CIB1 Mediated Regulation of Endothelial Cells and Pathological Angiogenesis

Calcium and integrin binding protein 1 (CIB1), a 22kDa EF-hand containing protein, that was originally identified to bind the platelet integrin [alpha]IIb, can also bind and regulate various other proteins. Among the newly identified CIB1-binding partners is the p21-activated kinase 1 (PAK1), which is known to regulate ECs and contribute to angiogenesis in vivo. Since CIB1 is present in highly vascularized tissue and is expressed in various types of ECs, we hypothesized that it may also have an important role in vascular tissue. The work described herein is a collection of studies that for the first time investigates the role of CIB1 in EC signaling, function, and angiogenesis. Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. We demonstrate here that CIB1 is necessary for various EC functions such as migration, proliferation, tubule formation, and monolayer permeability. CIB1 also regulates PAK1 activation, as well as downstream ERK1/2 phosphorylation and MMP-2 expression. Depletion of CIB1 in ECs attenuates their response to angiogenic growth factors such as VEGF and bFGF. In ex vivo and in vivo assays, CIB1-KO tissue also has an attenuated response to growth factors, demonstrating that CIB1 is necessary for a robust angiogenic response. Moreover, although we confirm that CIB1-KO mice have no defects in developmental vasculogenesis and angiogenesis, we demonstrate that CIB1 is essential for ischemia-induced and tumor-induced pathological angiogenesis. These findings are important since they differentiate between physiological and pathological forms of angiogenesis and identify CIB1 as novel target for pro- and anti-angiogenic therapy

Examining the Influential Factors on Urban Growth and Population Attraction: A Case Study of Almere, Netherlands

This paper explores the intricate nature of population attraction and urban growth, which are influenced by a wide range of social, economic, and environmental factors. Through a case study of Almere, Netherlands, this study investigates the connection between population attraction, urban quality of life, livability, and sustainability. To assess the impact of these factors on urban growth, the study developed a measurable indicator matrix based on a theoretical framework. The study’s results demonstrate that social life, urban economy, population standards, ease of access to services, transportation, and the quality of the built environment are significant factors in population attraction and urban growth. Additionally, the study revealed some previously unconsidered factors that play a crucial role in sustaining population attraction and urban growth. The study’s findings offer insights for urban planners and policymakers to design effective strategies that promote population attraction and foster sustainable urban growth

Amputation stump perfusion is predictive of post-operative necrotic eschar formation

BACKGROUND: A large proportion of patients develop poor amputation stump healing. We hypothesize that Laser-Assisted Fluorescent Angiography (LAFA) can predict inadequate tissue perfusion and healing. METHODS: Over an 8-month period we reviewed all patients who underwent lower extremity amputation and LAFA. We evaluated intra-operative LAFA global and segmental stump perfusion, and post-operative modified Bates-Jensen (mBJS) wound healing scores. RESULTS: In 15 patients, amputation stumps with lower global perfusion demonstrated higher mBJS (P = 0.01). Lower suture-line perfusion also correlated with more eschar formation (P \u3c 0.001). Diabetic patients had higher mBJS (P = 0.009), lower stump perfusion (P = 0.02), and increased eschar volume (P \u3c 0.001). CONCLUSION: LAFA is a useful adjunct for intra-operative stump perfusion assessment and can predict areas of poor stump healing and eschar formation. Diabetic patients seem to be at higher risk of stump eschar formation

Natriuretic peptide receptor-C is up-regulated in the intima of advanced carotid artery atherosclerosis

OBJECTIVE: Natriuretic peptide receptor-C (NPR-C/NPR-3) is a cell surface protein involved in vascular remodelling that is up-regulated in atherosclerosis. NPR-C expression has not been well characterized in human carotid artery occlusive lesions. We hypothesized that NPR-C expression correlates with intimal features of vulnerable atherosclerotic carotid artery plaque. METHODS: To test this hypothesis, we evaluated NPR-C expression by immunohistochemistry (IHC) in carotid endarterectomy (CEA) specimens isolated from 18 patients. The grade, location, and co-localization of NPR-C in CEA specimens were evaluated using two tissue analysis techniques. RESULTS: Relative to minimally diseased CEA specimens, we observed avid NPR-C tissue staining in the intima of maximally diseased CEA specimens (65%; p=0.06). Specifically, maximally diseased CEA specimens demonstrated increased NPR-C expression in the superficial intima (61%, p=0.17), and deep intima (138% increase; p=0.05). In the superficial intima, NPR-C expression significantly co-localized with vascular smooth muscle cells (VSMCs) and macrophages. The intensity of NPR-C expression was also higher in the superficial intima plaque shoulder and cap regions, and significantly correlated with atheroma and fibroatheroma vulnerable plaque regions (β=1.04, 95% CI=0.46, 1.64). CONCLUSION: These findings demonstrate significant NPR-C expression in the intima of advanced carotid artery plaques. Furthermore, NPR-C expression was higher in vulnerable carotid plaque intimal regions, and correlate with features of advanced disease. Our findings suggest that NPR-C may serve as a potential biomarker for carotid plaque vulnerability and progression, in patients with advanced carotid artery occlusive disease

Multimodal thrombectomy device for treatment of acute deep venous thrombosis

Deep vein thrombosis (DVT) is a potentially deadly medical condition that is costly to treat and impacts thousands of Americans every year. DVT is characterized by the formation of blood clots within the deep venous system of the body. If a DVT dislodges it can lead to venous thromboembolism (VTE) and pulmonary embolism (PE), both of which can lead to significant morbidity or death. Current treatment options for DVT are limited in both effectiveness and safety, in part because the treatment of the DVT cannot be confined to a defined sequestered treatment zone. We therefore developed and tested a novel thrombectomy device that enables the sequesteration of a DVT to a defined treatment zone during fragmentation and evacuation. We observed that, compared to a predicate thrombectomy device, the sequestered approach reduced distal DVT embolization during ex vivo thrombectomy. The sequestered approach also facilitated isovolumetric infusion and suction that enabled clearance of the sequestered treatment zone without significantly impacting vein wall diameter. Results suggest that our novel device using sequestered therapy holds promise for the treatment of high risk large-volume DVTs

Tumor growth and angiogenesis is impaired in CIB1 knockout mice

Abstract Background Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process more precisely on a molecular level. Previously we found that CIB1, a 22 kDa regulatory protein, plays a critical role in endothelial cell function, angiogenic growth factor-mediated cellular functions, PAK1 activation, MMP-2 expression, and in vivo ischemia-induced angiogenesis. Since pathological angiogenesis is highly dependent on many of these same processes, we hypothesized that CIB1 may also regulate tumor-induced angiogenesis. Methods To test this hypothesis, we allografted either murine B16 melanoma or Lewis lung carcinoma cells into WT and CIB1-KO mice, and monitored tumor growth, morphology, histology, and intra-tumoral microvessel density. Results Allografted melanoma tumors that developed in CIB1-KO mice were smaller in volume, had a distinct necrotic appearance, and had significantly less intra-tumoral microvessel density. Similarly, allografted Lewis lung carcinoma tumors in CIB1-KO mice were smaller in volume and mass, and appeared to have decreased perfusion. Intra-tumoral hemorrhage, necrosis, and perivascular fibrosis were also increased in tumors that developed in CIB1-KO mice. Conclusions These findings suggest that, in addition to its other functions, CIB1 plays a critical role in facilitating tumor growth and tumor-induced angiogenesis

Totally percutaneous endovascular repair for ruptured abdominal aortic aneurysms

PURPOSE: The PEVAR Trial demonstrated that compared to open femoral exposure, elective percutaneous endovascular AAA repair (ePEVAR) is associated with decreased perioperative morbidity and access site complications. We hypothesized that PEVAR for ruptured AAA (rPEVAR) may also improve perioperative morbidity compared to open femoral exposure (rEVAR). There are currently no reports that evaluate the utility and outcomes of rPEVAR. MATERIALS AND METHODS: From 2015 to 2021, all patients who underwent an endovascular repair of a ruptured AAA at a single institution were included in the study and grouped into rPEVAR and rEVAR. Demographics, procedural details (successful preclose technique, conversion to femoral cutdown), postoperative variables (blood transfusion, ICU and hospital length of stay) and short-term outcomes (30-day major adverse events (30-day MAE) and 30-day femoral access-site complications (30-day FAAC)) were collected and compared with 50 historical ePEVAR patients from the PEVAR Trial. Statistical significance was determined using RESULTS: 35 patients were identified (21 rPEVAR; 14 rEVAR), 86% were male with a mean age of 72 ± 9 years. All patients underwent emergent endovascular aortic repair with 100% technical success. Seventeen patients (49%) presented with evidence of hemorrhagic shock and 22 patients (63%) had blood transfusion. 30-day MAE occurred in 12 patients (34%) (7 rPEVAR; 5 rEVAR). There was no difference in demographic, perioperative outcomes and 30-day MAE rate between rPEVAR and rEVAR patients. Compared to ePEVAR patient (from PEVAR trial), rPEVAR patients had higher rate of 30-day MAE (34% vs. 6%; CONCLUSION: Emergent rPEVAR appears to have similar outcomes when compared to rEVAR. Although patients undergoing rPEVAR have higher 30-day major adverse events rate compared to ePEVAR, the method of percutaneous femoral cannulation does not appear to increase the overall procedural or 30-day femoral artery access-site complications