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We consider a resource extraction model with the possibility of extending the resource stock by drilling efforts and an oligopolistic competition of symmetric firms. Assuming a hyperbolic market demand, we adopt the open-loop Nash equilibrium to analyze and compare the outcomes of a private vs a common resource pool. For both cases, the drilling efforts of the individual firms strongly depend on the market structure. For a low competition, the efforts increase the number of firms, and the opposite is true for a high competition. On the other hand, aggregate drilling efforts are different among the two types of pools and are opposite to Schumpeterian's hypothesis (i.e., they are either an inverted U-shaped (private pools) or strictly increasing (single pools)).

ABSTRACT Introduction: The introduction of Single-Port (SP) platform opened the field to new surgical options, allowing to perform major urological robot-assisted procedures extraperitoneally and with a supine patient positioning (1–3). Nevertheless, a comprehensive description of different supine access options is still lacking (4–6). In this light, we provided a step-by-step guide of SP extraperitoneal supine access options also exploring preliminary surgical outcomes. Materials and methods: Transvesical access was performed by a transversal incision 3cm above the pubic bone, after the anterior abdominal sheet incision, the bladder was insufflated with a flexible cystoscope and the detrusor muscle was incised at the level of the bladder dome. Similarly, the extraperitoneal access was carried out with a 4cm incision above the pubic bone, once visualized the preperitoneal space the prevesical fat was gently spread. The Low Anterior Access was performed with a 3cm incision at the McBurney point, the abdominal muscles were then spread. A gentle dissection was used laterally to develop the retroperitoneal space. Results: Overall, sixteen different procedures were performed with supine extraperitoneal access on 623 consecutive patients. No intraoperative conversions occurred. The median access time was 16 (IQR 12-21), 11 (IQR 7-14) and 14 (IQR 10-18) minutes in case of transvesical, extraperitoneal and low anterior access, respectively. Notably, 81.5 % of patients were discharged on the same day with a postoperative opioid free rate of 73%. Conclusion: The Atlas provides a comprehensive step-by-step guide to successfully perform all major urological SP procedures extraperitoneally and with supine patient positioning.

Objective: Bisphenol A and phthalate are known endocrine disruptors and capable of inducing epigenetic changes in the human population. However, their impact on the placenta is less well studied. Our objective was to measure the effect of exposure to bisphenol A and benzyl butyl phthalate in first-trimester HTR8-SVneo and third-trimester 3A-sub E trophoblast cells by profiling the DNA methylation pattern of the imprinting control region of the IGF2 (insulin-like growth factor) and H19 genes. Methods: Human placental HTR8-SVneo and 3A-sub E cell lines were treated with two sub-lethal concentrations of bisphenol A and benzyl butyl phthalate. Demethylating agent, 5-azacytidine, was used as a positive control. Cells were harvested on post-treatment days 1 and 4. The methylation profile of six CpG dinucleotide sites, part of the CTCF 6 binding site of the IGF2/H19 imprinting control region, was determined by pyrosequencing. Results: In the first-trimester HTR8-SVneo cell line, we observed a significant increased methylation of the CpG sites 3, 4 when treated with a high concentration of bisphenol A or benzyl butyl phthalate while increased methylation at site 6 for both high and low dose treatment on day 4. Demethylation of the CpG sites 1, 4, and 6 was observed when treated with 5-azacytidine on day 4. In the third-trimester 3A-sub E cell line, no significant changes in the methylation profile were observed under any treatment conditions. Conclusions: The results of this study demonstrate the capability of epigenetic changes in human placenta cells induced by bisphenol A and benzyl butyl phthalate. The observed methylation changes only in the first-trimester HTR8-SVneo cells phthalate may reflect a window of epigenetic susceptibility related to these environmental toxicants.

Background: The role of redo partial nephrectomy (PN) for recurrent renal cell carcinoma (RCC) is still overlooked. Objective: To report our experience of salvage PN for local recurrence after previous nephron-sparing surgery (NSS). Design, setting, and participants: We prospectively gathered data from patients treated with robotic redo PN for locally recurrent RCC after previous NSS from January 2017 to January 2023. The type of surgical resection technique was assigned to the pathologic specimen according to the surface-intermediate-base (SIB) score. Surgical procedure: Redo PN was performed by using the Si Da Vinci robotic platform. Measurements: Operative time, warm ischemia time, and intra- and postoperative complications were recorded. The severity of postoperative complications and tumor stage were evaluated. Results and limitations: Overall, 26 patients entered the study. The median clinical diameter was 3.5 (interquartile range [IQR] 2.2–4.9) cm and the median Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score was 8 (IQR 7–9). In 14 (53.8%) cases, recurrence was at the level of previous tumor resection bed. The median operative time was 177 (IQR 148–200) min, and hilar clamping was performed in 14 (53.8%) cases with a median warm ischemia time of 16 (14.5–22) min. Pure enucleation (SIB score 0–1), hybrid enucleation (SIB score 2), and pure enucleoresection (SIB score 3) were recorded in 13 (50%), eight (30.8%), and five (19.2%) cases, respectively. The totality of recurrent RCC far from previous tumor resection bed received a SIB score of 0–1, while in 57.1% and 35.8% of recurrent RCC on previous tumor resection a hybrid enucleation and a pure enucleoresection were performed, respectively. At a median follow-up of 37 (IQR 16–45) mo, five (19%) patients experienced disease recurrence, being local and systemic in three (11.5%) and two (7.7%) patients, respectively. Conclusions: Our study highlights the feasibility and safety of redo PN for the treatment of locally recurrent RCCs after NSS, either on previous tumor resection bed or elsewhere in the kidney. Patient summary: Robotic redo partial nephrectomy is a challenging procedure. The surgeon needs to tailor the surgical strategy and tumor resection technique case by case, given the heterogeneity of clinical scenarios and the need to achieve maximal functional preservation while ensuring oncologic efficacy.

ABSTRACT Introduction: The aim of the study was to investigate clinical and surgical factors associated with early catheter replacement in patients treated with Holmium Laser Enucleation of the Prostate (HoLEP). Materials and Methods: Data of patients treated with HoLEP at our Institution by a single surgeon from March 2017 to January 2021 were collected. Preoperative variables, including non-invasive uroflowmetry and abdominal ultrasonography (US), were recorded. Bladder wall modifications (BWM) at preoperative US were defined as the presence of single or multiple bladder diverticula or bladder wall thickening ≥5 mm. Clinical symptoms were assessed using validated questionnaires. Only events occurred within the first week after catheter removal were considered. Results: Overall, 305 patients were included, of which 46 (15.1%) experienced early catheter replacement. Maintenance of anticoagulants/antiplatelets (AC/AP) therapy at surgery (p=0.001), indwelling urinary catheter (p=0.02) and the presence of BWM (p=0.001) were more frequently reported in patients needing postoperative re-catheterization. Intraoperative complications (p=0.02) and median lasing time (p=0.02) were significantly higher in this group. At univariate analysis, indwelling urinary catheter (p=0.02), BWM (p=0.01), ongoing AC/AP therapy (p=0.01) and intraoperative complications (p=0.01) were significantly associated with early catheter replacement. At multivariate analysis, indwelling urinary catheter (OR: 1.28; p=0.02), BWM (OR: 2.87; p=0.001), and AC/AP therapy (OR: 2.21; p=0.01) were confirmed as independent predictors of catheter replacement. Conclusions: In our experience the presence of indwelling urinary catheter before surgery, BWM and the maintenance of AC/AP therapy were shown to be independent predictors of early catheter replacement after HoLEP.

Background: Chronic Prostatitis/Chronic Pelvic Pain syndrome NIH-class III is a widespread condition affecting men universally, with existing treatments showing limited success. This study evaluated the efficacy and safety of a natural supplement, composed of Serenoa repens, Solanum lycopersicum, lycopene, and bromelain, in managing symptoms of this condition among a substantial patient group. Methods: In this prospective study, 245 patients diagnosed with Chronic Prostatitis/Chronic Pelvic Pain syndrome NIH-class III were treated with the aforementioned supplement, alongside lifestyle alterations, such as refraining from spicy foods, alcohol, caffeine, and cycling, for a duration of three months. Patients’ progress was assessed at one and three months using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the International Prostate Symptom Index (IPSS), quality of life (QoL) scores, and changes in total prostate-specific antigen (PSA) levels. Results: The supplement was well received with no serious adverse events reported. Significant improvements were observed in NIH-CPSI scores, IPSS, QoL scores, and a substantial decrease in total PSA levels at three months compared to baseline, with a positive trend noted from one-month to three-month evaluations. This was consistent in either patients with predominantly voiding or storage urinary symptoms. Conclusions: Our results suggest that this natural supplement in conjunction with lifestyle changes could offer a safe and effective alternative treatment for patients suffering from Chronic Prostatitis/Chronic Pelvic Pain syndrome NIH-class III. However, these findings require validation through further large-scale randomized controlled trials.

Purpose: The present study sought to provide reproducible and patient-oriented metrics to assess the rate of “successful” outcomes (Trifecta) following holmium laser enucleation of the prostate (HoLEP). Clinical and surgical predictors of failure to achieve Trifecta were investigated. Materials and Methods: We queried our prospectively collected database of all patients treated with HoLEP between March 2017 and January 2021. Trifecta was defined as the contemporary presence of: (1) no postoperative complication within 3 months; (2) no urinary incontinence at 3-months follow-up; and (3) 3-month postoperative max flow-rate >15 mL/s. Cases were grouped according to Trifecta achievement. All surgical procedures were carried out by a single surgeon. Surgical experience was divided into two different eras according to the number of procedures conducted (surgical era). Multivariate logistic regression analysis was performed to assess predictors of Trifecta failure. Results: Overall 305 patients were included. Of these, 192 patients (63.0%) achieved Trifecta. Preoperative patient-related features were comparable between the two groups, except for a higher post-void residual (PVR) in non-Trifecta patients (median 180 vs. 130 mL, p=0.003). A significant proportion of Trifecta patients (88.5%) were treated in the second surgical era and in 126 (65.6%) cases an en-bloc enucleation was performed. Multivariate analysis confirmed PVR ≥250 mL, first surgical era and standard three-lobes enucleation technique as independent predictors of Trifecta failure. Conclusions: In our experience the rate of “successful” HoLEP, defined according to our newly introduced Trifecta metric, was 63.0%. We demonstrated that surgical strategy together with rising experience and baseline PVR are key elements to forecast the outcomes.

ABSTRACT Introduction We assessed the efficacy and safety of holmium laser enucleation of the prostate (HoLEP) in patients with high comorbidity burden. Materials and methods Data from patients treated with HoLEP at our academic referral center from March 2017 to January 2021 were prospectively collected. Patients were divided according to their CCI (Charlson Comorbidity Index). Perioperative surgical data and 3-month functional outcomes were collected. Results Out of 305 patients included, 107 (35.1%) and 198 (64.9%) were classified as CCI ≥ 3 and < 3, respectively. The groups were comparable in terms of baseline prostate size, symptoms severity, post-void residue and Qmax. The amount of energy delivered during HoLEP (141.3 vs. 118.0 KJ, p=0.01) and lasing time (38 vs 31 minutes, p=0.01) were significantly higher in patients with CCI ≥ 3. However, median enucleation, morcellation and overall surgical time were comparable between the two groups (all p>0.05). Intraoperative complications rate (9.3% vs. 9.5%, p=0.77), median time to catheter removal and hospital stay were comparable between the two cohorts. Similarly, early (30 days) and delayed (>30 days) surgical complications rates were not significantly different between the two groups. At 3-month follow up, functional outcomes using validated questionnaires did not differ between the two groups (all p>0.05). Conclusions HoLEP represents a safe and effective treatment option for BPH also in patients with high comorbidity burden.

Objective: All forms of diabetes result from insufficient functional β-cell mass. Thus, achieving the therapeutic goal of expanding β-cell mass requires a better mechanistic understanding of how β-cells proliferate. Glucose is a natural β-cell mitogen that mediates its effects in part through the glucose-responsive transcription factor, carbohydrate response element binding protein (ChREBP) and the anabolic transcription factor, MYC. However, mechanistic details by which glucose activates Myc at the transcriptional level are poorly understood. Methods: Here, siRNA was used to test the role of ChREBP in the glucose response of MYC, ChIP and ChIPseq to identify potential regulatory binding sites, chromatin conformation capture to identify DNA/DNA interactions, and an adenovirus was constructed to expresses x-dCas9 and an sgRNA that specifically disrupts the recruitment of ChREBP to a specific targeted ChoRE. Results: We found that ChREBP is essential for glucose-mediated transcriptional induction of Myc, and for increases in Myc mRNA and protein abundance. Further, ChIPseq revealed that the carbohydrate response element (ChoRE) nearest to the Myc transcriptional start site (TSS) is immediately upstream of the gene encoding the lncRNA, Pvt1, 60,000 bp downstream of the Myc gene. Chromatin Conformation Capture (3C) confirmed a glucose-dependent interaction between these two sites. Transduction with an adenovirus expressing x-dCas9 and an sgRNA specifically targeting the highly conserved Pvt1 ChoRE, attenuates ChREBP recruitment, decreases Myc-Pvt1 DNA/DNA interaction, and decreases expression of the Pvt1 and Myc genes in response to glucose. Importantly, isolated and dispersed rat islet cells transduced with the ChoRE-disrupting adenovirus also display specific decreases in ChREBP-dependent, glucose-mediated expression of Pvt1 and Myc, as well as decreased glucose-stimulated β-cell proliferation. Conclusions: The mitogenic glucose response of Myc is mediated via glucose-dependent recruitment of ChREBP to the promoter of the Pvt1 gene and subsequent DNA looping with the Myc promoter.

Partial nephrectomy (PN) may be recommended for selected patients with advanced-stage (>cT2) renal cell carcinoma (RCC) with the aim of avoiding dialysis and chronic kidney disease–related comorbidities. The spread of robotic surgery has led to expansion of PN indications to more challenging scenarios and even frontier surgeries, including advanced-stage RCC. Here we describe the management of a patient with a solitary kidney diagnosed with multiple cT3a (renal vein thrombus) RCC who was treated using a conservative robotic approach. The most crucial surgical considerations for this procedure were: (1) tailored planning of the surgical approach using three-dimensional reconstruction software; (2) accurate boundary delineation for the tumors and thrombus; (3) avoiding unnecessary warm ischemia time; (4) performing an anatomical excision to follow eventual tumor bulging; and (5) en bloc removal of the main lesion and its thrombus. No perioperative complications were recorded. Histopathology revealed clear cell RCC for all four lesions with nucleolar grade 3 and negative surgical margins. At 12-mo follow-up the patient was disease-free. When performed by an experienced surgeon, PN plus venous thrombus excision for imperative cases with cT3 RCC may represent a valid treatment option with valuable oncological and functional outcomes. Patient summary: We describe the case of patient who had a single kidney with multiple kidney tumors and tumor extension into a blood vessel. The patient was treated with robot-assisted removal of the tumors, sparing as much kidney tissue as possible. This technique was found to be safe and effective, with no complications and good intermediate-term results.

ChREBP is a glucose-responsive transcription factor, which regulates glucose-mediated proliferation and cell death in pancreatic β-cells. Here the authors show that the acute feed forward induction of ChREBPβ is required for adaptive β-cell expansion, that chronic overexpression of ChREBPβ is toxic to β-cells, and offer mitigation strategies

Objectives: Thyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation and function. In the present study, we asked whether T3 and glucose signaling pathways coordinately regulate transcription of genes important for β-cell function and proliferation. Methods: RNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations and in the presence or absence of T3. Gene expression was also studies in sorted human β-cells, mouse islets and Ins-1 cells by RT-qPCR. Silencing of the thyroid hormone receptors (THR) was conducted using lentiviruses. Proliferation was assessed by ki67 immunostaining in primary human/mouse islets. Chromatin immunoprecipitation and proximity ligation assay were preformed to validate interactions of ChREBP and THR. Results: We found glucose-mediated expression of carbohydrate response element binding protein alpha and beta (ChREBPα and ChREBPβ) mRNAs and their target genes are highly dependent on T3 concentrations in rodent and human β-cells. In β-cells, T3 and glucose coordinately regulate the expression of ChREBPβ and PCK1 (phosphoenolpyruvate carboxykinase-1) among other important genes for β-cell maturation. Additionally, we show the thyroid hormone receptor (THR) and ChREBP interact, and their relative response elements are located near to each other on mutually responsive genes. In FACS-sorted adult human β-cells, we found that high concentrations of glucose and T3 induced the expression of PCK1. Next, we show that overexpression of Pck1 together with dimethyl malate (DMM), a substrate precursor, significantly increased β-cell proliferation in human islets. Finally, using a Cre-Lox approach, we demonstrated that ChREBPβ contributes to Pck1-dependent β-cell proliferation in mouse β-cells. Conclusions: We conclude that T3 and glucose act together to regulate ChREBPβ, leading to increased expression and activity of Pck1, and ultimately increased β-cell proliferation.

Background: Phytotherapeutic agents aroused an increasing interest either as alternative or in addition to conventional therapy in the management of BPH. The aim of the article was to evaluate the clinical and functional changes after add-on treatment with Serenoa repens associated with Solanum lycopersicum, lycopene and bromelain in patients with BPH presenting with mild to moderate LUTS and previously treated only with Alfuzosin over a 6–12 months period. Materials and methods: Between January and July 2019, patients with symptomatic BPH already on treatment with Alfuzosin (Al) 10 mg for at least 6–12-month were enrolled at three academic referral centres, included in a prospective treatment group, and managed with a combination treatment of Al and 6-month daily oral single-tablet supplementation of Serenoa repens and Solanum lycopersicum + lycopene + bromelain (SeR + SL + Ly + Br). A retrospective control group with comparable baseline characteristics was obtained by performing a propensity score matching from a database of 434 patients managed with Alfuzosin 10 mg/day only over a 6–12 months period between March 2015 and December 2018. IPSS, QoL questionnaires, voiding diary assessment, postvoid residual volume (PVR), maximal (Qmax) and average (Qave) urinary flow rates were evaluated at baseline in the treatment group at the moment of patient accrual, in the control group after 6-month of treatment with alfuzosin, and thereafter at 3 and 6 months in both groups. Results: Overall, 250 patients entered the study (n = 125 treatment group; n = 125 control group). Total IPSS score significantly decreased at 6-month assessment from baseline in the treatment vs control group (17 [IQR: 12–20] vs 12 [IQR: 9–14], p = 0.02) with a significative storage symptoms improvement detected both at 3- (p = 0.03) and 6-month evaluation (p = 0.001). PVR significantly improved at each follow-up visit with the most relevant reduction at 6-month assessment (125 cc vs. 102 cc; p = 0.02). Moreover, a significative improvement in LUTS-related quality of life (QoL) was recorded at 3- and 6-month assessment with a median decrease of −1 and −2 (p = 0.05 and p = 0.001 respectively) from baseline. Conclusions: Combination treatment with AB and SeR + SL + Ly + Br led to meaningful improvements in LUTS severity compared to AB as monotherapy, after a 6-month treatment period in men with mild to moderate LUTS/BPH.

Peyronie’s disease (PD), a fibrotic disorder of the tunica albuginea fully described in 1793 by French physician Francois de la Peyronie, is characterized by pain, plaque formation, penile deformity, and ultimately sexual function decline. The epidemio-logical data on PD vary considerably across previous studies, with recent evidence reporting a prevalence of up to 9%. PD is generally divided into two different phases: active or acute and stable or chronic. Plaque formation generally occurs during the acute phase, while during chronic phase pain usually tends to complete resolution and penile deformity stabilizes. PD’s pathophysiology is still subject of great discussion. Tunical mechanical stress and microvascular trauma are major contribu-tory factors. However, better understanding of the molecular pathophysiology of this condition remains paramount towards an in-depth comprehension of the disorder and the development of newer and more effective disease-targeted interventions. In this review we provide a detailed overview of natural history of PD, specifically focusing on clinical manifestations and the underlying molecular regulation patterns.

Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.

ABSTRACT Purpose: Robot-assisted partial nephrectomy (RAPN) is rapidly increasing its role in the nephron-sparing surgery setting (1). The recent introduction of technological advancements is leading more experienced surgeons to approach complex renal mass with a conservative intent (2, 3). In particular, three-dimensional reconstruction and the use of intraoperative ultrasonography are gaining attention as crucial tools to safely and effectively approach complex cases (4, 5). We aimed to video-report the management of highly complex renal mass treated with RAPN, focusing on preoperative surgical planning and intraoperative technical nuances. Materials and methods: A 73-year-old male patient was referred to our institution for an incidental detection of a 70 mm diameter, completely endophytic, hilar renal mass (PADUA score 13, RENAL score 11a). Contrast-enhanced CT scan images were processed by M3DICS (Turin, Italy) and used to obtain a 3D virtual model. RAPN was performed by a highly experienced surgeon using Da Vinci Si robotic platform with a three-arm configuration. Results: The overall operative time was 114 min, with a warm ischemia time of 16 min. No intraoperative or postoperative complications were recorded. According to the SIB score, the pure enucleation excision strategy was performed. Histopathological analysis revealed a pT3a low-grade oncocytic kidney tumor with negative surgical margins. with negative surgical margins. At 24-months follow up, no local or systemic recurrence was detected. Conclusions: Conservative management of complex renal masses is challenging with a highly nuanced decision-making process. In this regard, preoperative 3D models and intraoperative ultrasound (US) guidance play a pivotal role to develop a tailored surgical strategy according to patient’ and tumor's characteristics.

Objective: To report our technique of robotic enucleation for the management of renal masses focusing of preoperative considerations and intraoperative nuances. Patients and surgical procedure: In our center, all patients with suspicious renal mass amenable to partial nephrectomy and presenting an identifiable tumor pseudocapsule are submitted to robotic pure enucleation. Several steps have to be followed to perform a successful tumor enucleation. In particular, 1) preoperative evaluation of the tumor and renal anatomical complexity; 2) accurate intraoperative identification of the tumor margins; 3) reaching the tumor pseudocapsule through an anatomic resection strategy; 4) adapting the ischemia management in order to maintain a bloodless surgical field; 5) enucleative resection technique 6)minimizing tumor tensions; 7) anatomical renorraphy. Results: Pure enucleation is effectively performed. Conclusions: Tumor enucleation represents the most anatomical technique for partial nephrectomy since it maximizes the amount of healthy renal parenchyma spared. Evidence supports the adoption un pure enucleation whenever feasible.

Insulinomas are rare, benign beta cell tumours which overproduce insulin and have been associated to epigenetic alterations. Here the authors characterise insulinoma methylomes, finding changes in promoter methylation and chromatin structure proposed to drive the pathological expression of insulin.

Copper is an essential trace nutrient and an enzymatic cofactor necessary for diverse physiological and biological processes. Copper metabolism is uniquely controlled in the placenta and changes to copper metabolism have been linked with adverse birth outcomes. We investigated associations between patterns of DNA methylation (DNAm; measured at >485 k CpG sites) and copper concentration measured from placentae in two independent mother-infant cohorts: the New Hampshire Birth Cohort Study (NHBCS, n = 306) and the Rhode Island Child Health Study (RICHS, n = 141). We identified nine copper-associated differentially methylated regions (DMRs; adjusted P < 0.05) and 15 suggestive CpGs (raw P < 1e-5). One of the most robust variably methylated CpGs associated with the expression of the antioxidant, GSTP1. Our most robust DMR negatively associates with the expression of the zinc-finger gene, ZNF197 (FDR = 4.5e-11). Genes co-expressed with ZNF197, a transcription factor, are enriched for genes that associate with birth weight in RICHS (OR = 2.9, P = 2.6e-6, N = 194), genes that are near a ZNF197 consensus binding motif (OR = 1.34, P = 0.01, N = 194), and for those classified in GO biological processes growth hormone secretion (P = 3.4e-4), multicellular organism growth (P = 3.8e-4), and molecular functions related to lipid biosynthesis (P = 1.9e-4). Further, putative transcriptional targets for ZNF197 include genes involved in copper metabolism and placentation. Our results suggest that copper metabolism is tied to DNAm in the placenta and that copper-associated patterns in DNAm may mediate normal placentation and foetal development.

Imprinted genes play a pivotal role in placental processes underlying fetal development, and much interest centers on discerning whether these loci, via changes in DNA methylation and/or gene expression, inform disruptions in appropriate fetal growth. In this study, we comprehensively profiled DNA methylation across the placental imprintome and assessed the relationship with gene expression levels and aberrant fetal growth. Placental DNA methylation across 153 imprinted loci, including imprint control regions (ICR) and surrounding non-ICR regions, was surveyed using the Nimblegen TruSeq bisulfite sequencing platform among participants enrolled in the Rhode Island Child Health Study (RICHS, n = 163). Methylation and gene expression associations were assessed using eQTM analysis. Differential methylation analysis contrasting small (SGA) and large for gestational age (LGA) infants against appropriate for gestational age (AGA) infants was assessed using the DMRcate R package. We identified 34 SGA-related differentially methylated regions (DMRs) and 9 LGA-related DMRs (FDR

The possible role of JC virus in determining urinary tract involvement has only recently been recognized. The case of a man with laboratory-confirmed JC virus replication in the urine after a maintenance schedule of rituximab administered for a lymphoproliferative disorder is reported herein. The patient developed severe renal and urinary tract impairment, characterized by the onset of nephropathy, bilateral ureteral strictures, and a serious reduction in vesical compliance, ultimately requiring an ileal neobladder configuration. The renal and urinary tract involvement was finally attributed to JC virus reactivation. This observation suggests that renal and urinary tract diseases related to JC virus might be associated with long-term rituximab treatment.

Background: A marker of urothelial damage could be helpful for early detection and monitoring of local toxicity due to intravesical therapy for non-muscle invasive bladder cancer (NMIBC). The aim of the study was to investigate the correlation between fibronectin (FN) gene expression in bladder washings and local toxicity secondary to adjuvant intravesical therapy. Materials and methods: Patients undergoing adjuvant intravesical therapy for NMIBC and age-matched healthy patients were enrolled. Real time polymerase chain reaction was performed to analyze FN expression in bladder washings. Local toxicity was classified as: 0–1 mild (no medical therapy), 2 moderate (medical therapy and/or instillation postponed), 3 severe (discontinuation of therapy). Results: Seventy-two patients and 21 controls entered the study. A useful pellet was obtained in 58 patients and 18 controls. Intravesical Bacillus Calmette–Guerin (BCG), Epirubicin and Mitomycin C was offered to 69%, 13.8% and 17.2% of patients respectively. Compared with healthy controls (FN = 1.0 fold), overall median FN expression before adjuvant intravesical therapy was 1.73 fold [interquartile range (IQR) 0.8–2.3], while during therapy median FN expression increased to 3.41 (IQR: 1.6–6.1) fold. Considering 40 intermediate and high-risk patients undergoing intravesical BCG, median FN expression before adjuvant treatment was 1.92 [(IQR: 1.0–2.7) fold, increasing up to 4.1 (IQR: 1.9–6.6) during therapy. In more detail, FN increased during BCG therapy, showing a median expression of 4.22 (IQR: 2.2–5.5) and 6.16 (IQR: 2.6–8.7) fold in presence of grade 2 and 3 toxicity respectively, while remaining more or less stable in asymptomatic patients. After receiver operating characteristic curve analysis, FN value of 3.6 fold resulted, corresponding to 75% sensitivity and 69% specificity to predict grade 2–3 toxicity events (area under the curve 0.74, 95% confidence interval 0.63–0.85, p = 0.001). Conclusion: Our study validated the correlation between FN expression and urothelial damage. BCG seems to induce a urothelial activation with FN overexpression during adjuvant intravesical therapy. Grade of toxicity was related to FN expression.

The placenta plays a central role in the epigenetic programming of neurodevelopment by prenatal stress (PS), but this pathway is not fully understood. It difficult to study in humans because the conditions for intense, traumatic PS are almost impossible to create ethically. This study was able to capitalize on a 2012 disaster that hit New York, Superstorm Sandy, to examine the impact of traumatic stress on placental gene expression while also examining normative PS, and compare the two. Of the 303 expectant mothers participating in the Stress in Pregnancy Study, 95 women were pregnant when Superstorm Sandy struck. During their pregnancy, participants completed self-report measures of PS and distress that were combined, using latent profile analysis, into one global indicator of normative PS. Placental tissue was collected at delivery and frozen for storage. RNA expression was assessed for 40 placental genes known to associate with the stress response system and neurodevelopment in offspring. Results showed that normative PS increased expression of just MECP2, HSD11B2, and ZNF507, whereas Superstorm Sandy PS decreased expression of CDKL5, CFL1, DYRK1A, HSD11B2, MAOA, MAOB, NCOR1, and ZNF507. Interaction analyses indicated that Superstorm Sandy PS was associated with decreased gene expression for the low and high PS group for CFL1, DYRK1A, HSD11B2, MAOA, and NCOR1 and increased expression for the moderate PS group for FOXP1, NR3C1, and NR3C2. This study supports the idea that a moderate amount of normative PS may buffer the impact of traumatic PS, in this case caused by Superstorm Sandy, on placental gene expression, which suggests that the placenta itself mirrors the organism's ability to develop an epigenetic resilience to, and inoculation from, stress.

Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.

Infertility affects one in 6 couples in developed nations, resulting in an increasing use of assisted reproductive technologies (ART). Both ART and subfertility appear to be linked to lower birth weight outcomes, setting infants up for poor long-term health. Prenatal growth is, in part, regulated via epigenetically-controlled imprinted genes in the placenta. Although differences in DNA methylation between ART and control infants have been found, it remains unclear whether these differences are due to the ART procedures or to the underlying parental subfertility and how these methylation differences affect imprinted gene expression. In this study, we examined the expression of 108 imprinted genes in placental tissues from infants born to subfertile parents (n = 79), matched naturally-conceived controls (n = 158), and infants conceived using in vitro fertilization (IVF, n = 18). Forty-five genes were identified as having significantly different expression between the subfertile infants and controls, whereas no significant differences were identified between the IVF and control groups. The expression of 4 genes—IGF2, NAPIL5, PAX8-AS1, and TUBGCP5—was significantly downregulated in the IVF compared with the subfertile group. Three of the 45 genes significantly dysregulated between subfertile and control placentae—GRB10, NDN, and CD44 —were found to have a significant positive correlation between expression and birth weight. Methylation levels for these 3 genes and 4 others—MKRN3, WRB, DHCR24, and CYR61—were significantly correlated with expression. Our findings indicate that epigenetic differences in placentas resulting from IVF pregnancies may be related to the underlying subfertility in parents using IVF rather than the IVF procedure itself.

Abstract Background The placenta is the principal organ regulating intrauterine growth and development, performing critical functions on behalf of the developing fetus. The delineation of functional networks and pathways driving placental processes has the potential to provide key insight into intrauterine perturbations that result in adverse birth as well as later life health outcomes. Results We generated the transcriptome-wide profile of 200 term human placenta using the Illumina HiSeq 2500 platform and characterized the functional placental gene network using weighted gene coexpression network analysis (WGCNA). We identified 17 placental coexpression network modules that were dominated by functional processes including growth, organ development, gas exchange and immune response. Five network modules, enriched for processes including cellular respiration, amino acid transport, hormone signaling, histone modifications and gene expression, were associated with birth weight; hub genes of all five modules (CREB3, DDX3X, DNAJC14, GRHL1 and C21orf91) were significantly associated with fetal growth restriction, and one hub gene (CREB3) was additionally associated with fetal overgrowth. Conclusions In this largest RNA-Seq based transcriptome-wide profiling study of human term placenta conducted to date, we delineated a placental gene network with functional relevance to fetal growth using a network-based approach with superior scale reduction capacity. Our study findings not only implicate potential molecular mechanisms underlying fetal growth but also provide a reference placenta gene network to inform future studies investigating placental dysfunction as a route to future disease endpoints.

GWAS identified variants associated with birth weight (BW), childhood obesity (CO) and childhood BMI (CBMI), and placenta is a critical organ for fetal development and postnatal health. We examined the role of placental transcriptome and eQTLs in mediating the genetic causes for BW, CO and CBMI, and applied integrative analysis (Colocalization and MetaXcan). GWAS loci associated with BW, CO, and CBMI were substantially enriched for placenta eQTLs (6.76, 4.83 and 2.26 folds, respectively). Importantly, compared to eQTLs of adult tissues, only placental eQTLs contribute significantly to both anthropometry outcomes at birth (BW) and childhood phenotypes (CO/CBMI). Eight, six and one transcripts colocalized with BW, CO and CBMI risk loci, respectively. Our study reveals that placental transcription in utero likely plays a key role in determining postnatal body size, and as such may hold new possibilities for therapeutic interventions to prevent childhood obesity.

Polycystic ovary syndrome (PCOS) affects 5–15% of women. PCOS is a heterogeneous disorder displaying endocrine, metabolic, and reproductive dysfunction and cardiovascular risk manifestations. Evidence of heritability exists, but only a portion of the genetic transmission has been identified by genome-wide association studies and linkage studies, suggesting epigenetic phenomena may play a role. Evidence implicates intrauterine influences in the genesis of PCOS. This was a pilot study that aimed at identifying an epigenetic PCOS reprogramming signature by profiling the methylation of the DNA extracted from umbilical cord blood (UCB) from 12 subjects undergoing in vitro fertilization. Six subjects were anovulatory PCOS women diagnosed by Rotterdam criteria and six ovulatory non-PCOS women matched for age and body mass index. UCB was collected at delivery of the placenta; the DNA was extracted and submitted to methylation analysis. A differential methylation picture of prevalent hypomethylation affecting 918 genes was detected. Of these, 595 genes (64.8%) carried single or multiple hypomethylated CpG dinucleotides and 323 genes (35.2%) single or multiple hypermethylated CpG dinucleotides. The Ingenuity Pathway Analysis (IPA) online platform enlisted 908 of the 918 input genes and clustered 794 of them into 21 gene networks. Key features of the primary networks scored by IPA included carbohydrate and lipid metabolism, neurotransmitter signaling, cardiovascular system development and function, glycosaminoglycan signaling regulation and control of amino acid biosynthesis. Central to the network activities were genes controlling hormonal regulation (ESR1), mitochondrial activity (APP, PARK2), and glucose metabolism (INS). Regulatory pathways such as G-protein coupled receptor signaling, inositol metabolism, and inflammatory response were also highlighted. These data suggested the existence of a putative “PCOS epigenomic superpathway” with three main components: glucotoxic, lipotoxic, and inflammatory. If our results are confirmed, they hint at an epigenetic at risk PCOS “signature” may thus exist that may be identifiable at birth. Additional studies are needed to confirm the results of this pilot study.