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Ovarian carcinoma (OC) is a malignancy with grave prognosis owing to its high recurrence rate and broad resistance to a variety of apoptosis-inducing chemotherapeutic agents. Induction of alternative, non-apoptotic cell death represents a novel strategy for anti-cancer therapies worldwide. Ferroptosis is a recently defined type of non-apoptotic cell death driven by the accumulation of iron-dependent lipid reactive oxygen species (ROS), resulting in membrane damage and cell rupture. Lines of evidence suggested that OC may be susceptible to ferroptosis. However, the exact effects mediated by ferroptosis and the underlying regulatory mechanisms in OC are not fully characterized. Herein, we sought to explore the susceptibility of a number of OC cell line models towards ferroptosis and investigate the possibility of enhancing conventional platinum-based chemotherapy with ferroptosis inducers. Ferroptosis inducers Erastin and RSL3 dose-dependently induced ferroptotic cell death in ovarian cancer cell lines OVCAR3 and TUOC1, hallmarked by a significant decrease of GSH level and increase of ROS and lipid peroxidation levels after treatment. Treatment by a lipid ROS scavenger ferrostatin-1 (Fer-1), but not by the apoptosis inhibitor Z-VAD-FMK, significantly rescued OVCAR3 and TUOC1 cells from Erastin- and RSL3- induced cell death. Additionally, Erastin and RSL3 could significantly promote cytotoxicity of cisplatin in a cisplatin-resistant ovarian cancer cells OVCA420. Collectively, our results indicate a crucial role of ferroptosis in susceptibility of ovarian carcinomas, suggesting a potential anticancer strategy. Citation Format: Jing Li, Oscar Gee Wong, Annie Nga Cheung. Ovarian carcinoma cells are susceptible to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 987.

Radiofrequency renal denervation (RDN) is under investigation for treatment of hypertension with variable success. We developed preclinical models to examine the dependence of ablation biomarkers on RDN treatment parameters and anatomical variables. 129 porcine renal arteries were denervated with an irrigated RF catheter with multiple helically arrayed electrodes. Nerve effects and ablation geometries at 7d were characterized histomorphometrically and correlated with associated renal norepinephrine (NEPI) levels. NEPI exhibited a threshold dependence on the percentage of affected nerves (%AN) across the range of treatment durations (30–60sec) and power set-points (6–20W). For 15W/30sec treatments, NEPI reduction and %AN tracked with number of electrode treatments, confirming additive effects of helically staggered ablations. Threshold effects were only attained when ≥four electrodes were powered. Histomorphometry and computational modeling both illustrated that RF treatments directed at large neighboring veins resulted in sub-average ablation areas, and therefore contributed suboptimally to efficacy. Account for measured nerve distribution patterns and the annular geometry of the artery revealed that, regardless of treatment variables, total ablation area and circumferential coverage were the prime determinants of RDN efficacy, with increased efficacy at smaller diameters. SUMMARY: Large animal experiments supported by computational and statistical models that account for arterial microanatomy and nerve distribution explain the dependence of RDN efficacy on procedural parameters, e.g. number of electrode treatments, and anatomic parameters, e.g. arterial diameter and the proximity of veins to ablation sites.

For pathological investigation, vascular tissues implanted with biomaterials or medical devices require microscopic histology and scanning electron microscopy (SEM) assessment to evaluate biocompatibility with the vascular luminal surface. However, these valuable specimens are often susceptible to SEM and histology tissue preparation artifacts. Correlative variable pressure-scanning electron microscopy (VP-SEM) and histology methods were developed and evaluated, using current SEM technology, allowing direct imaging of hydrated samples without lengthy tissue processing, labor, equipment, and their sequela artifacts. Unstained and silver-stained, fixed swine carotid arteries were assessed using a cooling stage and an environmental secondary electron detector. After VP-SEM imaging, arteries were processed for histology evaluation. Assessment of luminal endothelial surface SEM images and tissue histology of the underlying mural wall was made to determine if low vacuum, cryo-freezing, electron beam exp...

available in PMC 2016 March 23, Aims: We sought to evaluate the incidence of embolic material in porcine brains following vascular interventions using hydrophilic-coated sheaths. Methods and results: A new self-expanding stent and delivery system (SDS) was deployed through a hydrophilic-coated (Flexor® Ansel; Cook Medical, Bloomington, IN, USA) guiding sheath into the iliac and/or carotid arteries of 23 anaesthetised Yucatan mini swine. The animals were euthanised at three, 30, 90 and 180 days and their brains were removed for histological analysis. In an additional single control animal, the guiding sheath was advanced but no SDS was deployed. Advancement of the coated guiding sheath with or without the SDS was associated with frequent foreign material in the arterioles of the brain. The embolic material was amorphous, non-refractile, non-crystalline, non-birefringent and typically lightly basophilic with a slightly stippled appearance on haematoxylin and eosin (H&E) stain. Material was observed at all time points involving 54% of all study animals (i.e., test and control) and in vitro after incubation in 0.9% saline. Conclusions: The hydrophilic coating on a clinically used guiding sheath readily avulses and embolises to the brain during deployment in a porcine model. Further documentation of this effect and monitoring in clinical scenarios are warranted., National Institutes of Health (U.S.) (NIH (R01 GM 49039))

Sex-related differences have been noted in cardiovascular anatomy, pathophysiology, and treatment responses, yet we continued to drive evaluation of vascular device development in animal models without consideration of animal sex. We aimed to understand sex-related differences in the vascular responses to stent implantation by analyzing the pooled data of endovascular interventions in 164 Yucatan mini-swine (87 female, 77 male). Bare metal stents (BMS) or drug-eluting stents (DES) were implanted in 212 coronary arteries (63 single BMS implantation, 68 single DES implantation, 33 overlapped BMS implantation, and 48 overlapped DES implantation). Histomorphological parameters were evaluated from vascular specimens at 3-365 days after stent implantation and evaluated values were compared between female and male groups. While neointima formation at all times after implantation was invariant to sex, statistically significant differences between female and male groups were observed in injury, inflammation, adventitial fibrosis, and neointimal fibrin deposition. These differences were observed independently, i.e., for different procedure types and at different follow-up timings. Only subtle temporal sex-related differences were observed in extent and timing of resolution of inflammation and fibrin clearance. These subtle sex-related differences may be increasingly important as interventional devices meld novel materials that erode and innovations in drug delivery. Erodible materials may act differently if inflammation has a different temporal sequence with sex, and drug distribution after balloon or stent delivery might be different if the fibrin clearance speaks to different modes of pharmacokinetics in male and female swine.

Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some of them fatal. To study the disease pathogenesis, we investigated the expression of Snx10 and created mouse models in which Snx10 was knocked down globally or knocked out in osteoclasts. Endocytosis is severely defective in Snx10-deficent osteoclasts, as is extracellular acidification, ruffled border formation, and bone resorption. We also discovered that Snx10 is highly expressed in stomach epithelium, with mutations leading to high stomach pH and low calcium solubilization. Global Snx10-deficiency in mice results in a combined phenotype: osteopetrosis (due to osteoclast defect) and rickets (due to high stomach pH and low calcium availability, resulting in impaired bone mineralization). Osteopetrorickets, the paradoxical association of insufficient mineralization in the context of a positive total body calcium balance, is thought to occur due to the inability of the osteoclasts to maintain normal calcium–phosphorus homeostasis. However, osteoclast-specific Snx10 knockout had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Moreover, supplementation with calcium gluconate rescued mice from the rachitic phenotype and dramatically extended life span in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized. We conclude that tissue-specific effects of Snx10 mutation need to be considered in clinical approaches to this disease entity. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes fatal consequences. These studies established an essential role for Snx10 in bone homeostasis and underscore the importance of gastric acidification in calcium uptake., Author Summary We found that Snx10, a molecule expressed in osteoclasts, was also expressed in the stomach. Studies in tissue specific or global knock-down mice showed that Snx10 deficiency resulted in a phenotype that was a consequence of deficiencies in both osteoclasts and gastric zymogenic cells. Our studies add to a growing list of genes, including atp6i (Tcirg1), whose expression is required both in bone and stomach to maintain normal gastric acidification and calcium absorption. This work provides additional insight into the mechanisms governing the regulation of bone accrual by the gastrointestinal tract. Because osteopetrorickets has not been described clinically in Snx10-related osteopetrosis, these findings highlight the importance of considering impaired acidification in both stomach and bone in osteopetrotic patients with mutations in SNX10 and other genes with similar patterns of expression and activities. Because defects in gastric differentiation and/or gastric acidification may cause or contribute to hypocalcemia, bone insufficiency, and early death, our results suggest that dietary calcium supplementation could be a life-saving intervention in these patients.

Peripheral vascular interventions frequently employ guiding sheaths with hydrophilic coatings raising the concern for the embolization of this material clinically as increasingly documented. A peripheral stent and delivery system (SDS) were deployed in the iliac and/or carotid arteries of 23