Cancer-associated point mutations within the extracellular domain of PTPRD affect protein stability and HSPG interaction.

PTPRD, a well-established tumor suppressor gene, encodes the protein tyrosine phosphatase-type D. This protein consists of three immunoglobulin-like (Ig) domains, four to eight fibronectin type 3 (FN) domains, a single transmembrane segment, and two cytoplasmic tandem tyrosine phosphatase domains. PTPRD is known to harbor various cancer-associated point mutations. While it is assumed that PTPRD regulates cellular functions as a tumor suppressor through the tyrosine phosphatase activity in the intracellular region, the function of its extracellular domain (ECD) in cancer is not well understood. In this study, we systematically examined the impact of 92 cancer-associated point mutations within the ECD. We found that 69.6% (64 out of 92) of these mutations suppressed total protein expression and/or plasma membrane localization. Notably, almost all mutations (20 out of 21) within the region between the last FN domain and transmembrane segment affected protein expression and/or localization, highlighting the importance of this region for protein stability. We further found that some mutations within the Ig domains adjacent to the glycosaminoglycan-binding pocket enhanced PTPRD's binding ability to heparan sulfate proteoglycans (HSPGs). This interaction is proposed to suppress phosphatase activity. Our findings therefore suggest that HSPG-mediated attenuation of phosphatase activity may be involved in tumorigenic processes through PTPRD dysregulation.

Perioperative changes in ganglioside monosialodihexosylganglioside (GM3) molecular species for benign prostatic hyperplasia: a preliminary report.

Benign prostatic hyperplasia (BPH) progresses with age and is associated with chronic inflammation. We focused on the relationship between BPH and ganglioside monosialodihexosylganglioside (GM3), a sialic acid-containing glycosphingolipid that is involved in chronic inflammation. GM3 molecular species would have a significant role in regulating inflammatory processes. In this prospective study, preoperative and postoperative serum samples were obtained from patients who underwent holmium laser enucleation of the prostate (HoLEP) for BPH. Preoperative and postoperative measurements of serum GM3 species were performed one month before and three months after HoLEP. Twenty-three patients were included in the study. The average patient age was 75 years, and the average prostate volume was 66 mL. The average weight of the surgically resected prostate tissue was 42 g. At three months after HoLEP, the serum concentration of GM3 species was found to have decreased after HoLEP compared with the preoperative concentration of GM3 species. Six GM3 species such as d18:1-17:0 [C17 acyl chain (-17:0) linked to a C18 sphingosine base with a double bond (d18:1-) by an amide linkage], were significantly reduced. The sample size was small; therefore, this study showed only preliminary results and could not evaluate prostate tissue inflammation. This study showed that the serum concentrations of several GM3 species, which indicate chronic inflammation, may be significantly reduced after BPH surgery.

Sialidase NEU3 Contributes to the Invasiveness of Bladder Cancer.

Bladder cancer is the 10th most commonly diagnosed cancer worldwide. The current standard treatment for advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. However, the response rate to chemotherapy is only 50%, owing to cisplatin resistance, and there is a need for novel therapies. Because the invasiveness of bladder cancer greatly influences patient prognosis, a mechanistic analysis of the invasive function can lead to therapeutic targets. Sialidases, which remove sialic acid residues from the nonreducing ends of sugar chains and catalyze the initial reaction in the degradation of sugar chains, are predicted to be involved in cell invasion and motility. However, the involvement of sialidases in bladder cancer, especially their relationship with the invasive ability, remains unclear. Here, using patient tissues and multiple bladder cancer cell lines, we show that the sialidase NEU3 is highly expressed in bladder cancer. Analysis of NEU3's function using its siRNA-mediated knockdown revealed that NEU3 contributes to bladder cancer invasiveness. Mechanistic analysis showed that NEU3 activates ERK and PI3K signaling. Our results show that NEU3 is involved in the malignancy of bladder cancer, and its suppression may lead to novel treatments for bladder cancer.

Catfish Egg Lectin Enhances the Cytotoxicity of Sunitinib on Gb3-Expressing Renal Cancer Cells.

Metastatic renal cell carcinoma (RCC) is not sufficiently responsive to anticancer drugs, and thus, developing new drugs for advanced RCC remains vital. We previously reported that the treatment of globotriaosylceramide (Gb3)-expressing cells with catfish (Silurus asotus) egg lectin (SAL) increased the intracellular uptake of propidium iodide (PI) and sunitinib (SU). Herein, we investigated whether SAL pretreatment affects the intracellular uptake and cytotoxic effects of molecular-targeted drugs in RCC cells. We analyzed Gb3 expression in TOS1, TOS3, TOS3LN, and ACHN human RCC cells. Surface Gb3 expression was higher in TOS1 and TOS3 cells than in TOS3LN and ACHN cells. In the PI uptake assay, 41.5% of TOS1 cells and 21.1% of TOS3 cells treated with SAL were positive for PI. TOS1 cell viability decreased to 70% after treatment with 25 µM SU alone and to 48% after pretreatment with SAL (50 µg/mL). Time-series measurements of the intracellular fluorescence of SU revealed significantly enhanced SU uptake in SAL-treated TOS1 cells compared to control cells. SAL treatment did not increase PI uptake in normal renal cells. Our findings suggest that adequate cytotoxic activity may be achieved even when SU is administered at a sufficiently low dose not to cause side effects in combination with SAL.

Cell migration is impaired in XPA-deficient cells.

Xeroderma pigmentosum (XP) is a hereditary disorder characterized by photosensitivity, predisposition to skin cancers, and neurological abnormalities including microcephaly and progressive neurodegeneration. A lack of nucleotide excision repair (NER) in patients with XP can cause hypersensitivity to the sun, leading to skin cancer, whereas the etiology of the neuronal symptoms of XP remains ambiguous. There are various neurological disorders that perturb neuronal migration, causing mislocalization and disorganization of the cortical lamination. Here, we investigated the role of the XP group-A (Xpa) gene in directed cell migration. First, we adopted an in utero electroporation method to transduce shRNA vectors into the murine embryonic cerebral cortex for the in vivo knockdown of Xpa. Xpa-knockdown neurons in the embryonic cerebral cortex showed abnormal cell migration, cell cycle exit, and differentiation. The genotype-phenotype relationship between the lack of XPA and cell migration abnormalities was confirmed using both a scratch assay and time-lapse microscopy in XP-A patient-derived fibroblasts. Unlike healthy cells, these cells showed impairment in overall mobility and the direction of motility. Therefore, abnormal cell migration may explain neural tissue abnormalities in patients with XP-A.

Congenital Palmar Duplication of the Index Finger: Ventral Polydactyly With Ventral Dimelia.

This report describes the case of a 10-month-old boy who presented with a duplicated index finger enveloped by palmar skin on the palmar side of the first web of the left hand. He was healthy without any other abnormalities except the hand anomaly. Surgical resection of the extra finger was performed with triangular flap at 15 months of age. The resected finger was composed of only palmar components: skin without nail or hair; flexor tendons; and digital nerves branching from the median nerve. Histological examination of the specimen demonstrated similar structures on both palmar and dorsal sides, that is, ridged, hairless, and glabrous skin with a high number of epithelial layers and thick corneous stratum and similar shaped tendons inserted into the symmetrical phalanx. This appears to be the first report in literature of an ectopic palmar index finger, a ventral polydactyly with ventral dimelia.

Novel quantitative software for automatically excluding red bone marrow on whole-body magnetic resonance imaging in patients with metastatic prostate cancer: A pilot study.

OBJECTIVES: To establish a novel quantitative method that automatically excludes the red bone marrow and accurately quantifies the tumor volume on whole-body magnetic resonance imaging using updated imaging software. To also evaluate the association between the quantified tumor volume and the prognosis of patients with metastatic prostate cancer. METHODS: This prospective analysis included patients diagnosed with metastatic hormone-sensitive or metastatic castration-resistant prostate cancer between 2017 and 2022. We developed an imaging software (Attractive BD_Score) that analyzed whole-body diffusion-weighted and in-phase and opposed-phase T1-weighted images to automatically exclude the red bone marrow. The quantified tumor volume was compared with that quantified by traditional whole-body diffusion-weighted imaging without red bone marrow exclusion. Prostate-specific antigen progression-free survival, time-to-pain progression, and overall survival were evaluated to assess the prognostic value of the quantified tumor volume. RESULTS: The quantified tumor volume was significantly smaller than that quantified by the traditional method in metastatic hormone-sensitive (median: 81.0 ml vs. 149.4 ml) and metastatic castration-resistant (median: 29.4 ml vs. 63.5 ml) prostate cancer. A highly quantified tumor volume was associated with prostate-specific antigen progression-free survival (p = 0.030), time-to-pain progression (p = 0.003), and overall survival (p = 0.005) in patients with metastatic hormone-sensitive prostate cancer and with poor prostate-specific antigen progression-free survival (p = 0.001) and time-to-pain progression (p = 0.005) in patients with metastatic castration-resistant prostate cancer. CONCLUSIONS: Our imaging method could accurately quantify the tumor volume in patients with metastatic prostate cancer. The quantified tumor volume can be clinically applied as a new prognostic biomarker for metastatic prostate cancer.

Early distribution of18 F-labeled AAV9 vectors in the cerebrospinal fluid after intracerebroventricular or intracisternal magna infusion in non-human primates.

BACKGROUND: The delivery of adeno-associated virus (AAV) vectors via the cerebrospinal fluid (CSF) has emerged as a valuable method for widespread transduction in the central nervous system. Although infusion into the cerebral ventricles is a common protocol in preclinical studies of small animals, the cisterna magna has been recognized as an alternative target for clinical studies because it can be reached in a less invasive manner using an intrathecal catheter via the subarachnoid space from a lumbar puncture. METHODS: We evaluated the early distribution of fluorine-18-labeled AAV9 vectors infused into the lateral ventricle or cisterna magna of four non-human primates using positron emission tomography. The expression of the green fluorescent protein was immunohistochemically determined. RESULTS: In both approaches, the labeled vectors diffused into the broad arachnoid space around the brain stem and cervical spinal cord within 30 min. Both infusion routes efficiently transduced neurons in the cervical spinal cord. CONCLUSIONS: For gene therapy that primarily targets the cervical spinal cord and brainstem, such as amyotrophic lateral sclerosis, cisterna magna infusion would be a feasible and effective administration method.

Survey of Areas Underserved by Plastic Surgery in Japan.

Background In Japan, there is a large regional disparity in plastic surgery availability. In order for plastic surgery to be widely available for all citizens, it is essential for at least one plastic surgery facility to be located in each secondary medical zone. Methods Using the Japan Society of Plastic and Reconstructive Surgery homepage and some databases, we extracted data on secondary medical zones that do not have a plastic surgery facility. The national and regional coverage rates were calculated. The coverage rate for each group divided by the degree of population concentration was also calculated. Results We found that 147 of 344 secondary medical zones did not have a plastic surgery facility, and the area coverage rate was found to be 57.27% nationwide. The coverage rate in terms of population was 87.07% (correlation coefficient of area and population coverage = 0.983). The area coverage rates in Hokkaido-Tohoku, Kanto, Chubu, Kansai, Chugoku-Shikoku, and Kyushu-Okinawa districts were 47.46, 72.15, 76.47, 62.79, 52.08, and 32.81%, respectively. The corresponding population coverage rates were 79.92, 91.62, 94.27, 90.59, 80.68, and 69.54%, respectively. The area coverage rates in metropolitan areas, provincial cities, and rural areas were 98.08, 75.90, and 15.87%, respectively. In contrast, the area coverage rate of dermatology was 62.79% and that of orthopaedics was 97.09%. Conclusion Unfortunately, it is estimated that more than 40% of secondary medical zones are underserved by plastic surgery, and 13% of the population is not able to fully benefit from this specialty in Japan.

Importance of considering interest in sex when evaluating satisfaction after robot-assisted radical prostatectomy.

OBJECTIVES: To assess the impact of patients' interest in sex on the satisfaction after robot-assisted radical prostatectomy, longitudinal changes of urinary and sexual functions and bothers were evaluated. METHODS: A total of 101 patients underwent robot-assisted radical prostatectomy in our institution. Based on sexual interest, they were divided into the high-interest and low-interest groups. Overall satisfaction, urinary function, urinary bother, sexual function, and sexual bother were evaluated using the expanded prostate cancer index composite questionnaire preoperatively and at 1, 3, 6, and 12 months after robot-assisted radical prostatectomy. We investigated the associations between the overall satisfaction and urinary function/urinary bother/sexual function/sexual bother scores (with higher score indicating better function and less impairment). RESULTS: In the high-interest group (n = 45), satisfaction correlated with high urinary function and urinary bother scores early after robot-assisted radical prostatectomy (urinary function: 1 and 3 months, urinary bother: 3 months postoperatively; P < 0.05) and then with high sexual bother score thereafter (sexual bother at 6 and 12 months after surgery; P < 0.05). Sexual function score did not correlate with satisfaction. In the low-interest group (n = 56), satisfaction correlated with high urinary function and urinary bother scores over time (urinary function: 3 and 6 months, urinary bother: at 3, 6 and 12 months postoperatively; P < 0.05). Neither sexual function nor sexual bother correlated with satisfaction postoperatively in the low-interest group. CONCLUSIONS: The impact of urinary and sexual functions and bothers on patients' overall satisfaction differed between patients with high- and low-interest in sex. The patient's interest in sex should be considered when assessing satisfaction after robot-assisted radical prostatectomy.

Pazopanib-Induced Liver Injury in Patients With Metastatic Renal Cell Carcinoma: A Report of Two Cases.

We report two cases of pazopanib (PAZ)-induced liver injury in patients with metastatic renal cell carcinoma. The first patient was a 70-year-old female who was diagnosed with right renal cell carcinoma and showed tumor embolism in the inferior vena cava. PAZ was started but discontinued after about one month due to a grade four liver injury. The second patient was a 60-year-old male who was diagnosed with left renal cell carcinoma and suspected multiple lung metastases. PAZ was started following a laparoscopic left radical nephrectomy but was stopped after about a month due to a grade three liver injury. We analyzed the plasma PAZ concentrations for treatment evaluation. High plasma PAZ concentrations were observed in both patients after PAZ treatment began. Severe liver injury after PAZ administration may be associated with high plasma PAZ concentrations; hence, we should reduce PAZ dosage early. We also recommend monitoring plasma PAZ concentrations, if possible, so that physicians can either reduce the dosage or discontinue treatment to avoid further liver damage.

Analysis of the circulating myeloid-derived suppressor cells during androgen deprivation therapy for prostate cancer.

INTRODUCTION: The present study showed the involvement of immunosuppressive myeloid-derived suppressor cells during the disease progression in a 69-year-old man with a prostate cancer. CASE PRESENTATION: The patient with metastatic PC (cT4N1M1ab) was initially treated with primary androgen deprivation therapy for 5 months and then chemotherapy with docetaxel, but he expired at the 8th month. In order to investigate whether myeloid-derived suppressor cells are implicated in the cancer exacerbation during androgen deprivation therapy, we assessed the long-term changes in peripheral blood myeloid-derived suppressor cell fractions by using flow cytometry. While prostate-specific antigen levels decreased after androgen deprivation therapy, the population of each myeloid-derived suppressor cell subsets increased during disease deterioration. CONCLUSION: Increase in myeloid-derived suppressor cells populations was correlated with prostate cancer progression.

Use of the SAND balloon catheter for safe and easy laparoscopic removal of adrenal cysts.

INTRODUCTION: Surgical resection should be considered for giant adrenal cysts if they are functional, if malignancy cannot be ruled out, or if there is a risk of bleeding. However, preventing cyst damage, including fluid leak, and ensuring a good field of view could be challenging in laparoscopic surgery. We report on our successful use of the SAND balloon catheter in laparoscopic adrenalectomy. CASE PRESENTATION: The patient was a 40-year-old man with a right adrenal cyst that exhibited growth tendency. We performed laparoscopic adrenalectomy using a SAND balloon catheter through a preexisting port. Use of the catheter allowed for not only aspiration of the cyst fluid without leakage into the operative field but also gentle grasping of the cyst wall, which enabled us to easily remove the adrenal gland, including the cyst. CONCLUSION: Use of the SAND balloon catheter facilitates safe and easy laparoscopic resection of giant adrenal cysts.

Efficacy and safety of holmium laser enucleation of the prostate for elderly patients: surgical outcomes and King's Health Questionnaire.

BACKGROUND: Holmium laser enucleation of the prostate (HoLEP) has been a widely utilized minimally invasive surgical procedure for benign prostate hyperplasia. The current study aimed to compare surgical outcomes and King's Health Questionnaire (KHQ) assessment scores following HoLEP between younger men and those aged ≥75 years. METHODS: This prospective single-center study compared perioperative complications, postoperative urinary conditions, and KHQ scores (nine categories) between men aged ≥75 years (group A) and men aged <75 years (group B) before and 1, 3, and 6 months after surgery. RESULTS: A total of 100 patients were included for analysis (group A, n=38 and group B, n=62). No differences in patient backgrounds, perioperative complications, such as perioperative decrease in hemoglobin, postoperative fever, postoperative indwelling catheterization duration, or postoperative hospitalization duration, and KHQ were observed between both groups. Both groups showed significantly better International Prostate Symptom Scores, quality of life, maximum urinary flow rate, and postvoid residual volume 1, 3, and 6 months after HoLEP compared to their respective preoperative levels (P<0.01). Regarding KHQ categories, both groups showed significantly better general health perceptions, impact on life, emotions, and sleep/energy 1 month after HoLEP; role limitations, physical limitations, and social limitations 3 months after HoLEP; and personal relationships and incontinence severity measures 6 months after HoLEP compared to their respective preoperative levels (P<0.05). CONCLUSIONS: HoLEP could be safe and effective even for men aged ≥75 years, comparing complications, urinary condition, and KHQ scores.

Reduction of fatty liver in rats by nicotinamide via the regeneration of the methionine cycle and the inhibition of aldehyde oxidase.

Nonalcoholic fatty liver disease, which has been rapidly increasing in the world in recent years, is roughly classified into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis. This study was based on our previous reports that stated that the combination treatment of N1-methylnicotinamide (MNA) and hydralazine (HYD) improves fatty liver in NAFL model rats. This finding was attributed to the MNA metabolism inhibition by HYD, which is a strong inhibitor of aldehyde oxidase (AO); this results in an increase in hepatic MNA and improved fatty liver. We hypothesized that orally administered nicotinamide (NAM), which is the precursor of MNA and is a form of niacin, would be efficiently metabolized by nicotinamide N-methyltransferase in the presence of exogenous S-adenosylmethionine (SAM) in NAFL rats. To address this issue, NAFL model rats were orally administered with NAM, SAM, and/or HYD. As a result, liver triglyceride (TG) and lipid droplet levels were barely altered by the administration of NAM, SAM, NAM+SAM, or NAM+HYD. By contrast, the triple combination of NAM+SAM+HYD significantly reduced hepatic TG and lipid droplet levels and significantly increased hepatic MNA levels. These findings indicated that the combination of exogenous SAM with AO inhibitors, such as HYD, has beneficial effects for improving fatty liver with NAM.

Role for phagocytosis in the prevention of neoplastic transformation in Drosophila.

Immunity is considered to be involved in the prevention of cancer. Although both humoral and cellular immune reactions may participate, underlying mechanisms have yet to be clarified. The present study was conducted to clarify this issue using a Drosophila model, in which neoplastic transformation was induced through the simultaneous inhibition of cell-cycle checkpoints and apoptosis. We first determined the location of hemocytes, blood cells of Drosophila playing a role of immune cells, in neoplasia-induced and normal larvae, but there was no significant difference between the two groups. When gene expression pattern in larval hemocytes was determined, the expression of immunity-related genes including those necessary for phagocytosis was reduced in the neoplasia model. We then asked the involvement of phagocytosis in the prevention of neoplasia examining animals where the expression of engulfment receptors instead of apoptosis was retarded. We found that the inhibition of engulfment receptor expression augmented the occurrence of neoplasia induced by a defect in cell-cycle checkpoints. This suggested a role for phagocytosis in the prevention of neoplastic transformation in Drosophila.