Lower extremity revascularization via endovascular and surgical approaches: A systematic review with emphasis on combined inflow and outflow revascularization.

This review is intended to help clinicians and patients understand the present state of peripheral artery disease, appreciate the progression and presentation of critical limb ischemia/chronic limb-threatening ischemia, and make informed decisions regarding inflow and outflow endovascular revascularization and surgical treatment options within the context of current debates in the medical community. A controlled literature search was performed to obtain research on outcomes of critical limb ischemia patients undergoing complete leg revascularization for peripheral artery disease inflow and outflow disease. Data for this review were identified by queries of medical and life science databases, expert referral, and references from relevant papers published between 1997 and 2019, resulting in 48 articles. The literature review herein indicates that endovascular revascularization-including ballooning, stenting, and atherectomy-is an effective peripheral artery disease therapy for both above the knee and below the knee disease, and can safely and effectively treat both inflow and outflow disease. As such, it plays a leading role in the therapy of lower extremity artery disease.

Characterization of androgen regulation of ZEB-1 and PSA in 22RV1 prostate cancer cells.

Two-thirds of patients who present with metastatic prostate cancer (PC) are dead within 5 years of diagnosis. The comparable survival rate for patients with localized disease is 100%, which clearly stresses the need for pursuing and developing bioassays that allow prediction of which localized cases are most likely to metastasize. The commonly assayed prostate specific antigen (PSA), while touted as a transformation biomarker, has recently proven to be problematic in the area of false positive diagnoses. It remains, however, a hallmark gene for studying androgen regulation as its expression is reliably stimulated by androgens such as dihydrotestosterone (DHT). Herein, we have elucidated the effects of flutamide (a defined anti-androgen) and DHT on the expression of PSA and Zinc finger E-box Binding factor (ZEB-1). Additionally, we assayed the androgenic capabilities of two DHT derivatives on expression of PSA. Our previous research had identified ZEB-1 as a putative biomarker for the onset of metastasis in prostate cancer. The expression of this gene is regulated by androgen and decreases sharply at metastasis. In the current study, the effects of 1 and 10 nM flutamide, in combination with 1 and 10 nM DHT, on expression of ZEB-1 and PSA, were investigated in 22Rv1, an androgen-responsive human PC cell line. Also in this cell line, the effects of testosterone propionate and dehydroisoandrosterone were studied. Our research confirmed the feasibility of considering ZEB-1 a metastatic PCa biomarker, using the highly sensitive technique of real-time polymerase chain reaction (RT-PCR). Interestingly, it also revealed the danger of using flutamide as a therapeutic antagonist, as we demonstrate herein its alarming capability to behave as an agonist.

Orbital atherectomy treatment of severely calcified native coronary lesions in patients with prior coronary artery bypass grafting: Acute and one-year outcomes from the ORBIT II trial.

AIMS: Patients undergoing percutaneous coronary intervention (PCI), with a history of coronary artery bypass grafting (CABG), may be at increased risk for mortality and repeat revascularization, compared with patients without prior CABG. In this post-hoc analysis of the ORBIT II trial, safety and efficacy of coronary orbital atherectomy (OA) to modify severe coronary artery calcium, prior to stent placement, was evaluated in subjects based on history of CABG. METHODS AND RESULTS: Comorbidities: diabetes, dyslipidemia, hypertension, and history of myocardial infarction (MI) were more prevalent in the CABG group. The in-hospital major adverse cardiac event (MACE) rate, defined as a composite of cardiac death, MI (CK-MB>3× ULN), and target vessel revascularization (TVR), was higher in the CABG group (16.9% vs. 8.5%, p=0.04), driven primarily by a higher incidence of MI (16.9% vs. 8.0%, p=0.03); however, Q-wave rates were low at 1.5% vs 0.5%, (p=0.38). There was no significant difference in rates of cardiac death (6.2% vs. 2.7%, p=0.17) and TVR (7.9% vs. 5.5%, p=0.47). CONCLUSIONS: Low rates of TVR, cardiac death, and Q-wave MI, suggest OA treatment to facilitate stent delivery is successful and provides durable outcomes in subjects with and without prior CABG. CONDENSED ABSTRACT: Patients with history of CABG have extensive coronary artery disease. Those who undergo PCI may be at increased risk for mortality and repeat revascularization, compared with patients without prior CABG. This post-hoc analysis of ORBIT II trial evaluated safety and efficacy of coronary OA to modify severe coronary artery calcium, prior to stent placement, based on subject history of CABG. The MACE rate was higher in the CABG group, driven by higher incidence of MI; however, Q-wave rates were low. OA treatment to facilitate stent delivery is successful, but higher incidence of non-Q-wave MI in CABG patients warrants further study.

Orbital atherectomy for treating de novo, severely calcified coronary lesions: 3-year results of the pivotal ORBIT II trial.

BACKGROUND/PURPOSE: The presence of heavy coronary artery calcification increases the complexity of percutaneous coronary intervention (PCI) and increases the incidence of major adverse cardiac events (MACE): death, myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis. The ORBIT II (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) trial reported low rates of procedural, 30-day, 1-year, and 2-year ischemic complications after treatment of de novo, severely calcified lesions with the Diamondback 360° Coronary Orbital Atherectomy System (OAS) (Cardiovascular Systems, Inc.). METHODS/MATERIALS: ORBIT II was a single-arm trial that enrolled 443 patients at 49U.S. sites; in this study, de novo, severely calcified coronary lesions were treated with OAS prior to stenting. The primary safety endpoint was 30-day MACE: the composite of cardiac death, MI, and TVR (inclusive of target lesion revascularization (TLR)). The primary efficacy endpoint was procedural success: stent delivery with a residual stenosis of <50% without the occurrence of in-hospital MACE.The present analysis reports the final, 3-year follow-up results from ORBIT II. RESULTS: The majority of subjects (88.2%) underwent PCI with drug-eluting stents after orbital atherectomy. There were 360 (81.3%) subjects who completed the protocol-mandated 3-year visit.The overall cumulative rate of 3-year MACE was 23.5%, including cardiac death (6.7%), MI (11.2%), and TVR (10.2%). The 3-year target lesion revascularization rate was 7.8%. CONCLUSIONS: In the final 3-year analysis of the ORBIT II trial, orbital atherectomy of severely calcified coronary lesions followed by stenting resulted in a low rate of adverse ischemic events compared with historical controls.Orbital atherectomy represents a safe and effective revascularization strategy for patients with severely calcified coronary lesions. SUMMARY: The ORBIT II trial enrolled 443 subjects to study orbital atherectomy followed by stenting for de novo severely calcified coronary lesions. The overall cumulative 3-year MACE rate was 23.5%, including cardiac death (6.7%), MI (11.2%), and TVR (10.2%); the 3-year target lesion revascularization rate was 7.8%. Orbital atherectomy of heavily calcified coronary lesions followed by stenting results in a low rate of adverse ischemic events compared with historical controls; it represents a reasonable revascularization strategy for patients with severely calcified coronary lesions.

Androgen Receptor Regulates Transcription of the ZEB1 Transcription Factor.

The zinc finger E-box binding protein 1 (ZEB1) transcription factor belongs to a two-member family of zinc-finger homeodomain proteins involved in physiological and pathological events mostly relating to cell migration and epithelial to mesenchymal transitions (EMTs). ZEB1 (also known as δEF1, zfhx1a, TCF8, and Zfhep) plays a key role in regulating such diverse processes as T-cell development, skeletal patterning, reproduction, and cancer cell metastasis. However, the factors that regulate its expression and consequently the signaling pathways in which ZEB1 participates are poorly defined. Because it is induced by estrogen and progesterone and is high in prostate cancer, we investigated whether tcf8, which encodes ZEB1, is regulated by androgen. Data herein demonstrate that tcf8 is induced by dihydrotestosterone (DHT) in the human PC-3/AR prostate cancer cell line and that this induction is mediated by two androgen response elements (AREs). These results demonstrate that ZEB1 is an intermediary in androgen signaling pathways.

Expression of the ZEB1 (deltaEF1) transcription factor in human: additional insights.

The zinc finger E-box binding transcription factor ZEB1 (deltaEF1/Nil-2-a/AREB6/zfhx1a/TCF8/zfhep/BZP) is emerging as an important regulator of the epithelial to mesenchymal transitions (EMT) required for development and cancer metastasis. ZEB1 promotes EMT by repressing genes contributing to the epithelial phenotype while activating those associated with the mesenchymal phenotype. TCF8 (zfhx1a), the gene encoding ZEB1, is induced by several potentially oncogenic ligands including TGF-beta, estrogen, and progesterone. TGF-beta appears to activate EMT, at least in part, by inducing ZEB1. However, our understanding of how ZEB1 contributes to signaling pathways elicited by estrogen and progesterone is quite limited, as is our understanding of its functional roles in normal adult tissues. To begin to address these questions, a human tissue mRNA array analysis was done. In adults, the highest ZEB1 mRNA expression is in bladder and uterus, whereas in the fetus highest expression is in lung, thymus, and heart. To further investigate the regulation of TCF8 by estrogen, ZEB1 mRNA was measured in ten estrogen-responsive cell lines, but it is only induced in the OV266 ovarian carcinoma line. Although high expression of ZEB1 mRNA is estrogen-dependent in normal human ovarian and endometrial biopsies, high expression is estrogen-independent in late stage ovarian and endometrial carcinomas, raising the possibility that deregulated expression promotes cancer progression. In contrast, TCF8 is at least partially deleted in 4 of 5 well-differentiated, grade I endometrial carcinomas, which may contribute to their non-aggressive phenotype. These data support the contention that high ZEB1 encourages gynecologic carcinoma progression.