MYCBPAP is a central apparatus protein required for centrosome-nuclear envelope docking and sperm tail biogenesis in mice.

The structure of the sperm flagellar axoneme is highly conserved across species and serves the essential function of generating motility to facilitate the meeting of spermatozoa with the egg. During spermiogenesis, the axoneme elongates from the centrosome, and subsequently the centrosome docks onto the nuclear envelope to continue tail biogenesis. Mycbpap is expressed predominantly in mouse and human testes and conserved in Chlamydomonas as FAP147. A previous cryo-electron microscopy analysis has revealed the localization of FAP147 to the central apparatus of the axoneme. Here, we generated Mycbpap knockout mice and demonstrated the essential role of Mycbpap in male fertility. Deletion of Mycbpap led to disrupted centrosome-nuclear envelope docking and abnormal flagellar biogenesis. Furthermore, we generated transgenic mice with tagged MYCBPAP, which restored the fertility of Mycbpap knockout males. Interactome analyses of MYCBPAP using Mycbpap transgenic mice unveiled binding partners of MYCBPAP including central apparatus proteins such as CFAP65 and CFAP70 that constitute the C2a projection and centrosome-associated proteins such as CCP110. These findings provide insights into a MYCBPAP-dependent regulation of the centrosome-nuclear envelope docking and sperm tail biogenesis.

Association between serum testosterone changes and parameters of the metabolic syndrome.

Testosterone production is important in males, and various physical and psychological abnormalities occur in individuals with low testosterone levels. In the present study, we aimed to examine the effects of longitudinal changes in total testosterone levels in the same cohort. We included 178 male subjects who visited our hospital multiple times between 2018 and 2023 for medical checkups for at least 3 years. The median baseline age and total testosterone level (TT) of the cohort were 61 years and 4.74 ng/mL, respectively. The patients were divided into four groups based on the difference in TT (ΔTT) between baseline and last visit (Q1, n = 45; Q2, n = 45; Q3, n = 44; Q4, n = 44). ΔTT values ranged from -3.07 to -0.78 ng/mL in Q1, from -0.75 to -0.05 ng/mL in Q2, from -0.03 to 0.73 ng/mL in Q3, and from 0.75 ng/mL to 3.4 ng/mL in Q4. The median ΔTT were -1.22 for Q1, -0.35 for Q2, +0.19 for Q3, and +1.43 for Q4. Decreased TT tended to increase body weight, body mass index, waist circumference, and visceral fat (p for trend 0.0136, 0.0272, 0.0354, and 0.0032, respectively), and decrease adiponectin level (p for trend 0.0219). Herein, we found that decreased TT increases visceral fat and decreases adiponectin levels.

KEAP1-NRF2 system regulates age-related spermatogenesis dysfunction.

Purpose: The average fatherhood age has been consistently increasing in developed countries. Aging has been identified as a risk factor for male infertility. However, its impact on various mechanisms remains unclear. This study focused on the KEAP1-NRF2 oxidative stress response system, by investigating the relationship between the KEAP1-NRF2 system and age-related changes in spermatogenesis. Methods: For examination of age-related changes, we used 10-, 30-, 60-, and 90-week-old mice to compare sperm count, sperm motility, and protein expression. For assessment of Keap1 inhibition, 85-week-old C57BL/6J mice were randomly assigned to the following groups: control and bardoxolone methyl (KEAP1 inhibitor). Whole-exome sequencing of a Japanese cohort of patients with non-obstructive azoospermia was performed for evaluating. Results: Sperm count decreased significantly with aging. Oxidative stress and KEAP1 expression in the testes were elevated. Inhibition of KEAP1 in aging mice significantly increased sperm count compared with that in the control group. In the human study, the frequency of a missense-type SNP (rs181294188) causing changes in NFE2L2 (NRF2) activity was significantly higher in patients with non-obstructive azoospermia than in healthy control group. Conclusions: The KEAP1-NRF2 system, an oxidative stress response system, is associated with age-related spermatogenesis dysfunction.

[A Case of Primary Adenocarcinoma Mucinous Subtype of the Bladder].

A 48-year-old man who presented with asymptomatic gross hematuria in July 202X had been followed up without treatment. In January 202X, he was referred to our department due to the exacerbation of his hematuria. Contrast-enhanced magnetic resonance imaging revealed bladder cancer suggested bilateral seminal vesicle and prostate invasion, and enlarged right internal and external iliac lymph nodes. The pathological diagnosis was mucinous bladder adenocarcinoma. Prostate biopsy results were negative. Upper and lower gastrointestinal examinations were unremarkable. We suspected bladder cancer cT4aN2M0. In March 202X＋1, the patient underwent robotic-assisted laparoscopic total bladder resection, pelvic lymph node dissection, and intracorporeal urinary tract modification (ileal conduit creation). The final diagnosis was primary mucinous adenocarcinoma pT4aN2M0 of the bladder. Given the heightened risk of recurrence, the patient was administered a three-month course of oxaliplatin and capecitabine (XELOX) as adjuvant postoperative chemotherapy. The patient remains free of progression at 8 months postoperatively. Adenocarcinoma of the bladder is an exceedingly rare entity, with no established chemotherapeutic protocols. Primary mucinous adenocarcinoma of the bladder is even more exceptional. Presently, only regimens similar to those for colorectal cancer or adenocarcinoma of unknown primary, including 5-fluorouracil, are considered. In our particular case, we elected to pursue XELOX therapy, aligning with the principles governing the management of colorectal cancer.

Pre-treatment metastatic growth rate is associated with clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been approved for the treatment of metastatic renal cell carcinoma (mRCC). However, the response rate is still limited, and it is urgent to pursue novel and concise markers of responses to ICIs that allow the determination of clinical benefits. Recently, it was reported that the metastatic growth rate (MGR) is an independent factor associated with clinical outcome for anticancer therapy in some types of cancer. METHODS: We investigated pre-treatment MGR before starting nivolumab for mRCC patients between September 2016 to October 2019. In addition, we examined clinicopathological factors including MGR and analyzed the correlation between pre-treatment MGR and clinical efficacy of nivolumab. RESULTS: Of all patients, the median age was 63 years (range, 42-81), and the median observation period was 13.6 months (range, 1.7-40.3). Twenty-three patients and sixteen patients were classified as the low and the high MGR group, respectively, with the cutoff value of 2.2 mm/month. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients in the low MGR group (p = 0.005 and p = 0.01). Importantly, in multivariate analysis, only the high MGR was significantly associated with a decrease of PFS (Hazard ratio (HR): 2.69, p = 0.03) and OS (HR: 5.27, p = 0.02). CONCLUSIONS: Pre-treatment MGR may serve as the simple and valid indicator obtained from imaging studies, and the prominent surrogate marker associated with OS and PFS in mRCC patients treated with nivolumab.

[A Case of Retroperitoneal Primary Castleman's Disease which was Difficult to Differentiate from Liposarcoma].

A 38-year-old man had a right lower retroperitoneal mass found by abdominal echography in a medical examination, and he consulted the internal medicine of Sumitomo Hospital. On the suspicion of malignant lymphoma, he received a laparotomy with biopsy. Pathological examination revealed that the tumor was either benign lymphadenopathy or low-grade malignant lymphoma, and he was follow-up. Two years later, he was introduced to our department because the follow-up computed tomography revealed signs of a tumor and a mass of adjunctive adipose tissue that increased markedly. Thus, we suspected that the tumor was liposarcoma before the operation, and performed retroperitoneal tumor resection. However, we found that the tumor was pathologically a hyaline vascular type of Castleman's disease and the pathological examination showed no malignant cells in the peritumoral adipose tissue. Since Castleman's disease lacks the characteristic symptoms or image findings, the preoperative diagnosis is generally difficult. Cases with growth of the peritumoral adipose tissue are rare, and the differentiation from the liposarcoma is usually difficult. We discussed how to perform the differential diagnosis of Castleman's disease, and especially about the differential diagnosis of liposarcoma.

[A Case of Androgen Insensivity Syndrome with a Seminoma in the Abdominal Undescended Testis].

A 48-year-old female was referred to our hospital for further urological examination of primary amenorrhea. She had been suffering from amenorrhea since 12 years old. Although she had normal female external genitalia, she had a blind-ended vagina with complete absence of the uterus.Laboratory tests showed high testosterone level and the 46 XY karyotype. Thus, our diagnosis was androgen insensivity syndrome. Magnetic resonance imaging showed bilateral intra-abdominal testes. We performed laparoscopic bilateral gonadalectomy. Pathological diagnosis was seminoma in the right gonad. She is free of recurrence 6 months after operation.

[A Case of Bilateral Adrenal Incidentaloma in which MTX-Related Lymphoproliferative Disease Could Be Diagnosed by Computed Tomography-Guided Biopsy and MTX Administration History].

The patient was a 76-year-old man. Because bilateral adrenal tumor (right adrenal gland 7 cm, left adrenal gland 1.5 cm) was detected in by computed tomography (CT) in methotrexate (MTX) administration for articular rheumatism from 2011, he was referred to this hospital in February, 2016. An endocrine examination, and imaging study did not lead to a definitive diagnosis and CT-guided lower needle biopsy was performed. The pathological diagnosis was diffuse large B cell lymphoma. Also, in situ hybridization revealed EBER-positive and the diagnosis of MTX-related lymphoproliferative disease (MTXLPD) was made in conjunction with the medical history. After MTX cancellation, the tumor became markedly smaller. The annual incidence of this disorder in the RA patients during MTX internal use is reported as 0.06%. According to the site of origin, lymphatic extranodal disease accounts for approximately half of the cases, but this is the third case of primary adrenal origin reported.

Multimodal therapy including robot-assisted radical cystoprostatectomy for locally advanced prostate cancer with bladder and ureteral invasion: A case report.

Introduction: It remains unclear whether robot-assisted radical cystoprostatectomy for locally advanced prostate cancer represents excessive treatment. Case presentation: A 58-year-old man presented with urinary retention and renal failure. Prostate-specific antigen level was 38.07 ng/mL and computed tomography scans revealed bilateral hydronephrosis due to prostate enlargement. Prostate biopsy revealed a Gleason score of 5 + 5 adenocarcinoma, and bilateral hydronephrosis persisted even after urethral catheter placement. We diagnosed locally advanced prostate cancer with bladder and ureteral invasion. Percutaneous bilateral nephrostomy was performed, and neoadjuvant hormone therapy was initiated. Four months after the start of hormone therapy, robot-assisted radical cystoprostatectomy and an intracorporeal ileal conduit were performed, followed by adjuvant radiation therapy for lymph node metastasis. Seven months after the surgery, the patient was free of disease with prostate-specific antigen level <0.03 ng/mL. Conclusion: Robot-assisted radical cystoprostatectomy can be an effective multimodal therapy for locally advanced prostate cancer with bladder and ureteral invasion by locally advanced prostate cancer.

[OUTCOME OF BLADDER PRESERVATION USING LOW DOSE CHEMORADIATION THERAPY IN PATIENTS WITH LOCALLY INVASIVE BLADDER CANCER].

(Purpose) We investigated the outcome of selective organ preservation in invasive bladder cancer using chemoradiation therapy. (Patients and method) We examined locally invasive bladder cancer in 60 patients (51 men, 9 women; mean age at treatment 66.1 years) who underwent chemoradiation therapy for bladder preservation in the Department of Urology at Sumitomo Hospital between 2000 and 2015. The clinical stage was T1, T2, T3 and T4 in 4, 24, 17, 4 patients. Our protocol includes transurethral resection of the bladder tumor (TURBT) and 46 Gy radiation (2 Gy/fraction) to the bladder with concurrent cisplatin chemotherapy (20 mg/body/day, 10 days, intravenously). The initial evaluation included urine cytology and transurethral bladder biopsy. If patients developed superficial residual or recurrent cancer, they were treated with TURBT and/or intravesical Bacillus Calmette-Guerin (BCG), while patients with invasive residual or recurrent cancer were advised to undergo a salvage cystectomy. The mean follow-up was 55 months. (Results) The first assessment after the chemoradiation therapy showed that the complete remission rate for evaluable cases was 72% (38/53) and bladder preservation was achieved in 56 patients (93%). The 1-, 3-, and 5-year overall survival rate was 95, 86, and 78%, respectively. The 1-, 3-, and 5-year cancer-specific survival rate was 97, 90, and 85%, respectively. The 5-year patient survival rate with an intact bladder was 68%. Hydronephrosis and cisplatin dose (<200 mg) were independent adverse factors of overall survival in a Cox model (HR 4.5 and 4.1, respectively). (Conclusions) Chemoradiation therapy for invasive bladder cancer can achieve similar survival rate to those in patients treated with radical cystectomy, and enable the majority of patients to preserve the bladder.

[A CASE THAT TS-1+CDDP THERAPY WAS EFFECTIVE FOR BLADDER PRIMARY SIGNET RING CELL ADENOCARCINOMA].

Since we experienced a case that S-1+Cisplatin (CDDP) therapy was effective for bladder primary signet ring cell adenocarcinoma of pT4N0M0, we report here the time course of its pathophysiology and the treatment of that patient, and discuss the justification of the chemotherapy for the T4 case with the comparison of the previous cases. The present case is a 66 years old man. Because he was aware of the urinary frequency and the sense of incongruity at abdominal region for approximately three months, he visited our hospital for the consultation of his symptoms in July, 2015. The anterior wall showed a torose lesion by cystoscopy from the left sidewall, and we found the histopathology signet ring cell adenocarcinoma after transurethral resection of the bladder tumor. As a result of thorough investigation of thoracic abdominal CT, whole body PET-CT and endoscopy of the upper gastrointestinal tract, we diagnosed it as bladder primary signet ring cell adenocarcinoma with cT3N0M0. Consequently, we tried total cystectomy in August, 2015, however both bladder and pelvic wall were adhered strongly each other; we gave up the total cystectomy and changed the strategy to the urinary diversion by bilateral ureterocutaneous fistula. A biopsy of the adhesion site of the right pelvic wall showed the invasion of the signet ring cell adenocarcinoma, which enabled us to diagnose as pT4bN0M0. Therefore, we performed the chemotherapy with the S-1+CDDP for 12 courses, 16 months from August, 2015 after the surgery. After the initiation of the chemotherapy, the tumor marker was tended to decrease for eight months, but turned to increase thereafter. Because there was no evidence for neither distant nor lymph node metastases of tumor revealed by CT and the MRI, we diagnosed it as Stable Disease at least by CT and MRI examinations for 16 months. The major side-effects were not found during the strengthened chemotherapy without the recurrence until January, 2017. Since this case is very rare, we report the time courses and treatment strategy of a patient with bladder primary signet ring cell adenocarcinoma.