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Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasis-promoting tumor-host interaction and a potential therapeutic target.

Robustness is a prominent feature of most biological systems, but most of the current efforts have been focused on studying homogeneous molecular networks. Here the authors propose a comprehensive framework for understanding how the interactions between genes, proteins, and metabolites contribute to the determinants of robustness.

Abstract The coronavirus disease 2019 (COVID-19) has been declared as pandemic by the World Health Organization and is causing substantial morbidity and mortality all over the world. Type 2 diabetes, hypertension, and cardiovascular disease significantly increase the risk for hospitalization and death in COVID-19 patients. Hypoglycemia and hyperglycemia are both predictors for adverse outcomes in hospitalized patients. An optimized glycemic control should be pursued in patients with diabetes and SARS-CoV-2 infection in order to reduce the risk of severe COVID-19 course. Both insulin and GLP-1RAs have shown optimal glucose-lowering and anti-inflammatory effects in type 2 diabetic patients and may represent a valid therapeutic option to treat asymptomatic and non-critically ill COVID-19 diabetic patients.

Abstract Cardiovascular outcome trials (CVOTs) have demonstrated a significant reduction of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D) treated by SGLT-2 inhibitors. This holds true in the presence of background therapy with statins in most patients. Noteworthy, this SGLT-2 inhibitors effect is unique because, at variance with other components of cardiorenal protection, MACE prevention does not appear to be a class effect. Here, we present meta-analysis of the four key CVOTs indicating a major role of renal function in determining the extent of MACE prevention, with the benefit increasing in more severe kidney disease, that is, a high-risk condition where effectiveness of the traditional approach with statins is reduced.

Miriam Longo,1,2 Lorenzo Scappaticcio,1 Giuseppe Bellastella,1,2 Vlenia Pernice,1 Paolo Cirillo,1 Antonietta Maio,1 Filomena Castaldo,1,2 Dario Giugliano,1,2 Katherine Esposito,1,3 Maria Ida Maiorino1,2 On Behalf of the METRO Study Group1Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy; 2Unit of Endocrinology and Metabolic Diseases, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy; 3Unit of Diabetes, University of Campania “Luigi Vanvitelli”, Naples 80138, ItalyCorrespondence: Maria Ida MaiorinoUnit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, Naples 80138, ItalyTel +39 0815665289Fax +39 0815665032Email mariaida.maiorino@unicampania.itPurpose: Type 1 diabetes is associated with high risk of cardiovascular disease (CVD). Reduced levels of circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) have been indicated as a risk factor for adverse cardiovascular outcomes and death in people at high cardiovascular risk. The aim of the present study was to evaluate the change in CPCs and EPCs levels in a population of young type 1 diabetic patients treated with intensive insulin regimen over a period of 2 years.Patients and Methods: A total of 204 type 1 diabetic patients, of whom 84 treated with insulin pump (CSII) and 120 with multiple daily insulin injections (MDI), completed a 2-year follow-up. Clinical measurements, including the indices of glycemic control and glucose variability, were collected at baseline and after 2 years. Both CPC and EPC cell count were assessed by flow cytometry.Results: Mean age of participants was 24.5 years and mean diabetes duration was 13.6 years. After 2 years, we found a significant reduction of HbA1c (− 0.3% versus baseline, P < 0.001), associated with decrease in mean amplitude of glucose excursion (MAGE) (− 0.5 mmol/L versus baseline, P< 0.001), continuous overall net glycemic action (CONGA) (− 0.2 mmol/L versus baseline, P=0.006), and blood glucose standard deviation (BGSD) (− 0.2 mmol/L versus baseline, P< 0.001). The number of all EPCs phenotypes, but not CPC cell count, significantly raised up in the entire population, with higher increase in CSII group. MAGE resulted as an independent predictor for increased levels of both CD34+ (P = 0.020) and CD34+KDR+ (P = 0.004) cell count in the whole population.Conclusion: Over a 2-year follow-up, young type 1 diabetic patients showed an increase in circulating EPCs levels, which was higher in patients with CSII. Glucose variability resulted as an independent predictor of the raised levels of EPCs in this selected population.Keywords: endothelial progenitor cells, circulating progenitor cells, glucose variability, type 1 diabetes, CSII, MDI

Complex diseases often share genetic determinants and symptoms, but the mechanistic basis of disease interactions remains elusive. Here, the authors propose a network topological measure to identify proteins linking complex diseases in the interactome, and identify mediators between COPD and asthma.

Varicocele affects 15% of male population but it is more frequently identified in patients searching medical care for infertility. The impact of varicocele on semen production and fertility is known, but the relationship between clinical varicocele and impaired hormonal production is not clear. In published literature there are some studies regarding hormonal alterations in patients with varicocele but no review in which all the hormonal findings are explained. The aim of this review is to evaluate, by most common search engine, what is known about hormonal alterations in varicocele-bearing patients, to verify if a cause-effect relationship is documented and to give a useful contribution to in clinical management of this kind of patients. We found contradictory results about hormonal status from literature. Some studies confirmed a decrease of testosterone levels and higher FSH and LH levels that normalize after varicocelectomy, others found lower than normal levels of dihydrotestosterone due to decreased activity of epididymal 5-α-reductase. Lower circulating Anti-Müllerian Hormone levels, accompanied by a decreased Inhibin-B level, were reported as indicators of the decreased Sertoli cells function in varicocele-bearing adult patients. The finding of higher basal 17-OH-progesterone concentrations in patients with varicocele was explained by some authors with a testicular C-17,20-lyase deficiency. There is no doubt that varicocele could led to hormonal alterations. This review proposes that the impaired free sexual steroid levels are the result of a slight, deep-rooted defect in the testes of a certain amount of men with varicocele but further multicentre, randomized controlled studies remain mandatory to better clarify the hormonal features of patients with varicocele and to assess the utility of hormonal evaluation for establishing the duration of varicocele and for better identifying patients who need surgical correction.

Objective: To report our technique for pure laparoscopic nephroureterectomy in horseshoe kidney, specifically focusing on vascular anatomy and surgical tips & tricks. Patient and surgical procedure: The clinical case of a 69 years-old woman with normal body mass index and controlled hypertension is presented. The patient came to our observation with gross hematuria. Cystoscopy was negative but urine cytology showed high grade atypia suggestive for transitional cell carcinoma. Computed tomography scan with urography showed a right-sided mid-lower calyx 28 mm lesion, in the setting of a horseshoe kidney. The 3D reconstruction showed the altered vascular anatomy, and the proximity of the renal isthmus to the caudal portion of the abdominal aorta. The patient was counseled for pure laparoscopic transperitoneal nephroureterectomy. Results: Operative time was 220 min. Blood losses were negligible. Length of hospitalization was 4 days. No Complications occurred. Hemoglobin at discharge was 12.1 g/dl. Creatinine at discharge was 1.0 mg/dl. Final pathology confirmed upper urinary tract transitional cell carcinoma of the medium-lower calyx, 2 cm in size, Ta, G2, R0. Conclusions: Although robotics is gaining broader diffusion due to intrinsic advantages, nephroureterectomy remains feasible and safe via a pure laparoscopic approach. Pure laparoscopic approach could represent the ideal indication in case of complex anatomy. Indeed, typical anatomical landmarks of nephrectomy can be altered in such cases. The possibility of a fast “port-hopping” is the most interesting peculiarity of pure laparoscopic approach, allowing for optic/instruments exchange by the operating surgeon. Vascular stapler is a viable instrument for resecting the isthmus of a horseshoe kidney in a bloodless field. In our experience, the 60 mm one with its higher moment of force performed better.

Objective To report our technique for thulium laser enucleation of prostate (ThuLEP) focusing on anatomical and surgical details to pursue an ejaculation sparing intent.Patient and surgical procedure The clinical cases of two obstructed patients with an 80 ml - no median lobe - and a 45 ml - with median lobe - prostates are shown. The patients were counseled for ejaculation sparing ThuLEP. The techniques are reported step by step in the full text manuscript and the accompanying video.Results Enucleation time were 60 and 20 min, with 70.000 and 32.000 joules delivered, respectively. Catheterization time was 2 days. No complications occurred. At one-month post-operation both patients had maximum urinary flow at uroflowmetry > 20 ml/s, with virtually absent post-void residual volume. Ejaculatory function was preserved in both patients.Conclusions Based on our experience, we believe that when the ejaculatory ducts’ orifices together with the deep adenomatous tissue accommodating the ejaculatory ducts and the parallel smooth muscular fibers of the genital sphincter are spared, there is the concrete chance to pair the relief from benign prostatic obstruction and the preservation of the ejaculatory function.

GPx8 is a mammalian Cys-glutathione peroxidase of the endoplasmic reticulum membrane, involved in protein folding. Its regulation is mostly unknown. We addressed both the functionality of two hypoxia-response elements (HREs) within the promoter, GPx8 HRE1 and GPx8 HRE2, and the GPx8 physiological role. In HeLa cells, treatment with HIFα stabilizers, such as diethyl succinate (DES) or 2-2'-bipyridyl (BP), induces GPx8 expression at both mRNA and protein level. Luciferase activity of pGL3(GPx8wt), containing a fragment of the GPx8 promoter including the two HREs, is also induced by DES/BP or by overexpressing either individual HIFα subunit. Mutating GPx8 HRE1 within pGL3(GPx8wt) resulted in a significantly higher inhibition of luciferase activity than mutating GPx8 HRE2. Electrophoretic mobility-shift assay showed that both HREs exhibit enhanced binding to a nuclear extract from DES/BP-treated cells, with stronger binding by GPx8 HRE1. In DES-treated cells transfected with pGL3(GPx8wt) or mutants thereof, silencing of HIF2α, but not HIF1α, abolishes luciferase activity. Thus GPx8 is a novel HIF target preferentially responding to HIF2α binding at its two novel functional GPx8 HREs, with GPx8 HRE1 playing the major role. Fibroblast growth factor (FGF) treatment increases GPx8 mRNA expression, and reporter gene experiments indicate that induction occurs via HIF. Comparing the effects of depleting GPx8 on the downstream effectors of FGF or insulin signaling revealed that absence of GPx8 results in a 16- or 12-fold increase in phosphorylated ERK1/2 by FGF or insulin treatment, respectively. Furthermore, in GPx8-depleted cells, phosphorylation of AKT by insulin treatment increases 2.5-fold. We suggest that induction of GPx8 expression by HIF slows down proliferative signaling during hypoxia and/or growth stimulation through receptor tyrosine kinases.