analysis indicated total testosterone, follicle stimulating hormone, and C-reactive protein as significant factors correlated with severe penile deformity, among which total testosterone was most relevant. CONCLUSION: The present findings confirmed that penile deformity severity is correlated with testosterone level in Japanese males with Peyronie's disease.

Colon Cancer Metastasis to the Right Testis: Case Report and Review of Literature.

Introduction: A metastatic testicular tumor is uncommon. We report here a case of testicular metastasis associated with recurrent colorectal cancer. Case Presentation. A 75-year-old male was presented with right scrotum pain one year after undergoing a right hemicolectomy combined with resection of the small intestine and omentum for ascending colon cancer (pT4N0M0). Magnetic resonance imaging of the pelvis showed a 7.3 × 5.4 × 4.5 cm mass consisting of a cystic solid tumor. A right inguinal orchiectomy was performed and right testicular pain improved after surgery. Pathology results showed that the tumor was a metastatic adenocarcinoma. The patient subsequently died two months later due to progression of the colon cancer. Conclusion: Although colorectal cancer metastasis to the testis is very uncommon, it should be kept in mind in clinical situations, especially for older males with a testicular mass or discomfort.

AJM300 (carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study consisted of two phases: a treatment phase and an open-label re-treatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6-10, endoscopic subscore of 2 or more, rectal bleeding subscore of 1 or more, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimisation method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥6 to ≤7, ≥8 to ≤10 points), any use of corticosteroid, anti-TNFα antibody, or immunosuppressants during the disease-active period (yes vs no), duration of induction therapy until randomisation (<4 weeks vs ≥4 weeks) as the minimisation factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, three times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary endpoint was the proportion of patients with a clinical response at week 8, and was analysed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score of 30% or more and 3 or more, a reduction in rectal bleeding score of 1 or more or rectal bleeding subscore of 1 or less, and an endoscopic subscore of 1 or less at week 8. The study is registered with ClinicalTrials.gov, NCT03531892, and is closed to recruitment. FINDINGS: Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n=102) or placebo (n=101). At week 8, 46 (45%) patients in the AJM300 group and 21 (21%) patients in the placebo group had a clinical response (odds ratio 3·30, 95% CI 1·73-6·29; p=0·00028). During the 8-week treatment and 16-week extension treatment periods, adverse events occurred in 39 (39%) of 101 patients in the placebo group and 39 (38%) of 102 patients in the AJM300 group. We found no difference in the incidence of adverse events between groups or after repeated administration of AJM300. The most common adverse event was nasopharyngitis (11 [11%] of 101 patients in the placebo group and ten [10%] of 102 patients in the AJM300 group). The most common treatment-related adverse event was also nasopharyngitis (four [4%] of 101 patients in the placebo group and three [3%] of 102 patients in the AJM300 group). Most adverse events were mild-to-moderate in severity. No deaths were reported. A serious adverse event was reported in the AJM300 group (one patient with anal abscess), but this was judged to be unrelated to study drug. INTERPRETATION: AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis. FUNDING: EA Pharma and Kissei Pharmaceutical. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

ABO Blood Type and Risk of Peyronie's Disease in Japanese Males.

PURPOSE: Although multiple mechanisms associated with Peyronie's disease (PD) have been proposed, details regarding etiologic factors, especially genetic, remain unclear. We examined the relationship of the ABO blood type system, known as a genetic factor associated with susceptibility to a number of diseases, with PD in Japanese males. MATERIALS AND METHODS: We compared 202 Japanese PD patients treated with surgery at our hospital between March 2004 and December 2019 with 846 randomly selected non-PD male patients who underwent urological surgery during the same period regarding distribution of ABO blood types. In addition, we assessed the risk of PD according to blood type group among all study participants using odds ratio (OR) and 95% confidence interval (CI) calculations. RESULTS: The distribution of individual blood types in the control group was nearly the same as that in the general Japanese population. In contrast, O, A, B, and AB blood types were noted in 37.6%, 36.1%, 14.9% and 11.4%, respectively, of the PD patients, which was significantly different from the control group, where blood type O was found in 29.1% and B in 23.2% (p<0.05). Our results showed that as compared with patients with blood group B, those with another blood type were more likely to develop PD, among which type O had a significantly increased OR of 2.018 (CI, 1.271-3.205). CONCLUSIONS: These are the first reported results showing that ABO blood type may be associated with risk of PD, though further investigations are needed.

Impact of eliminating urethral catheterization following ureterorenoscopic lithotripsy.

OBJECTIVES: To show that elimination of a urethral catheter in ureterorenoscopic lithotripsy cases is not disadvantageous. METHODS: We reviewed 164 non-catheterized patients (experimental group) and 656 catheterized patients (control group) with renal or ureteral stones treated at our institution. Inclusion criteria were initial operation, patient age 18 to 75 years, no dysuria, and no preoperative febrile urinary tract infection due to calculi. The primary areas of evaluation were patient background, stone characteristics, perioperative factors, and postoperative evaluation results. RESULTS: The proportion of women was significantly lower (24.4% vs 37.2%; P = 0.01) and the proportion of multiple stone cases was significantly higher (34.9% vs 19.2%; P < 0.001) in the experimental as compared to the control group, while there were no significant differences for patient background or stone characteristics. The percentages of short-term preoperative stent insertion (72.0% vs 33.0%; P = 0.009) and negative preoperative urine culture cases (58.0% vs 23.0%; P < 0.001) were significantly higher in the experimental than in the control group, with no differences regarding other perioperative factors. There was no significant difference for complete stone clearance rate between the groups (P = 0.339), while only one patient underwent re-catheterization and there were no cases of urinary retention. Interestingly, the rate of postoperative febrile urinary tract infection was significantly lower (P = 0.024) in the experimental (5.7%) than in the control (9.0%) group. CONCLUSION: Postoperative urethral catheterization can be eliminated in low-risk ureterorenoscopic lithotripsy cases, although additional studies are needed.

Sequestration of RBM10 in Nuclear Bodies: Targeting Sequences and Biological Significance.

RBM10 is an RNA-binding protein that regulates alternative splicing (AS). It localizes to the extra-nucleolar nucleoplasm and S1-1 nuclear bodies (NBs) in the nucleus. We investigated the biological significance of this localization in relation to its molecular function. Our analyses, employing deletion mutants, revealed that RBM10 possesses two S1-1 NB-targeting sequences (NBTSs), one in the KEKE motif region and another in the C2H2 Zn finger (ZnF). These NBTSs act synergistically to localize RBM10 to S1-1 NBs. The C2H2 ZnF not only acts as an NBTS, but is also essential for AS regulation by RBM10. Moreover, RBM10 does not participate in S1-1 NB formation, and without alterations of RBM10 protein levels, its NB-localization changes, increasing as cellular transcriptional activity declines, and vice versa. These results indicate that RBM10 is a transient component of S1-1 NBs and is sequestered in NBs via its NBTSs when cellular transcription decreases. We propose that the C2H2 ZnF exerts its NB-targeting activity when RBM10 is unbound by pre-mRNAs, and that NB-localization of RBM10 is a mechanism to control its AS activity in the nucleus.

A method for utilizing automated machine learning for histopathological classification of testis based on Johnsen scores.

We examined whether a tool for determining Johnsen scores automatically using artificial intelligence (AI) could be used in place of traditional Johnsen scoring to support pathologists' evaluations. Average precision, precision, and recall were assessed by the Google Cloud AutoML Vision platform. We obtained testicular tissues for 275 patients and were able to use haematoxylin and eosin (H&E)-stained glass microscope slides from 264 patients. In addition, we cut out of parts of the histopathology images (5.0 × 5.0 cm) for expansion of Johnsen's characteristic areas with seminiferous tubules. We defined four labels: Johnsen score 1-3, 4-5, 6-7, and 8-10 to distinguish Johnsen scores in clinical practice. All images were uploaded to the Google Cloud AutoML Vision platform. We obtained a dataset of 7155 images at magnification 400× and a dataset of 9822 expansion images for the 5.0 × 5.0 cm cutouts. For the 400× magnification image dataset, the average precision (positive predictive value) of the algorithm was 82.6%, precision was 80.31%, and recall was 60.96%. For the expansion image dataset (5.0 × 5.0 cm), the average precision was 99.5%, precision was 96.29%, and recall was 96.23%. This is the first report of an AI-based algorithm for predicting Johnsen scores.

Temporary pacemaker insertion for severe bradycardia following pneumoperitoneum during robot-assisted radical prostatectomy: a case report.

BACKGROUND: Pneumoperitoneum to maintain a constant gas flow to assist various surgeries is known to cause severe bradycardia and has been linked to heart failure;; however, a recent study demonstrated that it is not linked to poorer surgical outcomes; accordingly, it does not require routine preventive measures. Thus, whether there is a link between sudden bradycardia development and surgical procedures is controversial. We report the case of severe bradycardia that occurred along with a complete atrioventricular block (CAVB) during peritoneum creation in robot-assisted radical prostatectomy (RARP). CASE PRESENTATION: A 72-year-old man presented at our hospital with prostate cancer and underwent RARP. After pneumoperitoneum, severe bradycardia and CAVB were observed; thus, the surgery was extended by inserting a temporary pacemaker (TPM). CONCLUSION: Because of the difficulty in performing emergency procedures in robot-assisted surgeries, the current case is reported to provide an awareness that surgeons should be cautious of the possible complication of bradycardia and CAVB during such operations, and thus should take steps necessary for managing induction of such conditions.

Novel prediction scoring system for simple assessment of stone-free status after flexible ureteroscopy lithotripsy: T.O.HO. score.

OBJECTIVES: To develop a novel simple quantitative scoring model for predicting stone-free status after a flexible ureteroscopy lithotripsy procedure by standardizing the complexity of ureteral stone characteristics. METHODS: We retrospectively reviewed 586 patients with renal or ureteral stones who underwent flexible ureteroscopy lithotripsy at Abiko Toho Hospital, Chiba, Japan, from 2015 to 2018. Multivariate regression was applied to examine the relationship between preoperative descriptors and stone-free status, and a nomogram was developed using significant predictors. Next, the individual components of the nomogram were assigned points to form a simple scoring system. The predictive performance of this new scoring system was compared with the STONE score at optimal cut-off values using receiver operating characteristic curve and area under the curve analyses. RESULTS: Multivariate logistic regression findings showed that factors associated with stone-free status were length, Hounsfield unit and stone location. A nomogram prediction model was developed with an area under the curve value of 0.845, then consequently used to develop a new simple score system termed the T.O.HO. score consisting of three stone characteristics: (T)allness (1-5 points), (O)ccupied lesion (1-3 points) and (HO)unsfield units evaluation (1-3 points). The T.O.HO. score was significantly higher in stone remaining (7.66) than stone-free (5.27; P < 0.001) cases. The area under the curve for the T.O.HO. score was 0.833 at an optimal cut-off value of 7, whereas that for the STONE score was 0.683 at an optimal cut-off value of 9, showing the superiority of this new scoring system. CONCLUSION: The T.O.HO. score is a useful tool for predicting stone-free status in patients who have undergone a flexible ureteroscopy lithotripsy procedure.

A Study of Morphological Changes in Renal Afferent Arterioles Induced by Angiotensin II Type 1 Receptor Blockers in Hypertensive Patients.

BACKGROUND: Renin-angiotensin-aldosterone system blockers are known to reduce hypertrophy of vascular smooth muscle cells (SMCs) in hypertensive cases. However, we have reported marked proliferative changes of renal afferent arteriolar SMCs in rats induced by a long-term administration of angiotensin II type 1 receptor blockers (ARBs) and an angiotensin-converting enzyme inhibitor (ACEI). In this study, we examined the morphological changes of afferent arteriolar walls in human kidneys with or without ARBs/ACEIs. METHODS: Forty-four wedge resections were taken from patients aged 45-74 years from 92 nephrectomized kidneys due to malignancy at Toho University Omori Medical Center between 2013 and 2016. They were divided into the following three groups: 18 hypertensive patients treated with antihypertensive agents including ARBs or ACEIs (the HTARB group), 6 hypertensive patients treated with calcium channel blockers without ARBs/ACEIs (the HTCCB group), and 20 normotensive patients (the normotensive group) as a control. Cases expecting vascular changes such as diabetes were excluded. In each case renal arterioles were measured as the ratio of inner/outer arteriolar diameter, and pathologists estimated morphological abnormal changes, scoring each specimen independently. RESULTS: The ratio in the HTARB group was 0.39 ± 0.05 (mean ± SD), and was significantly the lowest among the three groups (0.46 ± 0.02 in the HTCCB, 0.53 ± 0.02 in the normotensive group; p = 0.0107 vs. HTCCB, p = 0.00001 vs. normotensive). The ratio in the three groups significantly correlated with the estimated glomerular filtration rate (r = 0.4915, p < 0.0007). The afferent arteriolar SMCs in the HTARB group frequently showed marked proliferative and irregular changes. The score of SMC abnormalities estimated regarding the proliferation, irregularity of the arrangement, and size in hilar afferent arteriolar SMCs was highest in the HTARB group and showed statistical significance (p = 0.0088, p = 0.00001, and p = 0.025 versus other two groups). CONCLUSIONS: We consider that these morphological changes in arterioles are induced by ARBs/ACEIs. These changes could induce an important suppression of glomerular hyperfiltration and could lead to glomerular ischemia. However, the clinical consequences of these morphological changes in correlation with ARBs/ACEIs were not sufficiently clear and require further analysis. We should consider renal arteriolar morphological changes when using ARBs/ACEIs.

Phospho-Ser727 triggers a multistep inactivation of STAT3 by rapid dissociation of pY705-SH2 through C-terminal tail modulation.

Signal transducer and activator of transcription 3 (STAT3) is involved in many biological processes, including immunity and cancer. STAT3 becomes phosphorylated at Tyr705 and Ser727 on IL-6 stimulation. Phospho-Tyr705 (pY705) stabilizes the STAT3 dimer with reciprocal interactions between pY705 and the SH2 of the other molecule and phospho-Ser727 (pS727) accelerates pY705 dephosphorylation. We study how pS727 regulates STAT3 in both structural and biological perspectives. Using STAT3 reconstituted in HepG2-stat3-knockout cells, we show that pS727, together with a handshake N-terminal domain (NTD) interaction, causes rapid inactivation of STAT3 for pY705 dephosphorylation and a chromosome region maintenance 1 (CRM1)-independent nuclear export, which is critical for faithful STAT3 response to the cellular signals. The various N-terminal tags, GFP-related Ruby and FLAG, rendered the export CRM1-dependent and especially FLAG-tag caused nuclear accumulation of STAT3, indicating the presence of conformational changes in inactivation. Impaired reactivation of STAT3 by S727A or FLAG-tag delayed or inhibited the IL-6-induced saa1 mRNA expression, respectively. The detailed analysis of the pY705-SH2 structure identified the C-terminal tail (CTT) from L706 to P715 as a key regulator of the CTT-CTT intermolecular and the CTT-SH2 intramolecular interactions that support pY705-SH2 association. The functional studies using multiple STAT3 mutants indicated that the degree of the two interactions determines the stability of pY705-SH2 interaction. Importantly, Pro715 was critical for the pS727's destabilizing activity and the known phosphorylation and acetylation at the CTT structurally inhibited the pY705-SH2 interaction. Thus, pS727 triggers pY705-SH2 dissociation by weakening the supportive interactions likely through CTT modulation, inducing rapid cycles of STAT3 activation-inactivation for proper function of STAT3.

Intestinal malrotation in a patient who underwent radical cystectomy and ileal conduit construction: A case report.

A 74-year-old male underwent laparoscopic radical cystectomy for invasive bladder cancer with open surgery for lymph node dissection and urinary diversion (ileal conduit). During the surgery, intestinal malrotation was diagnosed and Ladd procedure was performed. Ileal conduit was performed on the left side after considering the course of mesentery. Although a final diagnosis was reached during the surgery in this case, the presence of intestinal malrotation can be suspected based on the findings of contrast-enhanced computed tomography images obtained before the surgery. Images should be carefully inspected to detect intestinal malrotation when planning urinary diversion involving the intestinal tract.

RBM10 regulates centriole duplication in HepG2 cells by ectopically assembling PLK4-STIL complexes in the nucleus.

RNA-binding motif protein 10 (RBM10) primarily regulates alternative splicing of certain genes. Loss-of-function mutations in RBM10 have been frequently reported in patients with various cancers. However, how RBM10 levels affect cell proliferation and tumorigenesis remains unknown. To elucidate the role of RBM10 in cell proliferation, we established HepG2-RBM10 knockout cell lines and derivative doxycycline-inducible RBM10-expressing cells. RBM10 over-expression caused growth arrest in the M phase with a monopolar spindle because of impaired centriole duplication. Two RBM10 splicing mutants, one with F345A/F347A and the other with only the C-terminal half (401-930), were sufficient to cause growth arrest, whereas an RBM10 mutant with cytoplasmic localization forced by an NES did not show growth arrest. RBM10 over-expression induced the formation of many large nuclear domains containing RBM10, PLK4, STIL and SAS6, which are the regulatory proteins involved in centriole duplication. Consistently, the centrioles in the RBM10-over-expressing HepG2 cells lost PLK4 and STIL, accounting for the unsuccessful centriole duplication. In contrast, RBM10 depletion resulted in elevated levels of cytoplasmic PLK4 with a concomitant increase in the number of centrioles in HepG2 cells but not in A549 cells. Thus, nuclear RBM10 regulates normal chromosomal division in a cell-type-specific manner, independent of alternative RNA splicing.

The Tight Medial and High Convexity Subarachnoid Spaces Is the First Finding of Idiopathic Normal Pressure Hydrocephalus at the Preclinical Stage.

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) findings are often reported as characteristic radiological features of idiopathic normal pressure hydrocephalus (iNPH). However, the process of development of DESH remains unclear. The aim of the present study was to determine the dynamic deforming process and pathophysiology of iNPH. All patients >50 years of age who underwent whole body FDG-PET/CT scanning at Kindai University Hospital between May 2017 and April 2018 were included in this retrospective study, and their brain image findings and clinical information were assessed. We defined DESH-like findings, which had one or two equivocal features of the three components of DESH findings, as preclinical morphologic features of DESH (PMD). PMD were classified into six subtypes based on their component of DESH findings: PMD-T, only tight medial and high convexity subarachnoid spaces (TMC); PMD-S, only enlarged Sylvian fissures; PMD-V, only ventriculomegaly; PMD-TV, TMC and ventriculomegaly; PMD-TS, TMC and enlarged Sylvian fissures; PMD-SV, enlarged Sylvian fissures and ventriculomegaly. A total of 2196 cases (70.5 ± 9.3 years) were enrolled, with 54 cases (77.1 ± 5.9 years) with DESH findings, and 42 cases (72.9 ± 7.9 years) with PMD (five PMD-T, two PMD-V, 12 PMD-TV, 18 PMD-TS, and five PMD-SV). In each component of DESH, 35 of 42 (83.3%) cases with PMD had TMC. We suggest that the TMC is the first change on DESH findings in most iNPH cases, and may be an important part of the pathophysiology of iNPH.