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Chemotherapy drugs, such as gemcitabine and cisplatin (GC), are frequently administered to patients with advanced urothelial carcinoma, however the influence of the gut microbiota on their action is unclear. Thus, we investigated the effects of GC on the gut microbiome and determined whether oral supplementation with a probiotics mixture of Lactobacillus casei Shirota and Bifidobacterium breve enhanced the anti-tumor immune response. After subcutaneous inoculation with MBT2 murine bladder cancer cells, syngenic C3H mice were randomly allocated into eight groups. The gut microbiome cluster pattern was altered in both the GC and oral probiotics groups (p = 0.025). Both tumor-bearing conditions (no treatment) and GC chemotherapy influenced Pseudoclostridium, Robinsoniella, Merdimonas, and Phocea in the gut. Furthermore, comparison of the GC-treated and GC + probiotics groups revealed an association of four methyltransferase family enzymes and two short-change fatty acid-related enzymes with oral probiotics use. A significant difference in tumor volume was observed between the GC and GC + probiotics groups at week 2 of treatment. Additionally, decreased recruitment of cancer-associated fibroblasts and regulatory T cells, and activation of CD8

The level of 6-sulfatoxy-melatonin (SaMT), a metabolite of melatonin, in first-void morning urine reflects blood melatonin levels from the previous night. We investigated the association between urine SaMT and sleep quality deterioration in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical Bacillus Calmette-Guerin induction therapy (iBCG).We enrolled 51 patients who received iBCG once weekly for 6 or 8 weeks. Patient-reported outcomes were assessed with questionnaires including the International Prostate Symptom Score (IPSS) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQC30). Questionnaires were completed before (baseline), during, at completion, and 1 and 3 months after iBCG. Melatonin and SaMT levels at baseline were measured in serum and first-void morning urine samples, respectively.Based on changes in the QLQC30 insomnia subscale, 28 (55%) patients experienced sleep quality deterioration (deterioration group). Urine SaMT values in the deterioration group were lower than those in the non-deterioration group (P = 0.0015; 7.5 vs 15.4 ng/mg creatinine, respectively). Nocturia scores in the non-deterioration group decreased over time, while those of the deterioration group remained high after completion of iBCG. A binary logistic regression analysis revealed that low urine SaMT levels (≤ 9.6 ng/mg creatinine), high IPSS nocturia scores at baseline, and high IPSS storage subscores at baseline were associated with BCG-induced sleep quality deterioration.This study confirmed the association among urine SaMT levels, nocturia, and sleep disturbance in patients with NMIBC who receive iBCG. We should be aware of treatment-induced impairments to aid in appropriate decision-making.

The US Food and Drug Administration recently defined the clinical term "bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer" as a disease state resistant to adequate bacillus Calmette-Guérin therapy. There is a significant lack of prognostication for this disease even in patients who have undergone early radical cystectomy. This study aimed to identify the clinical outcomes and prognostic factors in Japanese patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer who underwent early radical cystectomy.Data from a large-scale multicenter retrospective study included 2879 patients with highest-risk or high-risk non-muscle-invasive bladder cancer who received intravesical bacillus Calmette-Guérin induction therapy between January 2000 and December 2019. A total of 141 patients (4.3%) met the criteria for bacillus Calmette-Guérin-unresponsive disease, of whom 47 (33.3%) underwent early radical cystectomy. Prognostic factors for three clinical endpoints, namely, unresectable lesion-free survival, cancer-specific survival, and overall survival, were identified.The highest-risk status at induction bacillus Calmette-Guérin was associated with short unresectable lesion-free survival (hazard ratio 7.85; P 0.05), cancer-specific survival (hazard ratio 12.24; P 0.05), and overall survival (hazard ratio 9.25; P 0.01). Moreover, extravesical tumors (pathological T3 or T4) on the radical cystectomy specimens were associated with poor prognosis and were found at a higher rate in patients with the highest-risk status at induction bacillus Calmette-Guérin than in those with high-risk status (35.7% vs 21.2%).The highest-risk status among the pre-bacillus Calmette-Guérin factors was associated with upstaging to extravesical tumors and poor prognosis despite early radical cystectomy procedures. Appropriate decision-making and the correct timing of radical cystectomy are vital to avoid treatment delays and improve outcomes.

Background Although routine surveillance imaging to examine upper urinary tract urothelial cancer recurrence during follow-up of non-muscle invasive bladder cancer is recommended, its necessity remains invalidated. We performed a single-institute long-term follow-up cohort study to identify risk factors for upper urinary tract urothelial cancer recurrence after non-muscle invasive bladder cancer treatment, as well as the clinical impact of routine surveillance imaging. Methods and materials A retrospective chart review of 864 patients with primary non-muscle invasive bladder cancer who underwent initial transurethral resection of bladder tumor between 1980 and 2020 was conducted. Oncological outcomes included upper urinary tract urothelial cancer recurrence-free survival and overall survival. Moreover, we examined the opportunities to diagnose its recurrence. Results Of 864 patients, 19 (2.2%) experienced upper urinary tract urothelial cancer recurrence. On multivariate Fine-Gray proportional regression analyses, a tumor size ≥ 30 mm and carcinoma in situ were independently associated with short upper urinary tract urothelial cancer recurrence-free survival. Recurrence was associated with shorter overall survival. Among the aforementioned 19 patients, recurrence was detected through routine imaging in 12 (63.2%), cystoscopy in two (10.5%), urine cytology in two (10.5%), presence of gross hematuria in one (5.3%), and unknown methods in two (10.5%). Conclusion Most patients experiencing upper urinary tract urothelial cancer recurrence were diagnosed by routine surveillance imaging, suggesting its clinical importance, especially for patients with non-muscle invasive bladder cancer accompanied by a tumor size ≥ 30 mm and carcinoma in situ.

Background Photodynamic diagnosis-assisted transurethral resection of bladder tumor reduces the risk of intravesical recurrence compared with conventional white light-transurethral resection of bladder tumor. However, the patient burden of costs for photodynamic diagnosis-transurethral resection of bladder tumor is higher than that for white light-transurethral resection of bladder tumor per installment, and the impact of the medical economics of photodynamic diagnosis-transurethral resection of bladder tumor is unclear. Therefore, we evaluated the Japanese health care system-based cost-effectiveness of photodynamic diagnosis-transurethral resection of bladder tumor compared with that of white light-transurethral resection of bladder tumor. Methods We conducted a retrospective chart review of 100 patients who underwent initial white light- or photodynamic diagnosis-transurethral resection of bladder tumor for non-muscle invasive bladder cancer from February 2012 to August 2019. Cumulative intravesical recurrences during 1000 post-operative days after the initial transurethral resection of bladder tumor were counted. Furthermore, the cumulative costs were calculated using the Diagnostic Procedure Combination and Per-Diem Payment System unique to Japan. The costs/year/person calculated using the person-year method was compared between the white light- and photodynamic diagnosis-transurethral resection of bladder tumor. Results Among the 100 patients, 40 (40%) and 60 (60%) underwent the initial white light- and photodynamic diagnosis-transurethral resection of bladder tumor, respectively. The cumulative incidence of bladder recurrence requiring hospitalization and transurethral resection of bladder tumor was 20 and 5% for the white light-transurethral resection of bladder tumor and photodynamic diagnosis-transurethral resection of bladder tumor, respectively. The costs for hospitalization and surgical procedures per white light- or photodynamic diagnosis-transurethral resection of bladder tumor were 348 228 and 481 820 Japanese yen, respectively. The cost/year/person by the person-year method was 8073 and 8557 Japanese yen for the white light- and photodynamic diagnosis-transurethral resection of bladder tumor, respectively. Conclusions The cost/year/person for hospitalization and surgical procedures was slightly different between the white light- and photodynamic diagnosis-transurethral resection of bladder tumor. Furthermore, photodynamic diagnosis-transurethral resection of bladder tumor can reduce intravesical recurrence and is more cost-effective than white light-transurethral resection of bladder tumor.

First-line pembrolizumab is available for recurrent disease within 12 months after the receipt of platinum-based perioperative chemotherapy. However, the benefit of first-line pembrolizumab is unclear. This study evaluated the oncological outcome of patients treated with pembrolizumab compared with chemotherapy as first-line therapy for early relapsing disease after the receipt of platinum-based perioperative chemotherapy.Data from a multicenter study included 454 patients diagnosed with unresectable or metastatic UC from November 2006 to July 2021. We identified patients with early and non-early relapsing disease. Oncological outcomes were evaluated using progression-free survival, overall survival, and survival with disease control.Fifty-three patients with early relapsing disease and 15 patients with non-early relapsing disease were identified. Of 53 patients with early relapsing disease, 26 (49.1%) were treated with pembrolizumab and 27 (50.9%) were treated with chemotherapy as first-line therapy. Fifteen patients with non-early relapsing disease were treated with chemotherapy. Early relapsing disease was associated with shorter progression-free survival and overall survival than non-early relapsing disease. Pembrolizumab was associated with longer progression-free survival and survival with disease control than chemotherapy in patients with early relapsing disease. There was no significant difference in overall survival between pembrolizumab and chemotherapy, but overall survival plateau with a long tail was observed in pembrolizumab.First-line pembrolizumab in earlier clinical settings for highly malignant tumors might improve the prognosis of patients with early relapsing disease after the receipt of platinum-based perioperative chemotherapy.

There is limited evidence regarding the tumor expression of nectins and their clinical implications in muscle invasive bladder cancer. Herein, we evaluated expression of Nectins 1-4 in 64 patients with muscle invasive bladder cancer who underwent radical cystectomy using a histochemical scoring method (H-score; immunohistochemical staining intensity multiplied by the percentage of positive-staining cells). The cutoff values were defined based on the median H-scores. Of the 64 patients, 45 (70%) had residual tumors in radical cystectomy specimens, while 13 (20%) had lymph node metastasis. The median (interquartile range) H-scores of Nectin-1, - 2, - 3, and - 4 expression were 0 (0-10), 80 (30-180), 5 (0-30), and 100 (33-160), respectively. The Nectin-4 H-score of the neuroendocrine variant was significantly lower than that of pure urothelial carcinoma (P = 0.015). Post-neoadjuvant chemotherapy pathological response (ypT2N0 residual disease and pN-negative) was achieved in 18 (49%) of the 37 patients who received neoadjuvant chemotherapy. Clinical stage II, not Nectin expression, was an independent factor associated with pathological response (P = 0.019, adjusted odds ratio 6.9, vs stage III/IV). There was no correlation in Nectin-4 tumor expression between transurethral resection and matched radical cystectomy specimens and between radical cystectomy specimens and matched lymph node metastatic lesions. However, there was a significant decrease in Nectin-4 expression in post-neoadjuvant chemotherapy radical cystectomy specimens compared to pre-neoadjuvant chemotherapy transurethral resection specimens (P = 0.008). Given the downregulation of Nectin-4 by chemotherapy and the significant discrepancy between radical cystectomy and matched lymph node metastasis specimens, baseline primary tumors may not be a suitable material for evaluating Nectin-4 expression and its potential as a predictive biomarker for enfortumab vedotin treatment.

Neonatal arterial ischemic stroke (NAIS) presents as seizures, including convulsions, subtle seizures, and apnea, and most patients experience neurological sequelae. Diagnosis is often delayed owing to low test sensitivity. The present study aimed to identify the early clinical diagnostic factors for NAIS in neonates with seizures.The present study included 54 patients born at ≥36 weeks of gestation during the last 15 years who presented to the neonatal intensive care unit with neonatal seizures and underwent brain magnetic resonance imaging (MRI), 6 of whom were diagnosed with NAIS. Maternal background, clinical characteristics, and transcranial pulsed Doppler sonography results were retrospectively reviewed.Of the 24 patients who presented with convulsions or subtle seizures, 3 (13%) were diagnosed with NAIS and 3 of 30 patients (10%) presented with apnea. Maternal premature ventricular contraction complications were higher in the NAIS group than in the non-NAIS group (p = 0.01). NAIS group showed lower mean middle cerebral artery (MCA) resistance index (RI) was lower the non-NAIS group (p = 0.009), while the left-right RI difference (p = 0.019), mean MCA blood velocity (MnV; p = 0.04), and left-right MnV difference (p 0.001) in cerebral blood flow velocities (CBFVs) were higher in the NAIS group.Our results revealed that maternal arrhythmia may be a diagnostic factor for NAIS in neonates with seizures. Early brain MRI is essential in neonates with seizures and findings of low MCA-RI, high MCA-MnV, or high left-right difference in CBFVs to distinguish between NAIS and non-NAIS.

To investigate the organ-specific response and clinical outcomes of mixed responses (MRs) to immune checkpoint inhibitors (ICIs) for unresectable or metastatic urothelial carcinoma (ur/mUC), we retrospectively analyzed 136 patients who received pembrolizumab. The total objective response rate (ORR) and organ-specific ORR were determined for each lesion according to the Response Evaluation Criteria in Solid Tumors version 1.1 as follows: (i) complete response (CR), (ii) partial response (PR), (iii) stable disease (SD), and (iv) progressive disease (PD). Most of the organ-specific ORR was 30–40%, but bone metastasis was only 5%. There was a significant difference in overall survival (OS) between responders and non-responders with locally advanced lesions and lymph node, lung, or liver metastases (HR 9.02 (3.63–22.4) p < 0.0001; HR 3.63 (1.97–6.69), p < 0.0001; HR 2.75 (1.35–5.59), p = 0.0053; and HR 3.17 (1.00–10.0), p = 0.049, respectively). MR was defined as occurring when PD happened in one lesion plus either CR or PR occurred in another lesion simultaneously, and 12 cases were applicable. MR was significantly associated with a poorer prognosis than that of the responder group (CR or PR; HR 0.09 (0.02–0.35), p = 0.004). Patients with bone metastases benefitted less. Care may be needed to treat patients with MR as well as patients with pure PD. Further studies should be conducted in the future.

In order to treat the iatrogenic ureteral stricture of more than 8 cm length after transurethral ureterolithotripsy, we planned to perform ureterocystoneostomy with psoas hitch and Boari flap. Because of the longer defect of the affected ureter than presurgically expected and the rigid and thickened ureteral stump resulting from chronic inflammation, anti-reflux technique by forming submucosal tunnel could not be achieved as in the standard Boari flap and we reluctantly anastomosed the ureteral stump to the end of the tubularized bladder wall flap in end-to-end fashion. In order to secure the anti-reflux mechanism we created a submucosal tunnel in the posterior bladder wall according to the technique reported by Casale and Rink where it originally worked as anti-incontinence mechanism of catheterizable vesicostomy. The follow-up examinations showed no recurrence of ureteral stricture nor occurrence of vesicoureteral reflux.

Cancer cachexia, characterized by continuous muscle wasting, is a key determinant of cancer‐related death; however, there are few medical treatments to combat it. Myostatin (MSTN)/growth differentiation factor 8 (GDF‐8), which is a member of the transforming growth factor‐β family, is secreted in an inactivated form noncovalently bound to the prodomain, negatively regulating the skeletal muscle mass. Therefore, inhibition of MSTN signaling is expected to serve as a therapeutic target for intractable muscle wasting diseases. Here, we evaluated the inhibitory effect of peptide‐2, an inhibitory core of mouse MSTN prodomain, on MSTN signaling. Peptide‐2 selectively suppressed the MSTN signal, although it had no effect on the activin signal. In contrast, peptide‐2 slightly inhibited the GDF‐11 signaling pathway, which is strongly related to the MSTN signaling pathway. Furthermore, we found that the i.m. injection of peptide‐2 to tumor‐implanted C57BL/6 mice alleviated muscle wasting in cancer cachexia. Although peptide‐2 was unable to improve the loss of heart weight and fat mass when cancer cachexia model mice were injected with it, peptide‐2 increased the gastrocnemius muscle weight and muscle cross‐sectional area resulted in the enhanced grip strength in cancer cachexia mice. Consequently, the model mice treated with peptide‐2 could survive longer than those that did not undergo this treatment. Our results suggest that peptide‐2 might be a novel therapeutic candidate to suppress muscle wasting in cancer cachexia., Peptide‐2 selectively suppressed the myostatin signal. The i.m. injection of peptide‐2 into tumor‐implanted C57BL/6 mice attenuated muscle wasting in cachexia model mice. The model mice treated with peptide‐2 could survive longer than those that did not undergo this treatment.

BACKGROUND Invasive candidiasis (IC) is a leading infectious cause of morbidity and mortality in premature infants. The objective of this study was to determine the prevalence of IC in newborns in the neonatal intensive care unit (NICU) of a tertiary hospital in Japan, and to identify specific predisposing factors for IC. METHODS We retrospectively collected data on demographics, clinical characteristics, and outcomes of infants with IC, who were discharged from a tertiary NICU in Japan between January 2009 and December 2020. We compared predisposing factors associated with the occurrence of early-onset IC (EOIC, < 72 hours) and late-onset IC (LOIC, ≥ 72 hours) with those of early-onset and late-onset bacterial sepsis, respectively. RESULTS Over 12 years, 3,549 infants were admitted to the NICU, including 344 extremely low birth weight (ELBW) infants. Eleven infants (including 9 ELBW infants) had IC (incidence 0.31%), and the mortality rate of IC was 0%. Four (36%) infants had EOIC and 7 (64%) had LOIC. All those with EOIC presented with skin lesions, and 86% with LOIC had thrombocytopenia. Maternal vaginal Candida colonization was a more specific predisposing factor for EOIC, while gestational age < 26 weeks, broad-spectrum antibiotic use, prior bacterial infection, prior gastrointestinal (GI) surgery, and GI diseases were more specific predisposing factors for LOIC. CONCLUSIONS The findings suggest that maternal vaginal Candida colonization and skin lesions in ELBW infants may contribute to early recognition of EOIC, and LOIC should be suspected if ELBW infants with several predisposing factors of LOIC have thrombocytopenia.

Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery (CA) aneurysms. High-dose intravenous immunoglobulin (IVIG) is the most standard treatment. However, the problem with current high-dose IVIG therapy is that it is inefficient for both patients and cost because it contains ineffective parts and requires a high total dose. It has recently been reported that sialic acid in the fragment crystallizable (Fc) region has an anti-inflammatory effect. Hypothesis: In the KD model, a small amount of sialic acid-rich (SR-)Fc has an anti-inflammatory effect equivalent to that of high-dose IVIG. Methods: A Candida albicans cell wall extract (CAWE)-induced KD-like vasculitis model was established in DBA/2 mice. IgG, antigen-binding fragment (Fab), and Fc with 2g/kg/0.5ml, and IgG, SR-IgG, and SR-Fc with 0.2g/kg/0.5ml, and placebo 0.5ml were administered intraperitoneally 3 times every other day (n=5, respectively). Four weeks after treatment, we compared the incidence of CA inflammation between each group. Histological analysis was performed by using a quantified scoring system: grade 1; 100cels/HPF, grade 4; distraction of elastic lamina, grade 5; neointimal proliferation. Results: All five mice in placebo group had the infiltration grade 3 or higher (100%), whereas none of the mice in IgG group had the infiltration (0%). In Fab group, three out of four had the infiltration (75%, one mouse died), whereas in Fc group, only one out of five had the infiltration (20%). In one-tenth dose IgG group, two out of four had the infiltration (50%, one mouse died), whereas in one-tenth dose SR-IgG and SR-Fc group, 20% or less of them had the infiltration (one out of five, zero out of five, respectively). Treatment with one-tenth dose SR-IgG and SR-Fc significantly suppressed CAWE-induced vasculitis ( p Conclusions: It was shown that the immunoglobulin effect was mainly in the Fc region and one-tenth dose SR-Fc had an anti-inflammatory effect equivalent to that of high-dose IgG in a Candida -induced KD mouse model. One-tenth doses SR-Fc may be an alternative treatment to high-dose IVIG in KD patients.

A newborn screening program for Pompe disease using dried blood spots (DBSs) was initiated in Japan. Here, we summarized this screening program and described the results of the GAA gene analysis. From April 2013 to November 2016, 103,204 newborns were screened; 71 had low acid alpha-glucosidase (AαGlu) activity. GAA sequencing showed that 32 (45.1%) and 37 (52.1%) of these newborns were homozygous and heterozygous for pseudodeficiency alleles c.[1726G>A; 2965G>A], respectively. Moreover, 24 of 32 newborns with homozygous c.[1726G>A; 2965G>A] alleles had no mutations, and the other eight had one mutation each. Thirty-five of 37 newborns with heterozygous c.[1726G>A; 2965G>A] alleles had one mutation, and the other two had two mutations each. Only one newborn who had two mutations did not harbor c.[1726G>A; 2965G>A] alleles. Thus, it was difficult to distinguish newborns with c.[1726G>A; 2965G>A] alleles from newborns with pre-symptomatic Pompe disease using AαGlu assays in DBSs or fibroblasts; GAA gene sequencing was necessary. Seventy-one newborns had 50 variants, including 21 mutations or predictably pathogenic variants, and 29 polymorphisms or predictably non-pathogenic variants. Four of 21 mutations or predictably pathogenic variants and four of 29 polymorphisms or predictably non-pathogenic variants were novel. No infantile-onset Pompe disease was detected, and three newborns were diagnosed with potential late-onset Pompe disease. In the literature, 156 variants have been reported for 296 patients from 277 families in 41 articles from Japan, Korea, Taiwan, and China. Our results provide insights into GAA gene mutation profiles and the relationship between GAA and Pompe disease in Asian populations.

Background: We describe the oncologic and functional outcomes and the surgical technique of the photodynamic diagnosis (PDD)-assisted en bloc transurethral resection of bladder tumor (EBTUR) using a rectangular cutting loop. Methods: We reviewed 40 patients with carcinoma in situ-free nonmuscle invasive bladder cancer undergoing PDD-TURBT. Of 40 patients, 12 underwent photodynamic diagnosis-assisted en bloc transurethral resection of bladder tumor (PDD-EBTUR) and 28 underwent PDD-assisted conventional TURBT (cTURBT). Two groups were matched in terms of clinicopathologic background and did not include patients treated with intravesical Bacillus Calmette-Guerin. The assessment of postoperative quality of life (QoL) was based on patient-reported outcome measure, including the International Prostate Symptom Score, Functional Assessment of Cancer Therapy-Bladder (FACT-BL), and 8-item Short Form (SF-8™) questionnaires before and 1 month after TUR. This study was approved by the Ethics commitee and all participants provided informed consent. Results: PDD guidance provided substantial help for circumferent demarcation around the bladder tumor, which precedes tumor dissection. One female patient (12%) treated by PDD-EBTUR had grade II bladder perforation requiring prolonged catheterization. Pathologic assessment of horizontal and vertical margins in resected specimens by PDD-EBTUR revealed that all specimens had muscularis propria, and the rate of en bloc resection was 100%. No patient had intravesical recurrence in the PDD-EBTUR group (median follow-up, 11 months), while two patients in the PDD-cTURBT group had Ta low-grade recurrent tumors (8 months). Postoperatively, scores of daytime frequency and nocturia were increased in both groups. QoL assessment using the FACT-BL and SF-8 revealed that postoperative deterioration of bladder-specific subscale and emotional/mental scores was found in the EBTUR group but not in the cTURBT group. Conclusions: Based on the initial experience on 12 patients, we considered that PDD-EBTUR is an acceptable surgical method. Further experience and research are mandatory to determine whether this technique yields better outcomes and has true clinical advantage.

Background Tenascin-C (TN-C) is an extracellular matrix glycoprotein related to tissue inflammation. Our previous retrospective study conducted in 2016 revealed that the serum tenascin-C level was higher in patients with Kawasaki disease (KD) who were resistant to intravenous immunoglobulin (IVIG) and developed coronary artery lesions (CALs). The present study is a prospective cohort study to assess if the serum level of tenascin-C could be used as a novel biomarker to predict the risk of resistance to initial treatment for high-risk patients. Methods A total of 380 KD patients were registered and provided serum samples for tenascin-C measurement before commencing their initial treatment. Patients who did not meet the inclusion criteria were excluded from analysis; of the 181 remaining subjects, there were 144 low-risk patients (Kobayashi score: ≤4 points) and 37 high-risk patients (Kobayashi score: ≥5 points). The initial treatments for low-risk patients and high-risk patients were conventional therapy (IVIG with aspirin) and prednisolone combination therapy, respectively. The patient clinical and laboratory data, including the serum tenascin-C level, were compared between initial treatment responders and non-responders. Results In the low-risk patients, there was no significant difference in the median levels of serum tenascin-C between the initial therapy responders and non-responders. However, in the high-risk patients, the median serum tenascin-C level in initial therapy non-responders was significantly higher than that in initial therapy responders (175.8 ng/ml vs 117.6 ng/ml). Conclusions Serum tenascin-C could be a biomarker for predicting the risk of high-risk patients being non-responsive to steroid combination therapy. Trial registration This study was a prospective cohort study. It was approved by the ethics committee of each institute and performed in accordance with the Declaration of Helsinki.

This study aimed to evaluate the concordance of the microbiologic findings of preoperative urine cultures and intraoperative stone cultures in patients undergoing transurethral lithotripsy (TUL). A total of 164 patients treated with TUL for whom preoperative urine cultures and intraoperative stone cultures were performed were included in this study. The preoperative urine cultures were positive in 57 patients (34.8%) and the stone cultures were positive in 58 patients (35.4%). Enterococcus faecalis was the most common organism detected in the intraoperative stone cultures (22. 9%). The concordance rate between the preoperative urine cultures and intraoperative stone cultures was 45.6%. Eleven patients (6.7%) developed a fever of38.5°C postoperatively. Among the 11 patients, 9 patients showed positive preoperative urine cultures and 10 patients showed positive stone cultures. The results of the urine culture performed when the patient had a fever of 38.5°C or higher showed 54.5% consistency with the results of the preoperative urine culture or stone culture. Although the results of the preoperative urine cultures and intraoperative stone cultures may not be highly consistent, these cultures should be actively performed because they provide useful information regarding postoperative infections.

MazF is an endoribonucleolytic toxin that cleaves intracellular RNAs in sequence-specific manners. It is liberated in bacterial cells in response to environmental changes and is suggested to contribute to bacterial survival by inducing translational regulation. Thus, determining the cleavage specificity provides insights into the physiological functions of MazF orthologues. Nitrospira, detected in a wide range of environments, is thought to have evolved the ability to cope with their surroundings. To investigate the molecular mechanism of its environmental adaption, a MazF module from Nitrospira strain ND1, which was isolated from the activated sludge of a wastewater treatment plant, is examined in this study. By combining a massive parallel sequencing method and fluorometric assay, we detected that this functional RNA-cleaving toxin specifically recognizes the AACU, AACG, and AAUU motifs. Additionally, statistical analysis suggested that this enzyme regulates various specific functions in order to resist environmental stresses.

The recent eighth tumor-node-metastasis (TMN) staging system classifies renal cell carcinoma (RCC) with perirenal fat invasion (PFI), renal sinus fat invasion (SFI), or renal vein invasion (RVI) as stage pT3a. However, limited data are available on whether these sites have similar prognostic value or recurrence rate. We investigated the recurrence rate based on tumor size, pathological invasion sites including urinary collecting system invasion (UCSI), and clinically detected renal vein thrombus (cd-RVT) with pT3aN0M0 RCC. We retrospectively reviewed 91 patients with pT3aN0M0 RCC who underwent surgical treatment. Patients with tumor size &gt, 7 cm, UCSI, three invasive sites (PFI + SFI + RVI), and cd-RVT showed a significant correlation with high recurrence rates (hazard ration (HR) 2.98, p = 0.013, HR 8.86, p &lt, 0.0001, HR 14.28, p = 0.0008, and HR 4.08, p = 0.0074, respectively). In the multivariate analysis, tumor size of &gt, 7 cm, the presence of UCSI, and cd-RVT were the independent predictors of recurrence (HR 3.39, p = 0.043, HR 7.31, p = 0.01, HR 5.06, p = 0.018, respectively). In pT3a RCC, tumor size (7 cm cut-off), UCSI, and cd-RVT may help to provide an early diagnosis of recurrence.

Background Transplant renal vein thrombosis (TRVT) is a severe vascular complication and is caused by various factors, including recipient factors, donor factors, immunosuppression regimens, and surgical techniques. Despite adequate interventions, including thrombolytic therapy or surgical thrombectomy, successful salvage of the allograft is often difficult. We observed a case of TRVT induced by compression of the renal vein immediately after intraoperative abdominal closure. Case presentation A 41-year-old male underwent ABO-compatible living kidney transplantation. The donor was his 45-year-old sister, and her right kidney was donated. The allograft had a single artery and vein. One of the preoperative recipient problems was obesity (body mass index, 33.4 kg/m2). Intraoperative Doppler ultrasonography (US) revealed sufficient blood flow throughout the allograft, and urine output was also observed. After surgery, hematuria was observed; the urine output decreased and serum creatinine levels increased to 7.0 mg/dL. Doppler US showed a decrease in diastolic flow and an elevated resistive index, which were similar findings to those noted in acute rejection. Although steroid pulse therapy was initiated, allograft dysfunction was worsening. On postoperative day 4, surgical exploration revealed TRVT; consequently, thrombectomy was performed. The urine output increased, and serum creatinine levels decreased to 1.8 mg/dL. The cause of TRVT development may be that the transplant renal vein was relatively short, due to the right kidney being compressed by surrounding tissues after abdominal closure, and that TRVT was gradually developing due to stagnant blood flow. Conclusion Although TRVT is induced by multiple factors, an accurate diagnosis is often difficult. Understanding these factors, including obesity, and considering TRVT as a cause of allograft dysfunction are important during the pre-, peri-, and postoperative periods. Knowledge of TRVT can lead to early and accurate diagnosis and intervention, resulting in better outcomes for the patients with allograft dysfunction.

Background Abnormalities in the number of vessels can be found for both the umbilical artery and vein. We sometimes encounter cases of a decreased number of umbilical cord vessels, such as a single umbilical artery. In contrast, there may be an increase from three to four vessels within the umbilical cord. A supernumerary umbilical vein is particularly very rare, and it is generally found in combination with congenital anomalies. We report a case of a partial supernumerary umbilical vein. Case presentation The previous pregnancy of a 37-year-old healthy Japanese woman (gravida 2, para 1) had been uncomplicated, and the resulting child was alive and well. Prenatal examination at 36 weeks of gestation revealed the coexistence of a four-vessel part and a normal three-vessel part of the umbilical cord. A healthy female neonate weighing 2726 g was born at 38 weeks of gestation. The umbilical cord measured 40 cm in length; the four-vessel part continued to a distance of 18 cm from the surface of the infant’s body, and the remaining umbilical cord comprised three vessels. On histological examination, the fetal side of the umbilical cord had two arteries and two veins, and the placental side had two arteries and one vein. Isolated supernumerary umbilical veins tend to be overlooked. We consider that it is important to evaluate the number of umbilical cord vessels in the second trimester using ultrasound combined with color Doppler in at least three sites: the insertion sites on both the fetal abdomen and placenta, and the free loop of the umbilical cord. Conclusions Prenatal diagnosis of isolated supernumerary umbilical cord vessels tends to be overlooked. However, supernumerary vessels of the umbilical can be associated with fetal congenital anomalies. The number of vessels within the umbilical cord must be examined because the detection of such abnormalities may lead to the prenatal diagnosis of other congenital anomalies.

Transforming growth factor-β (TGF-β) is a potent growth inhibitor in normal epithelial cells. However, a number of malignant tumors produce excessive amounts of TGF-β, which affects the tumor-associated microenvironment by furthering the progression of tumorigenicity. Although it is known that the tumor-associated microenvironment often becomes hypoxic, how hypoxia influences TGF-β signaling in this microenvironment is unknown. We investigated whether TGF-β signaling is influenced by long-term exposure to hypoxia in Lewis lung carcinoma (LLC) cells. When the cells were exposed to hypoxia for more than 10 days, their morphology was remarkably changed to a spindle shape, and TGF-β-induced Smad2 phosphorylation was enhanced. Concomitantly, TGF-β-induced transcriptional activity was augmented under hypoxia, although TGF-β did not influence the activity of a hypoxia-responsive reporter. Consistently, hypoxia influenced the expression of several TGF-β target genes. Interestingly, the expressions of TGF-β type I receptor (TβRI), also termed activin receptor like kinase-5 (ALK5), and TGF-β1 were increased under the hypoxic condition. When we monitored the hypoxia-inducible factor-1 (HIF-1) transcriptional activity by use of green fluorescent protein governed by the hypoxia-responsive element in LLC cells transplanted into mice, TGF-β-induced Smad2 phosphorylation was upregulated in vivo. Our results demonstrate that long-term exposure to hypoxia might alter responsiveness to TGF-β signaling and affected the malignancy of LLC cells.

Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. Some anthracyclines are known to be NS3 helicase inhibitors and have a hydroxyanthraquinone moiety in their structures, mitoxantrone, a hydroxyanthraquinone analogue, is also known to inhibit NS3 helicase. Therefore, we hypothesized that the hydroxyanthraquinone moiety alone could also inhibit NS3 helicase. Here, we performed a structure–activity relationship study on a series of hydroxyanthraquinones by using a fluorescence-based helicase assay. Hydroxyanthraquinones inhibited NS3 helicase with IC50 values in the micromolar range. The inhibitory activity varied depending on the number and position of the phenolic hydroxyl groups, and among different hydroxyanthraquinones examined, 1,4,5,8-tetrahydroxyanthraquinone strongly inhibited NS3 helicase with an IC50 value of 6 µM. Furthermore, hypericin and sennidin A, which both have two hydroxyanthraquinone-like moieties, were found to exert even stronger inhibition with IC50 values of 3 and 0.8 µM, respectively. These results indicate that the hydroxyanthraquinone moiety can inhibit NS3 helicase and suggest that several key chemical structures are important for the inhibition.

The detection of carcinoma in situ (CIS) is essential for the management of high-risk non-muscle invasive bladder cancers. Here, we focused on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) combined with photodynamic diagnosis (PDD) for the detection of CIS. A total of 45 patients undergoing pre-surgical DCE-MRI and PDD-assisted endoscopic surgery accompanied by biopsies of the eight segmentations were analyzed. Immunohistochemical analysis of the biopsies revealed hypervascularity of CIS lesions, a cause of strong submucosal contrast-enhancement. It was found that 56 (16.2%) of 344 biopsies had pathologically proven CIS. In the DCE-MRI, the overall sensitivity and specificity for detecting CIS were 48.2% and 81.9%, respectively. We set out two different combinations of PDD and DCE-MRI for detecting CIS. Combination 1 was positive when either the PDD or DCE-MRI were test-positive. Combination 2 was positive only when both PDD and DCE-MRI were test-positive. The overall sensitivity of combinations 1 and 2 were 75.0% and 37.5%, respectively (McNemar test, vs PDD alone, p = 0.041 and p &lt, 0.001, respectively). However, the specificity was 74.0% and 91.7%, respectively (vs PDD alone, both p &lt, 0.001). Our future goal is to establish &lsquo, MRI-PDD fusion transurethral resction of the bladder tumor (TURBT), which could be an effective therapeutic and diagnostic approach in the clinical management of high-risk disease.

Microbes are known to withstand environmental stresses by using chromosomal toxin–antitoxin systems. MazEF is one of the most extensively studied toxin–antitoxin systems. In stressful environments, MazF toxins modulate translation by cleaving single‐stranded RNAs in a sequence‐specific fashion. Previously, a chromosomal gene located at DR0417 in Deinococcus radiodurans was predicted to code for a MazF endoribonuclease (MazFDR 0417); however, its function remains unclear. In the present study, we characterized the molecular function of MazFDR 0417. Analysis of MazFDR 0417‐cleaved RNA sites using modified massively parallel sequencing revealed a unique 4‐nt motif, UACA, as a potential cleavage pattern. The activity of MazFDR 0417 was also assessed in a real‐time fluorometric assay, which revealed that MazFDR 0417 strictly recognizes the unique tetrad UACA. This sequence specificity may allow D. radiodurans to alter its translation profile and survive under stressful conditions.

Conventional cryptosystems are supposed to be used for the personal communication. However, the secure and effective communication system is more and more required for inter-organization cryptosystem. In this paper, we redefine the inter-organization cryptosystem using the public-key cryptosystem. We also propose an effective scheme of inter-organization cryptosystem using two of the RSA cryptosystems. We then implemented the prototype of the proposed scheme.

Under environmental stress, microbes are known to alter their translation patterns using sequence-specific endoribonucleases that we call RNA interferases. However, there has been limited insight regarding which RNAs are specifically cleaved by these RNA interferases, hence their physiological functions remain unknown. In the current study, we developed a novel method to effectively identify cleavage specificities with massive parallel sequencing. This approach uses artificially designed RNAs composed of diverse sequences, which do not form extensive secondary structures, and it correctly identified the cleavage sequence of a well-characterized Escherichia coli RNA interferase, MazF, as ACA. In addition, we also determined that an uncharacterized MazF homologue isolated from Pseudomonas putida specifically recognizes the unique triplet, UAC. Using a real-time fluorescence resonance energy transfer assay, the UAC triplet was further proved to be essential for cleavage in P. putida MazF. These results highlight an effective method to determine cleavage specificity of RNA interferases.