Conditionally mutant animal model for investigating the invasive trophoblast cell lineage.

Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade the uterus, where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome-editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 (Prl7b1) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their roles in trophoblast-guided uterine spiral artery remodeling.

CITED2 is a conserved regulator of the uterine-placental interface.

Establishment of the hemochorial uterine-placental interface requires exodus of trophoblast cells from the placenta and their transformative actions on the uterus, which represent processes critical for a successful pregnancy, but are poorly understood. We examined the involvement of CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) in rat and human trophoblast cell development. The rat and human exhibit deep hemochorial placentation. CITED2 was distinctively expressed in the junctional zone (JZ) and invasive trophoblast cells of the rat. Homozygous Cited2 gene deletion resulted in placental and fetal growth restriction. Small Cited2 null placentas were characterized by disruptions in the JZ, delays in intrauterine trophoblast cell invasion, and compromised plasticity. In the human placentation site, CITED2 was uniquely expressed in the extravillous trophoblast (EVT) cell column and importantly contributed to the development of the EVT cell lineage. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.

TAF7L regulates early stages of male germ cell development in the rat.

Male germ cell development is dependent on the orchestrated regulation of gene networks. TATA-box binding protein associated factors (TAFs) facilitate interactions of TATA-binding protein with the TATA element, which is known to coordinate gene transcription during organogenesis. TAF7 like (Taf7l) is situated on the X chromosome and has been implicated in testis development. We examined the biology of TAF7L in testis development using the rat. Taf7l was prominently expressed in preleptotene to leptotene spermatocytes. To study the impact of TAF7L on the testis we generated a global loss-of-function rat model using CRISPR/Cas9 genome editing. Exon 3 of the Taf7l gene was targeted. A founder was generated possessing a 110 bp deletion within the Taf7l locus, which resulted in a frameshift and the premature appearance of a stop codon. The mutation was effectively transmitted through the germline. Deficits in TAF7L did not adversely affect pregnancy or postnatal survival. However, the Taf7l disruption resulted in male infertility due to compromised testis development and failed sperm production. Mutant germ cells suffer meiotic arrest at late zygotene/early pachynema stages, with defects in sex body formation. This testis phenotype was more pronounced than previously described for the subfertile Taf7l null mouse. We conclude that TAF7L is essential for male germ cell development in the rat.

Reactive oxygen species are involved in the signaling of equine sperm chemotaxis.

Sperm chemotaxis may facilitate the finding of the oocyte. Only capacitated spermatozoa can orient their movement by chemotaxis, which as well as capacitation, is regulated in part by the cAMP-PKA pathway. Reactive oxygen species (ROS) are produced during sperm capacitation which is closely related to chemotaxis. Then, the ROS participation in the chemotactic signaling can be expected. Here we studied the role of ROS in the chemotaxis signaling of equine spermatozoa which produce high quantities of ROS because of their energy metabolism. The level of capacitated and chemotactic spermatozoa was increased with 0.1 and 0.2 mM hydrogen peroxide (H2O2), which was involved in the chemotactic signaling. By combining a concentration gradient of H2O2 with inhibitors/chelators of some of the signaling pathway elements, we showed that the activation of NOX (membrane NADPH oxidase) increases the intracellular ROS which activate the chemotaxis AMPc-PKA pathway. Our results provide evidence about the participation of ROS in the chemotactic signaling mediated by progesterone (P).

Effect of repeated prostate biopsies on erectile function in men on active surveillance for prostate cancer.

PURPOSE: Active surveillance is becoming an increasingly common management strategy for low grade prostate cancer and involves repeat prostate biopsies over time. It has been hypothesized that serial biopsies can lead to reduced erectile function in patients on active surveillance and we explored this hypothesis in a longitudinally followed cohort. MATERIALS AND METHODS: We identified 342 men on active surveillance whose first biopsy occurred between 2000 and 2009. We investigated erectile function using patient reported outcomes, namely the 6 erectile function questions from the IIEF-6 (International Index of Erectile Function). We estimated the change in erectile function with time using locally weighted scatterplot smoothing. RESULTS: The median (IQR) patient age in this cohort was 64 years (58-68). Median followup on active surveillance was 3.5 years (2.3-5.0) and the median number of biopsies was 5 (3-6). During the first 4 years on active surveillance erectile function decreased 1.0 point per year (95% CI 0.2, 1.7) on the IIEF-6 (scale 1 to 30). When stratified by comorbidities or number of biopsies we see an almost identical decrease in erectile function with time. The use of phosphodiesterase-5 inhibitors increased from 5% to 27% from baseline to year 5 on active surveillance. CONCLUSIONS: In this longitudinally followed active surveillance cohort we observed a small decrease in erectile function and an increase in the use of phosphodiesterase-5 inhibitors with time. While we cannot separate out the effect of multiple biopsies from that of the natural aging process on erectile function in this observational study, our data suggest that active surveillance related biopsies do not have a large impact on erectile function.

Osteoporotic vertebral fractures: Natural history and impact.

Osteoporosis, and the consequences derived from it, such as fragility fractures, constitute a growing public health problem. Suffering from a fracture of this nature is the main risk factor for suffering a new fracture. It is documented that vertebral compression fractures lead to significant morbidity and mortality, in the short and long term, as well as other complications, such as sagittal imbalance and hyperkyphosis of the segment. However, we have not found documentation that analyzes the medium and long-term consequences of these injuries, assessing the type of treatment used, and the economic impact they represent. The purpose of this review is to analyze the main recent literature on the subject and make a breakdown of the consequences of these fractures in various spheres, such as economic, quality of life, sagittal balance and radiographic parameters, pain or mortality; as well as a brief analysis of epidemiology and natural history. Conclusion Osteoporotic fractures constitute an emerging problem, both in the medical and economic fields. The consequences and sequelae on the patient are multiple and although surgical options offer good long-term results, it is necessary to properly select the patient, through multidisciplinary teams, to try to minimize potential complications.

Osteoporotic vertebral fractures: Natural history and impact. / Fracturas vertebrales osteoporóticas: historia natural e impacto.

Osteoporosis, and the consequences derived from it, such as fragility fractures, constitute a growing public health problem. Suffering from a fracture of this nature is the main risk factor for suffering a new fracture. It is documented that vertebral compression fractures lead to significant morbidity and mortality, in the short and long term, as well as other complications, such as sagittal imbalance and hyperkyphosis of the segment. However, we have not found documentation that analyzes the medium and long-term consequences of these injuries, assessing the type of treatment used, and the economic impact they represent. The purpose of this review is to analyze the main recent literature on the subject and make a breakdown of the consequences of these fractures in various spheres, such as economic, quality of life, sagittal balance and radiographic parameters, pain or mortality; as well as a brief analysis of epidemiology and natural history. CONCLUSION: Osteoporotic fractures constitute an emerging problem, both in the medical and economic fields. The consequences and sequelae on the patient are multiple and although surgical options offer good long-term results, it is necessary to properly select the patient, through multidisciplinary teams, to try to minimize potential complications.

Recommendations on the treatment of metastatic hormone-sensitive prostate cancer: Patient selection.

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC.

GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy.

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.

GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models.

The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.

TAF7L REGULATES EARLY STAGES OF MALE GERM CELL DEVELOPMENT.

Male germ cell development is dependent on the orchestrated regulation of gene networks. TATA-box binding protein associated factors (TAFs) facilitate interactions of TATA-binding protein with the TATA element, which is known to coordinate gene transcription during organogenesis. TAF7 like (Taf7l) is situated on the X chromosome and has been implicated in testis development. We examined the biology of TAF7L in testis development using the rat. Taf7l was prominently expressed in preleptotene to leptotene spermatocytes. To study the impact of TAF7L on the testis we generated a global loss-of-function rat model using CRISPR/Cas9 genome editing. Exon 3 of the Taf7l gene was targeted. A founder was generated possessing a 110 bp deletion within the Taf7l locus, which resulted in a frameshift and the premature appearance of a stop codon. The mutation was effectively transmitted through the germline. Deficits in TAF7L did not adversely affect pregnancy or postnatal survival. However, the Taf7l disruption resulted in male infertility due to compromised testis development and failed sperm production. Mutant germ cells suffer meiotic arrest at the zygotene stage, with defects in sex body formation and meiotic sex chromosome inactivation. This testis phenotype was more pronounced than previously described for the subfertile Taf7l null mouse. We conclude that TAF7L is essential for male germ cell development in the rat.

CONDITIONALLY MUTANT ANIMAL MODEL FOR INVESTIGATING THE INVASIVE TROPHOBLAST CELL LINEAGE.

Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade into the uterus where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 ( Prl7b1 ) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their contributions to trophoblast-guided uterine spiral artery remodeling.

Budget impact analysis of transurethral water vapor therapy for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia in the Spanish national healthcare system.

BACKGROUND: Several surgical treatments are available for managing lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). Water vapor thermal therapy (WVTT) is a new minimally invasive therapy. This study estimates the budget impact of introducing WVTT for LUTS/BPH into the Spanish health care system. METHODS: A model simulated the evolution of men over 45 years of age with moderate-severe LUTS/BPH after surgical treatment, over a 4-year time horizon, from the Spanish public health care service´s perspective. The technologies in scope included those most used in Spain: WVTT, transurethral resection (TURP), photoselective laser vapourization (PVP) and holmium laser enucleation (HoLEP). Transition probabilities, adverse events and costs were identified from the scientific literature and validated by a panel of experts. Sensitivity analyses were performed by varying the most uncertain parameters. RESULTS: Per intervention, WVTT resulted in savings of €3,317, €1,933 and €2,661 compared to TURP, PVP and HoLEP. Over a 4-year time horizon, when performed in 10% of the cohort of 109,603 Spanish males with LUTS/BPH, WVTT saved €28,770,125 against the scenario without WVTT availability. CONCLUSIONS: WVTT could reduce the cost of managing LUTS/BPH, increase the quality of health care and reduce the length of procedure and hospital stay.

Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape.

The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells. We show that integrating chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enables identification of transcription factors and regulatory mechanisms critical for extravillous trophoblast cell development. We elucidate functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of extravillous trophoblast cell development. EPAS1 is identified as an upstream regulator of key extravillous trophoblast cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, is linked to pregnancy loss and birth weight. Collectively, we reveal activation of a dynamic regulatory network and provide a framework for understanding extravillous trophoblast cell specification in trophoblast cell lineage development and human placentation.

The role of minimally invasive spine surgery in the treatment of vertebral metastasis: A narrative review. / El papel de la cirugía mínimamente invasiva de columna en el tratamiento de las metástasis vertebrales: una revisión narrativa.

BACKGROUND: Spinal metastases are a very common problem which dramatically affects the quality of life of cancer patients. The objective of this review is to address the issue of how minimally invasive surgery can play an important role in treating this pathology. METHODS: A literature review was performed, searching in the Google Scholar, PubMed, Scopus and Cochrane databases. Relevant and quality papers published within the last 10 years were included in the review. RESULTS: After screening the 2184 initially identified registers, a total of 24 articles were included for review. CONCLUSION: Minimally invasive spine surgery is specially convenient for fragile cancer patients with spinal metastases, because of its reduced comorbidity compared to conventional open surgery. Technological advances in surgery, such as navigation and robotics, improve accuracy and safety in this technique.

Water vapor thermal therapy: Technical variations among spanish hospitals and efficacy at 2-year follow-up.

AIM: The aim of this work is to evaluate the initial experience with water vapor thermal therapy (WVTT) for benign prostatic hyperplasia (BPH) in Spanish university hospitals, as well as to describe the differences in technique and follow-up between centers. MATERIALS AND METHODS: This retrospective observational multicenter study collected baseline characteristics, surgical, postoperative and follow-up data at 1, 3, 6, 12 and 24 months, including validated questionnaires, flowmetric variations, complications, and the need for pharmacological or surgical treatment following the procedure. Possible triggers for postoperative acute urinary retention (AUR) were also analyzed. RESULTS: A total of 105 patients were included. No differences were observed between the groups with and without AUR with respect to catheterization time (5 and 4.3 days respectively, P=.178), or prostate volume (47.9g and 41.4g respectively, P=.147). The mean improvement at 3, 6, 12 and 24 months in terms of peak flow was 5.3, 5.2, 4.2 and 3.8ml/s, respectively. As for ejaculation, an improvement was observed after 3 months of follow-up and was maintained over time. CONCLUSIONS: Minimally invasive treatment for BPH with WVTT shows good functional outcomes at 24 months follow-up, without significant impairment of sexual function and a low incidence of complications. There are minor inter-hospital variations, mainly in the immediate postoperative period.

[Translated article] The role of minimally invasive spine surgery in the treatment of vertebral metastasis: A narrative review.

BACKGROUND: Spinal metastases are a very common problem which dramatically affects the quality of life of cancer patients. The objective of this review is to address the issue of how minimally invasive surgery can play an important role in treating this pathology. METHODS: A literature review was performed, searching in the Google Scholar, PubMed, Scopus and Cochrane databases. Relevant and quality papers published within the last 10 years were included in the review. RESULTS: After screening the 2184 initially identified registers, a total of 24 articles were included for review. CONCLUSION: Minimally invasive spine surgery is specially convenient for fragile cancer patients with spinal metastases, because of its reduced comorbidity compared to conventional open surgery. Technological advances in surgery, such as navigation and robotics, improve accuracy and safety in this technique.

[Translated article] The role of minimally invasive spine surgery in the treatment of vertebral metastasis (Part 1): A clinical review.

Spinal metastases represent a significant burden on the quality of life in patients affected by active oncological disease due to the high incidence of pain syndromes, spinal deformity, and neurological impairment. Surgery plays a decisive role in improving quality of life by controlling pain, restoring neurological function and maintaining spinal stability, as well as contributing to the response to medical therapy. Minimally invasive surgery (MIS) is a treatment option in certain patients with high surgical risk since it has a low rate of complications, intraoperative bleeding, hospital stay, and offers similar results to open surgery. In this review, we present the role of MIS in this pathology and some cases treated in our hospital.

The role of minimally invasive spine surgery in the treatment of vertebral metastasis (part 1): A clinical review. / El papel de la cirugía mínimamente invasiva de columna en el tratamiento de las metástasis vertebrales (parte 1): una revisión clínica.

Spinal metastases represent a significant burden on the quality of life in patients affected by active oncological disease due to the high incidence of pain syndromes, spinal deformity, and neurological impairment. Surgery plays a decisive role in improving quality of life by controlling pain, restoring neurological function and maintaining spinal stability, as well as contributing to the response to medical therapy. Minimally invasive surgery (MIS) is a treatment option in certain patients with high surgical risk since it has a low rate of complications, intraoperative bleeding, hospital stay, and offers similar results to open surgery. In this review, we present the role of MIS in this pathology and some cases treated in our hospital.

Ureteroileal anastomosis stricture after urinary diversions performed by open, laparoscopic and robotic approaches. Incidence and management in a tertiary care center.

INTRODUCTION: Ureteroileal anastomosis stricture is a frequent complication after radical cystectomy and ileal conduit or orthotopic neobladder formation. We analyze their incidence based on the technique for urinary diversion and on the surgical approach (open, laparoscopic or robot-assisted). Stricture management is described, along with surgical outcomes. MATERIAL AND METHODS: Descriptive retrospective study over 6 years in patients who underwent urinary diversion using ileum (ileal conduit or orthotopic neobladder). Demographic data, comorbidities, surgical approach, complications, and outcomes were collected. Minimum follow-up of 1 year. Comparison between groups using Chi-square test for dichotomous variables. Quantitative variables were compared using the Student's t-test for independent groups or Mann-Whitney test. Statistical significance if P < .05. RESULTS: The study included 182 patients (84% males and 16% females). Mean age 68 years. Cystectomy approach: laparoscopic (67/37%), robot-assisted (63/35%), open (43/24%). Urinary diversion: ileal conduit (138/76%) and orthotopic ileal neobladder (44/24%). Uretericre implantation technique: Bricker (108/59%) and Wallace (47/26%). Ureteroileal anastomosis strictures (50/27%): bilateral (26), left (16) and right (8). Strictures according to cystectomy approach: laparoscopic (23/46%), robot-assisted (16/32%), open (9/18%). Treatment of strictures (33/18%): ureteric reimplantation (13), indwelling nephrostomy (13), endoscopic dilatation (4), nephroureterectomy (2), endoureterotomy (1). Ureteroileal reimplantation approach: laparoscopic (5/38%), robot-assisted (6/46%), open (2/15%). Outcomes after reimplantation: restenosis (0/0%), reintervention (3/23%), contralateral ureteroileal stricture (1/8%). CONCLUSION: Surgical approach in cystectomy does not influence future development of ureteroileal strictures. Laparoscopic and robot-assisted ureteroileal reimplantation achieves high success rates.