A Nutrient-Deficient Microenvironment Facilitates Ferroptosis Resistance via the FAM60A-PPAR Axis in Pancreatic Ductal Adenocarcinoma.

Ferroptosis, a nonapoptotic form of cell death, is an emerging potential therapeutic target for various diseases, including cancer. However, the role of ferroptosis in pancreatic cancer remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis and chemotherapy resistance, attributed to its high Kirsten rats arcomaviral oncogene homolog mutation rate and severe nutritional deficits resulting from a dense stroma. Several studies have linked rat sarcoma (RAS) mutations to ferroptosis, suggesting that inducing ferroptosis may be an effective strategy against oncogenic RAS-bearing tumors. We investigated the role of Family With Sequence Similarity 60 Member A (FAM60A) in this study, a protein closely associated with a poor prognosis and highly expressed in PDAC and tumor tissue from KrasG12D/+;Trp53R172H/+; Pdx1-Cre mice, in regulating ferroptosis, tumor growth, and gemcitabine sensitivity in vitro and in vivo. Our results demonstrate that FAM60A regulates 3 essential metabolic enzymes, ACSL1/4 and GPX4, to protect PDAC cells from ferroptosis. Furthermore, we found that YY1 transcriptionally regulates FAM60A expression by promoting its transcription, and the Hippo-YY1 pathway is restricted in the low-amino-acid milieu in the context of nutrient deprivation, leading to downstream suppression of peroxisome proliferator-activated receptor and ACSL1/4 and activation of GPX4 pathways. Importantly, FAM60A knockdown sensitized PDAC cells to gemcitabine treatment. A new understanding of FAM60A transcriptional regulation pattern in PDAC and its dual function in ferroptosis reliever and chemotherapy resistance is provided by our study. Targeting FAM60A may therefore offer a promising therapeutic approach for PDAC by simultaneously addressing 2 major features of the disease (high RAS mutation rate and tumor microenvironment nutrient deficiency) and preventing tumor cell metabolic adaptation.

46,XY disorders of sex development: the use of NGS for prevalent variants.

46,XY disorders of sex development (DSD) present with diverse phenotypes and complicated genetic causes. Precise genetic diagnosis contributes to accurate management, and targeted next-generation sequencing (NGS) and whole-exome sequencing are powerful tools for investigating DSD. However, the prevalent variants resulting in 46,XY DSD remain unclear, especially those associated with mild forms, such as isolated hypospadias, inguinal cryptorchidism, and micropenis. From 2019 to 2021, 74 patients with 46,XY DSD (48 typical and 26 mild) from the First Affiliated Hospital of Sun Yat-sen University were enrolled in our cohort study for targeted NGS or whole-exome sequencing. Our targeted 46,XY DSD panel included 108 genes involved in disorders of gonadal development and differentiation, steroid hormone synthesis and activation, persistent Müllerian duct syndrome, idiopathic hypogonadotropic hypogonadism, syndromic disorder, and others. Variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign following the American College of Medical Genetics guidelines. As a result, 28 of 74 (37.8%) patients with pathogenic and/or likely pathogenic variants acquired genetic diagnoses. The Mild DSD patients acquired a diagnosis rate of 30.7%. We detected 44 variants in 28 DSD genes from 31 patients, including 33 novel and 11 reported variants. Heterozygous (65%) and missense (70.5%) variants were the most common. Variants associated with steroid hormone synthesis and activation were the main genetic causes of 46,XY DSD. In conclusion, 46,XY DSD manifests as a series of complicated polygenetic diseases. NGS reveals prevalent variants and improves the genetic diagnoses of 46,XY DSD, regardless of severity.

Application of the Mathieu combined tunnel technique for repairing glans dehiscence after failed hypospadias repair.

Repairing glans dehiscence after failed hypospadias repair is challenging for pediatric surgeons. Here, we introduced and evaluated a newly modified Mathieu technique, Mathieu combined tunnel (MCT), which involves multiple custom-designed flaps for the shortage of flap source material after repeated operations; we also constructed a tunnel to avoid the glans incision that may carry new risks of dehiscence. This retrospective study included 26 patients who were consecutively admitted to the First Affiliated Hospital of Sun Yat-Sen University (Guangzhou, China) for glans dehiscence repair after failed hypospadias repair from October 2014 to October 2020; sixteen patients underwent surgery using the MCT (MCT group) and ten patients underwent surgery using the tubularized incised plate (TIP) technique (TIP group). The operative time, blood loss, postoperative complications, normal urethral meatus rate, success rate, and Hypospadias Objective Penile Evaluation (HOPE) score were compared between the two groups. The MCT group achieved an overall satisfactory penile appearance and voiding function, with a higher rate of normal urethral meatus (15/16, 93.8%) and a lower rate of glans dehiscence (1/16, 6.2%), compared with the TIP group (70.0% and 30.0%, respectively). However, these differences were not statistically significant, possibly because of the limited number of patients (all P > 0.05). Mean postoperative HOPE scores were similar in the MCT group (mean ± standard deviation: 8.83 ± 0. 89) and TIP group (8.94 ± 0.57) (P > 0.05). No significant differences were found between the two groups in terms of blood loss and success rate, nor in the rates of various complications (e.g., fistula, urethral stricture, and glans dehiscence). In conclusion, the MCT technique appears to be feasible and reliable for repairing glans dehiscence after failed hypospadias repair.

Leukemia propagating cells rebuild an evolving niche in response to therapy.

Residence of cancer-propagating cells (CPCs) within preferential microenvironmental niches has a major part in evading therapy. However, the nature of niches involved and the mechanisms protecting CPCs remain largely unknown. We addressed these issues in mouse transplantation models of acute lymphoblastic leukemia (ALL). When the engrafted leukemic cells substantially damaged adjacent microenvironment in the bone marrow (BM), after chemotherapy small foci of CPCs were retained, surrounded by sheaths of supporting cells that comprise a protective niche. We investigated patients' BM biopsies and found evidence of a similar process in patients receiving induction therapy. The efficacy of chemotherapy was enhanced by interfering with the niche formation or function. We therefore identified a therapy-induced niche that protects CPCs.

[Foley catheter versus urethral stent plus gastric tube for urine drainage following urethroplasty].

OBJECTIVE: To compare the advantages and disadvantages of the Foley catheter draining method versus the urethral stent plus gastric tube draining method for urine drainage following urethroplasty for hypospadias. METHODS: We retrospectively analyzed the clinical data of 361 cases of hypospadias treated by urethroplasty. After operation, 91 of the cases received urine drainage with the Foley catheter (group A) and 270 with a urethral stent plus a gastric tube (group B). We compared the incidence rates of bladder irritation, fistula, urethral stricture, and urethral diverticulum between the two groups of patients. RESULTS: No statistically significant differences were found between groups A and B in the incidences of bladder irritation (9.89% vs 10.70%, P > 0.05) and urethral diverticulum (1.09% vs 2.22%, P > 0.05). The incidence rate of fistula was markedly higher in group A than in B (20.80% vs 13.30%, P < 0.05), and so was that of urethral stricture (10.90% vs 5.55%, P < 0.05). CONCLUSION: The urethral stent plus gastric tube draining method is more effective than the Foley catheter draining method for urine drainage following urethroplasty.

Nicotine decreases beta-amyloid through regulating BACE1 transcription in SH-EP1-α4ß2 nAChR-APP695 cells.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects the elderly population. Deposition of beta-amyloid (Aß) in the brain is a hallmark of AD pathology. In our previous study, we have constructed a cell line expressing human APP695 (hAPP695) in SH-EP1 cells stably transfected with human nicotinic receptor (nAChR) α4 subunit and ß2 subunit gene. In present study, we found that activation of α4ß2 nAChR by nicotine and epibatidine decreased secreted Aß level in the cell line and hippocampal neurons, but had no effects on full-length APP695 and sAPP-α. Nicotine also decreases BACE1 and PSEN1 expression, as well as ERK1 and NFκB P65 subunit expression in the cell line. Furthermore, BACE1 promoter activity is, but PSEN1 not, decreased by nicotine in the cell line. All the results suggest that activation of α4ß2 nAChR decreases Aß through regulating BACE1 transcription by ERK1-NFκB pathway. Additionally, analysis of BACE1 promoter activity by dual-luciferase reporter assay may be useful for drug screening as a high throughput method.