En-block butterfly excision of posterior compartment deep endometriosis: The first experience with the new surgical robot Hugo™ RAS.

Background: Minimally invasive surgery is the gold standard treatment for deep endometriosis when medical management fails. In selected cases, such as when bowel or urinary tract are involved, robotic assisted surgery can be useful due to its characteristics of high dexterity and manoeuvrability. This is the first case of robotic en-bloc excision of posterior compartment deep endometriosis performed with the new HugoTM RAS system. Objective: The purpose of this video article is to show for the first time the feasibility of bowel surgery for deep endometriosis with this new robotic device. Materials and Methods: A 24-years-old woman affected by severe dysmenorrhea, chronic pelvic pain, dyschezia and dyspareunia underwent to deep endometriosis excision using the new robotic platform HugoTM RAS system at the Unit of Gynaecological Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Main outcome measures: Intraoperative data, docking set up, post-operative outcomes up to three months follow up were evaluated. Results: The surgical procedure was carried out without intra-operative or post-operative complications, operative time (OT) was 200 minutes, while docking time was 8 minutes. No system errors or faults in the robotic arms were registered. Post-operative complete disease-related symptoms relief was reported. Conclusion: According to our results, the introduction of this new robotic platform in the surgical management of deep endometriosis seems to be feasible, especially in advanced cases. However, further studies are needed to demonstrate the benefits of this surgical system and the advantages of robotic surgery compared to laparoscopy in this subset of patients.

Characterization of circulating immune cells and correlation with Tie2/Angiopoietins level in well differentiated neuroendocrine gastroenteropancreatic tumors: a cross-sectional analysis.

PURPOSE: The immune environment represents a new, but little explored, tool for understanding neuroendocrine neoplasms (NENs) behavior. An immunosuppressed microenvironment is hypothesized to promote NENs progression. A missing profiling of circulating leukocyte and peripheral blood mononuclear cells (PBMCs) subpopulations would open new perspectives in the still limited diagnostic-therapeutic management of NENs. METHODS: A cross-sectional case-control pilot study was performed recruiting 30 consecutive subjects: 15 patients naïve to treatment, with histologically proven gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and 15 healthy controls, matched for age and sex. PBMCs subpopulations were studied by flow cytometry. Soluble Tie2 (sTie2), Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2) were evaluated by ELISA. RESULTS: Immune cell profiling revealed a significant lower CD3-CD56+ natural killer (NK) cell count in NETs vs controls (p = 0.04). NK subset analysis showed a reduced relative count of CD56+CD16+ NK cells (p =0.002) in NETs vs controls. Patients with NET showed a higher percentage of CD14+CD16++ non-classical monocytes (p = 0.01), and a lower percentage of CD14+CD16+ intermediate monocytes (p = 0.04). A decrease in percentage (p = 0.004) of CD4+ T-helper lymphocytes was found in NET patients. Evaluation of cellular and serum angiopoietin pathway mediators revealed in NET patients a higher relative count of Tie2-expressing monocytes (TEMs) (p < 0.001), and high levels of Ang-1 (p = 0.003) and Ang-2 (p = 0.002). CONCLUSIONS: Patients with GEP-NET presented an immunosuppressed environment characterized by a low count of cytotoxic NK cells, a high count of anti-inflammatory non-classical monocytes, and a low count of T-helper lymphocytes. Higher levels of TEMs and angiopoietins suggest a crosstalk between innate immunity and angiogenic pathways in NETs.

Surgical and functional impact of nerve-sparing radical hysterectomy for parametrial deep endometriosis: a single centre experience.

Background: Deep endometriosis (DE) usually creates a distortion of the retroperitoneal anatomy and may infiltrate the parametria with an oncomimetic pathway similar to cervical cancer. The condition represents a severe manifestation of endometriosis that may result in a functional impairment of the inferior hypogastric plexus. An extensive surgical resection may be required with an associated risk of increased neurogenic postoperative pelvic organ dysfunction. Objectives: To evaluate the post-operative function and complications following hysterectomy with posterolateral parametrial resection for DE. Materials and Methods: In total, 23 patients underwent radical hysterectomy for DE with the parametria involved. The severity of pain was assessed by the Visual Analogue Scale (VAS) score. The KESS, GQLI, BFLUTS and FSFI were used to examine the gastrointestinal, urinary and sexual functions respectively. Intra and post-operative complications were recorded. Main outcome measures: The main outcomes were gastrointestinal, urinary and sexual function and intra and post-operative complications. Results: Dyschezia, dyspareunia and chronic pelvic pain were significantly reduced following hysterectomy. Furthermore, an improvement of gastrointestinal function was observed, while sexual functions, examined by FSFI and urinary symptoms, examined by BFLUTS, was not shown to be significant. Conclusion: The modified nerve-sparing radical hysterectomy for DE results in an improvement of symptoms. Nevertheless, despite the nerve-sparing approach, this procedure may be associated with a not-negligible risk of post-operative bladder voiding deficit. What is new?: This is the first study that focuses on parametrial endometriosis using validated questionnaires to assess functional outcomes following radical hysterectomy for DE.

Hysteroembryoscopy and hysteroscopic uterine evacuation of early pregnancy loss: A feasible procedure in selected cases.

Hysteroscopic uterine evacuation of early pregnancy loss using tissue removal devices seems to be a safe and feasible procedure in selected cases. The hysteroscopic approach allows the precise localisation of the gestational sac inside the uterine cavity. The endoscopic approach allows one to perform hysteroembryoscopy before uterine evacuation and this technique appears to be more accurate than dilatation & curettage for fetal chromosome karyotyping, with lower maternal cell contamination. This "under vision" procedure may reduce retained products of conception rates and risk of intrauterine adhesions formation.

MicroRNA loaded edible nanoparticles: an emerging personalized therapeutic approach for the treatment of obesity and metabolic disorders.

Obesity is a metabolic chronic disease whose prevalence is strongly growing in the last years, reaching pandemic proportions. Nowadays weight loss, achieved through lifestyle changes, is the first line therapeutic objective, although great inter-individual variabilities influence response to treatment, suggesting the involvement of epigenetic factors. In this contest, there is increasing recognition of the role of small RNA molecules, particularly microRNAs in the epigenetic regulation of genes involved in adipose tissue and glucose metabolism and several microRNAs have been found to be dysregulated in obesity and metabolic diseases. The development of novel personalized therapeutic strategies using microRNAs bears promise. However, the application of naked microRNAs has been hampered by their low specificity and sensitivity. In a recent issue of Theranostics, Kumar et al. explored the possibility of microRNA delivery through ginger-derived nanoparticles (GDNPs) as an alternative therapeutic approach for obesity treatment. The results reported by Kumar et al., addressing non-coding RNAs and edible plant derived nanoparticles, open new perspectives for the application of this innovative and safe delivery system in the clinical practice for the treatment of obesity and other metabolic disorders.

Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury.

The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c-Kit(TgD814Y) receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-Kit(TgD814Y) mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit(+) cardiac cell number was not different compared with wt mice. However, when c-Kit(TgD814Y) mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit(+)CD31(+) endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45(-)c-Kit(+) cardiac stem cells isolated from transgenic c-Kit(TgD814Y) mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival.

Fgf9 inhibition of meiotic differentiation in spermatogonia is mediated by Erk-dependent activation of Nodal-Smad2/3 signaling and is antagonized by Kit Ligand.

Both fibroblast growth factor 9 (Fgf9) and Kit Ligand (Kl) signal through tyrosine kinase receptors, yet they exert opposite effects on meiotic differentiation in postnatal spermatogonia, Fgf9 acting as a meiosis-inhibiting substance and Kl acting as a promoter of the differentiation process. To understand the molecular mechanisms that might underlie this difference, we tried to dissect the intracellular signaling elicited by these two growth factors. We found that both Fgf9 and Kl stimulate Erk1/2 activation in Kit+ (differentiating) spermatogonia, even though with different time courses, whereas Kl, but not Fgf9, elicits activation of the Pi3k-Akt pathway. Sustained Erk1/2 activity promoted by Fgf9 is required for induction of the autocrine Cripto-Nodal-Smad2/3 signaling loop in these cells. Nodal signaling, in turn, is essential to mediate Fgf9 suppression of the meiotic program, including inhibition of Stra8 and Scp3 expression and induction of the meiotic gatekeeper Nanos2. On the contrary, sustained activation of the Pi3k-Akt pathway is required for the induction of Stra8 expression elicited by Kl and retinoic acid. Moreover, we found that Kl treatment impairs Nodal mRNA expression and Fgf9-mediated Nanos2 induction, reinforcing the antagonistic effect of these two growth factors on the meiotic fate of male germ cells.

SOHLH1 and SOHLH2 directly down-regulate STIMULATED BY RETINOIC ACID 8 (STRA8) expression.

As the name implies, Stimulated by Retinoic Acid 8 is an early retinoic acid (RA) responsive gene pivotal for the beginning of meiosis in female and male germ cells. Its expression is strictly time-dependent and cell-specific (pre-meiotic germ cells) and likely requires a complex mechanism of regulation. In this study, we demonstrate a direct negative control of SOHLH1 and SOHLH2, 2 germ cell specific bHLH transcription factors, on Stra8 expression. We observed a negative correlation between STRA8 and SOHLH1 expression in prepuberal differentiating mouse KIT(+) spermatogonia and found that SOHLH1 and SOHLH2 were able to directly and cooperatively repress STRA8 expression in cell lines in vitro through binding to its promoter. We also identified 2 canonical E-Box motives in the Stra8 promoter that mediated the negative regulation of SOHLH1 and SOHLH2 on these gene both in the cell lines and KIT(+) spermatogonia. We hypothesize that this novel negative activity of SOHLH1 and SOHLH2 in male cooperates with that of other transcription factors to coordinate spermatogonia differentiation and the RA-induced meiosis and in female ensures STRA8 down-regulation at mid-end stages of meiotic prophase I.

[Non-immunological therapy in nephropathies leading to chronic renal failure and in post-transplant chronic renal dysfunction]. / La terapia non immunologica delle nefropatie con insufficienza renale cronica e della disfunzione cronica da trapianto.

With its aging population, the Western world is experiencing a significant increase in the prevalence of chronic kidney disease, which has actually been defined as ''pandemic''. The high mortality and comorbidity, especially in terms of cardiovascular disease, have led to a significant increase in hospitalizations and rising public health expenditure, setting a trend that will become unsustainable in the next decades, even in the most developed countries. These epidemiological data have underlined the need for prevention campaigns and urged researchers and clinicians to develop new and more specific treatments able to slow down the progression of chronic kidney disease towards dialysis. To obtain such results, a deeper understanding of the pathogenetic mechanisms of nephropathy progression is mandatory. Once sclerosis is established and the initial pathogenetic noxa, whether or not involving the glomeruli, has been extinguished, the sclerotic progression of different nephropathies follows a standard pathway, irrespective of the initial cause. The achievement of an effective therapy for this condition, in native kidneys as well as transplanted organs, is the third-millennium challenge for nephrologists. In this review we will first describe the main risk factors and pathogenetic mechanisms involved in nephropathy progression and then discuss the results obtained with drugs that basic research has identified as potentially useful in experimental animal models as well as rigorous clinical trials.