TWEAK-Fn14-RelB Signaling Cascade Promotes Stem Cell-like Features that Contribute to Post-Chemotherapy Ovarian Cancer Relapse.

Disease recurrence in high-grade serous ovarian cancer may be due to cancer stem-like cells (CSC) that are resistant to chemotherapy and capable of reestablishing heterogeneous tumors. The alternative NF-κB signaling pathway is implicated in this process; however, the mechanism is unknown. Here we show that TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are strong inducers of alternative NF-κB signaling and are enriched in ovarian tumors following chemotherapy treatment. We further show that TWEAK enhances spheroid formation ability, asymmetric division capacity, and expression of SOX2 and epithelial-to-mesenchymal transition genes VIM and ZEB1 in ovarian cancer cells, phenotypes that are enhanced when TWEAK is combined with carboplatin. Moreover, TWEAK in combination with chemotherapy induces expression of the CSC marker CD117 in CD117- cells. Blocking the TWEAK-Fn14-RelB signaling cascade with a small-molecule inhibitor of Fn14 prolongs survival following carboplatin chemotherapy in a mouse model of ovarian cancer. These data provide new insights into ovarian cancer CSC biology and highlight a signaling axis that should be explored for therapeutic development. IMPLICATIONS: This study identifies a unique mechanism for the induction of ovarian cancer stem cells that may serve as a novel therapeutic target for preventing relapse.

Glomerular permselectivity to macromolecules in reflux nephropathy: microalbuminuria during acute hyperfiltration due to aminoacid infusion.

Reflux nephropathy is an important cause of chronic renal failure in children. After the parenchymal scar, the progression is thought to be mediated by glomerular hypertension in remnant nephrons resulting in modifications in permselectivity to macromolecules. Proteinuria correlates with a progressive course. The glomerular permselectivity to macromolecules in basal conditions and after acute hemodynamic stress was investigated in 28 children whose bilateral vesico-ureteric reflux (VUR) had been previously surgically corrected (meanly 5.6 years before) and with normal creatinine clearance (CrCl). Bilateral renal scarring (0 to 8 scale for both kidneys) was 4.3 +/- 1.6. Albuminuria (UAE) was evaluated in basal conditions and under acute hyperfiltration induced by amino acid (Aa) infusion. After isotonic saline at 310 ml/hour/1.73 m2, 6 mg/kg/min of Aa were infused for 2 hrs. UAE was significantly higher than controls in basal conditions (p < 0.01), and further increased after Aa infusion (p < 0.02). Microalbuminuria was detectable in 53.5% of the children in basal conditions and in 64.3% after Aa. Also urinary beta 2 microglobulin significantly increased at the end of the test (p < 0.001). CrCl significantly increased at the first hour (p < 0.05). Children with severe renal parenchymal scarring had greater UAE (p < 0.01) and beta 2M (p < 0.02) values after provocative test than those with mild renal damage. In 8 children GFR and ERPF were measured by means of inulin and p-hippurate clearance respectively. The variations in UAE during Aa infusion were significantly correlated with GFR dynamics (p < 0.05) while they were not influenced by ERPF modifications.(ABSTRACT TRUNCATED AT 250 WORDS)

[Screening of urologic pathology in newborns with prenatal and postnatal echography]. / Screening delle patologie urologiche nel neonato con ecografia prenatale e postnatale.

We compared the results, by prenatal ultrasonography, effected on 2592 foetus at the 15th-25th-35th weeks of gestation with the ones, made by postnatal ultrasonography, effected the 5th day of life on 2539 infants born from pregnancies previously monitored. We considered the obstructive and not obstructive malformations. The prenatal ultrasonography put in evidence 19 cases of urological pathology, which is 0.75%. The postnatal research established the truth of 14 cases, which is 0.55%; 7 cases underwent a precocious surgical operation. Percentage of positive false is 0.2%. The postnatal ultrasonography made evident 30 cases which can be considered pathological: 25 uropathy obstructive cases and 5 uropathy not-obstructive cases; 3 of them underwent precocious surgical operation. The result is 44 pathological cases (1.74% of infants). We also considered an heterogeneous group of non-nephro-urological anomalies (0.47%), a casual medical report of this research; in particular, 10 cases of surrenal hematoma and 1 case of neuroblastoma. The Authors remark that it's useful to complete the prenatal ultrasonographic research with another postnatal ultrasonographic research, particularly in the nephro-urological pathology; and they hope this system can be much more diffuse.

[Antibiotic prevention with aztreonam in urologic surgery in children]. / Profilassi antibiotica con aztreonam nella chirurgia urologica pediatrica.

In a group of 51 children aged 3 days-17 years old, 40 were given operative 8 endoscopic and 3 percutaneous surgery, while all received antibiotic prophylaxis with Aztreonam (Squibb Azactam) for the prevention of surgical infections. Preoperative uroculture revealed sterile urine in all 51 but 49 needed excretory catheters at various levels: urethral, pyelic. Drug treatment was started preoperatively at the time of narcosis and continued until catheter removal. Aztreonam was chosen for its anti-Gram negative action and absence of toxicity as reported in the literature. Urine cultures at the end of treatment and 7 days later revealed sterile urine in 49 (96%) of the children, while 2 presented asymptomatic infection by Gram positive bacteria. No significant side effects definitely attributable to the drug were encountered.

[Crossed testicular ectopia: description of a case with retention of the orthotopic gonad]. / L'ectopia testicolare crociata: descrizione di un caso con ritenzione della gonade ortotopica.

A case of transverse ectopia of the testis with ortotopic undescended testis in a baby of 2 - 1/2 years is reported. The authors stress the unusual association of ectopic and maldescended testis and describes the surgical treatment.