Urinary bladder metastasis from breast cancer: A rare case report.

Breast cancer is a major contributor to cancer-related morbidity and mortality in women, which is primarily attributed to metastases. Common metastatic sites include the lungs, liver, and bone, whereas bladder metastasis is rare. We report a case of bladder metastasis from breast cancer in a 61-year-old woman, highlighting the challenges in diagnosis and treatment. The patient, previously diagnosed with invasive lobular carcinoma, presented with renal failure and underwent transurethral resection of bladder tumor. Pathological analysis confirmed metastasis from breast cancer. Bladder metastasis from breast cancer demands vigilance and prompt intervention because of its potential prognostic impact.

Iliacus Myositis and Bacteremia Caused by Non-typhoidal Salmonella in a Healthy Adult: A Case Report.

Typically, non-typhoidal Salmonella (NTS) causes gastroenteritis; however, NTS can also lead to extraintestinal manifestations like bacteremia, meningitis, and abscess in vulnerable populations such as children, elderly, and immunocompromised individuals. Extraintestinal manifestations in an immunocompetent patient are uncommon. Here, we report a case of iliacus myositis and bacteremia caused by NTS in a healthy adult. A previously healthy 23-year-old Japanese woman presented to the emergency room due to a one-day history of vomiting, abdominal pain, and diarrhea. She had a fever, and her blood test showed leukocytosis. Computed tomography (CT) of the abdomen and pelvis revealed a thickening of the ascending colon. She was diagnosed with gastroenteritis and treated with antibiotics. Blood culture at that time was negative, but Salmonella serogroup 09 was detected in stool culture. Subsequently, her symptoms improved; however, on day 13, she returned to our hospital complaining of pain in her left thigh. CT scan of the abdomen and pelvis revealed no abscess or muscle inflammation, but due to persistent symptoms, the patient was admitted to the hospital, and antibiotics were initiated. Salmonella serogroup 09 was detected from the blood culture obtained at the time of admission. Magnetic resonance imaging of the hip joint and CT of the abdomen and pelvis after admission revealed inflammation in the left iliacus muscle and an abscess near the left ilium. The patient was treated successfully with antibiotics. This case highlights two findings. First, NTS can cause bacteremia even in a healthy adult with no risk factors for bacteremia. Second, NTS bacteremia can cause complications in an immunocompetent adult. This case implies that even in the case of NTS infection in otherwise healthy individuals, if there are signs of bacteremia or complications, it is essential to conduct blood culture and additional tests.

Human mpox presenting with penile edema and ulcer: A case report.

Human mpox, which has spread worldwide since May 2022, is characterized by symptoms involving the genital area; however, its treatment methods and clinical course are not completely understood. Furthermore, penile swelling in human mpox can be difficult to differentiate from cellulitis and antibiotic use has been reported in such cases. Herein, we report a case of human mpox in Japan with prominent penile swelling and persistent penile ulcers that improved without specific treatment. The patient was a Japanese man in his 20s with a history of having sexual intercourse with men frequently. He visited Tokyo Metropolitan Toshima Hospital because of a fever and rash in the genital area. Physical examination revealed vesicles on the limbs, penile pigmentation, and significant penile swelling and redness. There were no signs of cellulitis and symptomatic treatment was initiated with outpatient follow-up. After 7 days, an improving trend in penile swelling, redness, and pain was observed. However, a partially black skin ulcer with exudate was observed at the left coronal sulcus of the penis. Therefore, the symptomatic treatment was continued. On illness day 28, the penile swelling completely improved; however, the penile ulcer and pain persisted, and the exudate was observed again. By illness day 63, the pain in his anogenital area had disappeared, and the penile skin ulcer had healed. The following observations were noted in this case: (i) human mpox can improve without specific treatment such as tecovirimat administration and (ii) skin lesions in the genital area may change over time.

Bilateral adrenal metastases from renal cell carcinoma after robot-assisted partial nephrectomy.

Renal cell carcinoma often metastasizes to the adrenals; however, bilateral adrenal metastases are rare. We here report a patient with bilateral adrenal metastases from renal cell carcinoma after robot-assisted partial nephrectomy and review relevant published reports. A 64-year-old man underwent robot-assisted partial nephrectomy for a left renal tumor. During follow-up, he was diagnosed with bilateral adrenal metastases. He underwent left adrenalectomy followed by right partial adrenalectomy to preserve adrenal function. The renal tumor later metastasized to other parts of the body. He continues to receive systemic treatment and remains in partial remission. Patients with pT1aN0M0 renal cell carcinoma generally have a favorable prognosis. However, occasional such patients develop multiple metastases. To the best of our knowledge, this is the first reported case of bilateral adrenal metastases after partial nephrectomy. Clinicians should keep this rare scenario in mind.

Effectiveness and Safety of a Mixture of Nobiletin and Tangeretin in Nocturia Patients: A Randomized, Placebo-Controlled, Double-Blind, Crossover Study.

Nobiletin and tangeretin (NoT) are flavonoids derived from the peel of Citrus depressa, and they have been found to modulate circadian rhythms. Because nocturia can be considered a circadian rhythm disorder, we investigated the efficacy of NoT for treating nocturia. A randomized, placebo-controlled, double-blind, crossover study was conducted. The trial was registered with the Japan Registry of Clinical Trials (jRCTs051180071). Nocturia patients aged ≥50 years who presented nocturia more than 2 times on a frequency-volume chart were recruited. Participants received NoT or a placebo (50 mg once daily for 6 weeks), followed by a washout period of ≥2 weeks. The placebo and NoT conditions were then switched. Changes in nocturnal bladder capacity (NBC) were the primary endpoint, and changes in nighttime frequency and nocturnal polyuria index (NPi) were secondary endpoints. Forty patients (13 women) with an average age of 73.5 years were recruited for the study. Thirty-six completed the study, while four withdrew. No adverse events directly related to NoT were observed. NoT had little effect on NBC compared with the placebo. In contrast, NoT significantly changed nighttime frequency by -0.5 voids compared with the placebo (p = 0.040). The change in NPi from baseline to the end of NoT was significant (-2.8%, p = 0.048). In conclusion, NoT showed little change in NBC but resulted in decreased nighttime frequency with a tendency toward reduced NPi.

Trapping and manipulating skyrmions in two-dimensional films by surface acoustic waves.

Skyrmions, topologically stable spin structures with particle-like properties, are promising for spintronics applications such as skyrmion racetrack memory. Though reliable control of skyrmion motion is essential for the operation of spintronics devices, the straight motion of skyrmions along the driving force is in general difficult due to an inevitable transverse force originating from their topology. Here, we propose a method of precise manipulation of skyrmions based on surface acoustic waves (SAWs) propagating in two dimensions. Using two standing SAWs, saddle-shape local potentials like quadrupole ion traps are created to trap skyrmions robustly. Furthermore, by tuning the frequencies of the SAWs, we show that trapped skyrmions not only move in straight lines but also move precisely in any direction in a two-dimensional thin film. These results could be helpful for the future design of spintronics devices based on skyrmions.

Up-regulation of secretory leukocyte protease inhibitor in human samples might have a potential role of predicting prostate cancer recurrence and progression after surgery and hormonal therapy.

Using new castration-resistant prostate cancer (CRPC) cell lines developed from LNCaP cells as a model for CRPC, we searched for novel biomarkers by analyzing the proteins secreted in culture supernatants. The results showed that the levels of secretory leukocyte protease inhibitor (SLPI) in these cell lines were 4.7-6.7 times higher than those secreted in parental LNCaP. Patients with localized prostate cancer (PC) and who expressed SLPI had a significantly lower prostate-specific antigen (PSA) progression-free survival rate than those who did not. Multivariate analysis revealed that SLPI expression was an independent risk factor for PSA recurrence. By contrast, when immunostaining of SLPI was performed on consecutive prostate tissue samples obtained from 11 patients, both in hormone naive (HN) and castration resistant (CR) conditions, only one patient expressed SLPI in the HNPC state; however, four of the 11 patients expressed SLPI in the CRPC state. In addition, two of these four patients were resistant to enzalutamide, and there was a discrepancy between their serum PSA levels and radiographic progression of the disease. These results suggest that SLPI can be a predictor of prognosis in patients with localized PC and disease progression in CRPC patients.

[Evaluation of Patients with Localized Prostate Cancer in whom Long-Term Successful Androgen Deprivation Therapy was Ceased].

We evaluated the clinical course of patients with localized prostate cancer in whom long-term successful androgen deprivation therapy (ADT) was ceased. Study subjects were 24 patients with stage B prostate cancer who were initially treated with ADT for a median duration of 93 months. The median age at the cessation of ADT was 84 years. The median nadir serum prostate specific antigen (PSA) level was 0.022 ng/ml. The median duration of follow-up from the cessation of ADT was 31 months. During follow-up, five patients showed PSA elevation of ≥2 ng/ml from the nadir. Serum testosterone level was tested in 20 patients, and five showed testosterone recovery ≥0.5 ng/ml. Seven patients died from diseases other than prostate cancer, but there were no deaths caused by prostate cancer. This study demonstrated that long-term successful ADT for localized prostate cancer could be ceased with adequate follow-up evaluation.

Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology.

While amyloid-ß lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

Oligonucleotide Synthesis on Porous Glass Resins Containing Activators.

For the advancement of nucleic acid-related research, high-efficiency, low-cost synthesis of high-purity oligonucleotides is necessary. Herein, we introduced hydroxybenzotriazole (HOBt) activators on controlled pore glass resins to improve the efficiency of chain elongation (the synthesis efficiency increased from 48% without an activator to 92% with an activator). In particular, the use of the resin containing 6-trifluoromethyl HOBt with a linker of lauric acid and succinic acid significantly improved the synthesis efficiency for both DNA and RNA syntheses.

A cross-species approach for the identification of Drosophila male sterility genes.

Male reproduction encompasses many essential cellular processes and interactions. As a focal point for these events, sperm offer opportunities for advancing our understanding of sexual reproduction at multiple levels during development. Using male sterility genes identified in human, mouse, and fruit fly databases as a starting point, 103 Drosophila melanogaster genes were screened for their association with male sterility by tissue-specific RNAi knockdown and CRISPR/Cas9-mediated mutagenesis. This list included 56 genes associated with male infertility in the human databases, but not found in the Drosophila database, resulting in the discovery of 63 new genes associated with male fertility in Drosophila. The phenotypes identified were categorized into six distinct classes affecting sperm development. Interestingly, the second largest class (Class VI) caused sterility despite apparently normal testis and sperm morphology suggesting that these proteins may have functions in the mature sperm following spermatogenesis. We focused on one such gene, Rack 1, and found that it plays an important role in two developmental periods, in early germline cells or germline stem cells and in spermatogenic cells or sperm. Taken together, many genes are yet to be identified and their role in male reproduction, especially after ejaculation, remains to be elucidated in Drosophila, where a wealth of data from human and other model organisms would be useful.

Clinical Impact of Detecting Low-Frequency Variants in Cell-Free DNA on Treatment of Castration-Resistant Prostate Cancer.

PURPOSE: Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from patients with CRPC and investigate the clinical utility of detecting variants with variant allele frequency (VAF) below 1%. EXPERIMENTAL DESIGN: This prospective, multicenter cohort study enrolled patients with CRPC eligible for treatment with abiraterone or enzalutamide. We performed targeted sequencing of pretreatment cfDNA and paired leukocyte DNA with molecular barcodes, and ctDNA variants with a VAF ≥0.1% were detected using an in-house pipeline. We investigated progression-free survival (PFS) and overall survival (OS) after different ctDNA fraction cutoffs were applied. RESULTS: One hundred patients were analyzed (median follow-up 10.7 months). We detected deleterious ATM, BRCA2, and TP53 variants even in samples with ctDNA fraction below 2%. When the ctDNA fraction cutoff value of 0.4% was applied, significant differences in PFS and OS were found between patients with and without defects in ATM or BRCA2 [HR, 2.52; 95% confidence interval (CI), 1.24-5.11; P = 0.0091] and TP53 (HR, 3.74; 95% CI, 1.60-8.71; P = 0.0014). However, these differences were no longer observed when the ctDNA fraction cutoff value of 2% was applied, and approximately 50% of the samples were classified as ctDNA unquantifiable. CONCLUSIONS: Detecting low-frequency ctDNA variants with a VAF <1% is important to identify clinically informative genomic alterations in CRPC.

[A Case of Emphysematous Pyelonephritis Complicated by Bacterial Endophthalmitis in which Multidisciplinary Therapy Led to Preservation of the Kidney].

A 49-year-old male with untreated diabetes mellitus type 2 experienced eyesight deterioration and general malaise, and was treated for uveitis and orbital cellulitis. Later, he was taken to a local hospital via ambulance for a consciousness disorder and was diagnosed with bilateral infectious endophthalmitis, a right ureteral stone, and emphysematous pyelonephritis. He was then referred to our hospital for further examination and treatment. We immediately initiated intravenous antibiotic therapy with meropenem and glycemic control with continuous subcutaneous insulin infusion, and placed a ureteral and percutaneous drain tube into the right ureter and the emphysema, respectively. We performed a diagnostic and therapeutic vitrectomy on the patient's left eye. Urinary, blood, and vitreous cultures were positive for Klebsiella aerogenes. Abdominal contrast-enhanced computed tomography showed bilaterally comparable renal contrast enhancement. On the 60th hospital day, we performed endoscopic combined intrarenal surgery (ECIRS) and completely removed the urinary stone. Although he lost light sensitivity in his right eye, his left eyesight improved, and his blood glucose level was adequately managed by oral medication. Three months after the surgery, he was discharged from our hospital and he showed no sign of recurrence of the infection at ten months after surgery.

Predictive factors and radiological findings of adrenohepatic adhesion during laparoscopic adrenalectomy.

Purpose: This retrospective study aimed to identify predictive factors and imaging features of adrenohepatic adhesion found during laparoscopic right adrenalectomy. Materials and Methods: Altogether, 77 patients underwent laparoscopic right adrenalectomy between January 2005 and December 2018. Adrenohepatic adhesion was defined as strict adhesion that required either partial adrenalectomy with coagulation of residual tissue or partial hepatectomy to accomplish complete resection. We assessed their surgical video records to determine if adrenohepatic adhesion was present. Age, sex, body mass index, tumor size, tumor diagnosis and radiological findings (attachment between the liver and the adrenal gland, diameters of the right and left adrenal veins and its ratio) were evaluated as preoperative variables. Results: Adrenohepatic adhesion was present in 11 of the 77 patients (14.3%). Age, sex, and body mass index were not statistically significant factors. Tumor size was significantly small in adhesion group (14.2 mm vs. 25.9 mm, p=0.02). Attachment to the liver and adrenal gland was frequently seen regardless of the adhesion. The mean right/left adrenal veins diameters ratio was significantly lower in the adhesion group (0.8 vs. 1.1, p=0.01). Multivariate logistic regression analysis demonstrated the right/left adrenal veins diameters ratio was the only significant predictor of adhesion. The sensitivity, specificity, negative predictive value and positive predictive value were 0.82, 0.76, 0.43, and 0.95 respectively when the optimal cutoff value for the ratio was 0.9 (area under the curve, 0.75; 95% confidence interval, 0.60-0.90). Conclusions: The right/left adrenal veins diameters ratio was possible predictor of adrenohepatic adhesion.

[A Case of Castration-Resistant Prostate Cancer after Prostatectomy Treated with Resection of A Solitary Metastatic Site].

A 72-year-old man underwent a bilateral nerve-sparing radical retropubic prostatectomy (RRP) with pelvic lymph node dissection 11 years earlier. His prostate specific antigen (PSA) value at diagnosis was 61.024 ng/ml. Bone scans and computed tomographic (CT) scans showed no metastasis. Pathological findings and stage were adenocarcinoma, Gleason score 4+3, positive surgical margin, pT3b, and no lymph node metastasis. The postoperative PSA nadir was 0.218 ng/ml, and salvage radiotherapy (SRT, total 66 Gy) was performed six months after RRP. However, the PSA value continued to rise after SRT. Therefore, androgen deprivation therapy (ADT) was started 11 months after SRT. Nine years postoperatively, the PSA value showed a continuous rise despite ADT, and prostate cancer was considered to be castration-resistant. Although he was taking enzalutamide, his PSA value rose to 18. 271 ng/ml. Repeated bone scans and CT scans were negative. Eleven years after RRP, the fluoro-2-deoxy-D-glucosepositronemissiontomography (FDG-PET) revealed a nodule lesiondorsal to the left pubic bone. The patient underwent a resection of the lesion. Three months after the resection, his PSA level declined to 0.038 ng/ml, thus ADT was discontinued. Thirteen months after the resection, PSA re-elevation was absent, and follow-up without ADT is ongoing.

Comprehensive Exploration of Target-specific Ligands Using a Graph Convolution Neural Network.

Machine learning approaches are widely used to evaluate ligand activities of chemical compounds toward potential target proteins. Especially, exploration of highly selective ligands is important for the development of new drugs with higher safety. One difficulty in constructing well-performing model predicting such a ligand activity is the absence of data on true negative ligand-protein interactions. In other words, in many cases we can access to plenty of information on ligands that bind to specific protein, but less or almost no information showing that compounds don't bind to proteins of interest. In this paper, we suggested an approach to comprehensively explore candidates for ligands specifically targeting toward proteins without using information on the true negative interaction. The approach consists of 4 steps: 1) constructing a model that distinguishes ligands for the target proteins of interest from those targeting proteins that cause off-target effects, by using graph convolution neural network (GCNN); 2) extracting feature vectors after convolution/pooling processes and mapping their principal components in two dimensions; 3) specifying regions with higher density for two ligand groups through kernel density estimation; and 4) investigating the distribution of compounds for exploration on the density map using the same classifier and decomposer. If compounds for exploration are located in higher-density regions of ligand compounds, these compounds can be regarded as having relatively high binding affinity to the major target or off-target proteins compared with other compounds. We applied the approach to the exploration of ligands for ß-site amyloid precursor protein [APP]-cleaving enzyme 1 (BACE1), a major target for Alzheimer Disease (AD), with less off-target effect toward cathepsin D. We demonstrated that the density region of BACE1 and cathepsin D ligands are well-divided, and a group of natural compounds as a target for exploration of new drug candidates also has significantly different distribution on the density map.

Consecutive Prostate Cancer Specimens Revealed Increased Aldo⁻Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer.

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer.

The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (AR T878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.

[A Case of Nivolumab-Induced Isolated Adrenocorticotropic Hormone Deficiency Presenting Dyspnea].

A 66-year-old man had undergone multiple treatments for metastatic renal cell carcinoma, including 11 cycles of nivolumab, which was discontinued because of disease progression. About three weeks after discontinuing nivolumab, he reported suffering from worsening of dyspnea. Pulse oximetry showed no desaturation. His cardiovascular and pulmonary functions were normal. His dyspnea slowly worsened with no underlying diagnosis. Two months after symptoms developed, he was diagnosed with isolated adrenocorticotropic hormone deficiency. His dyspnea disappeared soon after receiving hydrocortisone. Nivolumab-induced isolated adrenocorticotropic hormone deficiency may not present with typical symptoms, and can occur even after discontinuing nivolumab. Cortisol levels should be routinely monitored in patients who receive nivolumab.