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Ultrasound-assisted catheter directed thrombolysis (USAT) has been shown to improve hemodynamic function and reduce bleeding complications in patients with acute massive or submassive pulmonary embolism. We performed a meta-analysis to better evaluate the efficacy and safety of USAT. We conducted an extensive literature search in PUBMED, MEDLINE, and EMBASE databases from January 1, 2008 to December 31, 2018. Efficacy outcomes of interest were pulmonary artery systolic pressure, mean pulmonary pressure, ratio of right ventricular to left ventricular diameter, cardiac index, tricuspid annular plane systolic excursion, Miller Index Score, and Qanadli Score. Safety outcomes were in-hospital mortality, long-term mortality, major and minor bleeding complications, and recurrent pulmonary embolism. Meta-analysis was performed using Cochrane Collaboration Review Manager (version 5.1). Effect size was estimated using random effects model, with 95% confidence intervals (CIs). Twenty-eight studies (n = 2,135) met inclusion criteria. Compared with pretreatment parameters, post-USAT was associated with a reduction in the mean Miller Index Score and Qanadli Score by 10.55 (95% CI −12.98 to −8.12) and 15.64 (95% CI −19.08 to −12.20), respectively. Cardiac index and tricuspid annular plane systolic excursion improved by 0.68 L/m2 (95% CI 0.49 to 0.87) and 3.68 mm (95% CI 2.43 to 4.93), respectively. Pulmonary artery systolic pressure and mean pulmonary pressure after therapy were reduced by a mean difference of 16.69 mm Hg (95% CI −19.73 to −13.65) and 12.13 mm Hg (95% CI −14.67 to −9.59) respectively. The right ventricular to left ventricular diameter dimension ratio decreased by 0.35 (95% CI −0.40 to −0.30) after therapy. In-hospital mortality in patients who underwent USAT was 2.9%, and total long-term mortality was 4.1%. Major and minor bleeding complications were seen in in 5.4% and 6.0% of patients, respectively. Recurrent events occurred in 0.2% of patients after USAT. In conclusion, USAT is a safe and effective procedure associated with significant hemodynamic and clinical improvement in patients with massive and submassive pulmonary embolism.

Obesity is associated with enhanced tumor growth and progression. Within the adipose tissue are adipose-derived stromal/stem cells (ASCs) that have been shown to convert into carcinoma-associated fibroblast (CAFs) in the presence of tumor-derived factors. However, the impact of obesity on the ASCs and on the conversion of ASCs into CAFs has not been demonstrated. In the current study, ASCs isolated from lean donors (BMI 30, obASCs). The contribution of tumor-derived factors on the conversion of ASCs to CAFs was investigated. Following exposure to cancer cells, obASCs expressed higher levels of CAF markers, including NG2, alpha-SMA, VEGF, FAP, and FSP, compared to lnASCs. To investigate the crosstalk between ASCs and breast cancer cells, MCF7 cells were serially cocultured with lnASCs or obASCs. After coculture with lnASCs and obASCs, MCF7 cells demonstrated enhanced proliferation and expressed an invasive phenotype morphologically, with more pronounced effects following exposure to obASCs. Long-term exposure to obASCs also enhanced the expression of protumorgenic factors. Together, these results suggest that obesity alters ASCs to favor their rapid conversion into CAFs, which in turn enhances the proliferative rate, the phenotype, and gene expression profile of breast cancer cells.

Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.

Inflammatory cytokines and growth factors drive angiogenesis independently; however, their integrated role in pathologic and physiologic angiogenesis is not fully understood. Suppressor of cytokine signaling-3 (SOCS3) is an inducible negative feedback regulator of inflammation and growth factor signaling. In the present study, we show that SOCS3 curbs pathologic angiogenesis. Using a Cre/Lox system, we deleted SOCS3 in vessels and studied developmental and pathologic angiogenesis in murine models of oxygen-induced retinopathy and cancer. Conditional loss of SOCS3 leads to increased pathologic neovascularization, resulting in pronounced retinopathy and increased tumor size. In contrast, physiologic vascularization is not regulated by SOCS3. In vitro, SOCS3 knockdown increases proliferation and sprouting of endothelial cells costimulated with IGF-1 and TNFα via reduced feedback inhibition of the STAT3 and mTOR pathways. These results identify SOCS3 as a pivotal endogenous feedback inhibitor of pathologic angiogenesis and a potential therapeutic target acting at the converging crossroads of growth factor– and cytokine-induced vessel growth.

Introduction The steady increase in the incidence of obesity among adults has been paralleled with higher levels of obesity-associated breast cancer. While recent studies have suggested that adipose stromal/stem cells (ASCs) isolated from obese women enhance tumorigenicity, the mechanism(s) by which this occurs remains undefined. Evidence suggests that increased adiposity results in increased leptin secretion from adipose tissue, which has been shown to increased cancer cell proliferation. Previously, our group demonstrated that ASCs isolated from obese women (obASCs) also express higher levels of leptin relative to ASCs isolated from lean women (lnASCs) and that this obASC-derived leptin may account for enhanced breast cancer cell growth. The current study investigates the impact of inhibiting leptin expression in lnASCs and obASCs on breast cancer cell (BCC) growth and progression. Methods Estrogen receptor positive (ER+) BCCs were co-cultured with leptin shRNA lnASCs or leptin shRNA obASCs and changes in the proliferation, migration, invasion, and gene expression of BCCs were investigated. To assess the direct impact of leptin inhibition in obASCs on BCC proliferation, MCF7 cells were injected alone or mixed with control shRNA obASCs or leptin shRNA obASCs into SCID/beige mice. Results ER+ BCCs were responsive to obASCs during direct co-culture, whereas lnASCs were unable to increase ER+ BCC growth. shRNA silencing of leptin in obASCs negated the enhanced proliferative effects of obASC on BCCs following direct co-culture. BCCs co-cultured with obASCs demonstrated enhanced expression of epithelial-to-mesenchymal transition (EMT) and metastasis genes (SERPINE1, MMP-2, and IL-6), while BCCs co-cultured with leptin shRNA obASCs did not display similar levels of gene induction. Knockdown of leptin significantly reduced tumor volume and decreased the number of metastatic lesions to the lung and liver. These results correlated with reduced expression of both SERPINE1 and MMP-2 in tumors formed with MCF7 cells mixed with leptin shRNA obASCs, when compared to tumors formed with MCF7 cells mixed with control shRNA obASCs. Conclusion This study provides mechanistic insight as to how obesity enhances the proliferation and metastasis of breast cancer cells; specifically, obASC-derived leptin contributes to the aggressiveness of breast cancer in obese women. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0622-z) contains supplementary material, which is available to authorized users.

Background Follicle mites of the genus Demodex are found on a wide diversity of mammals, including humans; surprisingly little is known, however, about the evolution of this association. Additional sequence information promises to facilitate studies of Demodex variation within and between host species. Here we report the complete mitochondrial genome sequences of two species of Demodex known to live on humans—Demodex brevis and D. folliculorum—which are the first such genomes available for any member of the genus. We analyzed these sequences to gain insight into the evolution of mitochondrial genomes within the Acariformes. We also used relaxed molecular clock analyses, based on alignments of mitochondrial proteins, to estimate the time of divergence between these two species. Results Both Demodex genomes shared a novel gene order that differs substantially from the ancestral chelicerate pattern, with transfer RNA (tRNA) genes apparently having moved much more often than other genes. Mitochondrial tRNA genes of both species were unusually short, with most of them unable to encode tRNAs that could fold into the canonical cloverleaf structure; indeed, several examples lacked both D- and T-arms. Finally, the high level of sequence divergence observed between these species suggests that these two lineages last shared a common ancestor no more recently than about 87 mya. Conclusions Among Acariformes, rearrangements involving tRNA genes tend to occur much more often than those involving other genes. The truncated tRNA genes observed in both Demodex species would seem to require the evolution of extensive tRNA editing capabilities and/or coevolved interacting factors. The molecular machinery necessary for these unusual tRNAs to function might provide an avenue for developing treatments of skin disorders caused by Demodex. The deep divergence time estimated between these two species sets a lower bound on the time that Demodex have been coevolving with their mammalian hosts, and supports the hypothesis that there was an early split within the genus Demodex into species that dwell in different skin microhabitats. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-1124) contains supplementary material, which is available to authorized users.

Objective— Regulation of angiogenesis is critical for many diseases. Specifically, pathological retinal neovascularization, a major cause of blindness, is suppressed with dietary ω3-long-chain polyunsaturated fatty acids (ω3LCPUFAs) through antiangiogenic metabolites of cyclooxygenase and lipoxygenase. Cytochrome P450 epoxygenases (CYP2C8) also metabolize LCPUFAs, producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to transdihydrodiols. The effect of these enzymes and their metabolites on neovascularization is unknown. Approach and Results— The mouse model of oxygen-induced retinopathy was used to investigate retinal neovascularization. We found that CYP2C (localized in wild-type monocytes/macrophages) is upregulated in oxygen-induced retinopathy, whereas sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a ω3LCPUFA-enriched diet, retinal neovascularization increases in Tie2 -driven human- CYP2C8 –overexpressing mice ( Tie2-CYP2C8-Tg ), associated with increased plasma 19,20-epoxydocosapentaenoic acid and retinal epoxide:diol ratio. 19,20-Epoxydocosapentaenoic acids and the epoxide:diol ratio are decreased with overexpression of sEH ( Tie2-sEH-Tg ). Overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls. The proangiogenic role in retina of CYP2C8 with both ω3LCPUFA and ω6LCPUFA and antiangiogenic role of sEH in ω3LCPUFA metabolism were corroborated in aortic ring assays. Conclusions— Our results suggest that CYP2C ω3LCPUFA metabolites promote retinal pathological angiogenesis. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization.

PURPOSE. Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective b-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects. METHODS. Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups. RESULTS. None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor. CONCLUSIONS. Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of b-adrenergic receptors is an appropriate therapeutic approach for treating ROP. (Invest Ophthalmol Vis Sci. 2012;53:2968‐2977)