ADIPOSE-DERIVED STROMAL CELLS PROMOTE SURVIVAL OF ENDOTHELIAL CELLS AND KERATINOCYTES IN WOUND HEALING MODEL

poster abstractBurn wounds are a significant medical challenge today. Current treat-ment includes the use of skin grafts or wound healing scaffolds to protect the wound and promote healing. However, pre-existing conditions and fac-tors such as smoking can compromise normal healing thru decreased growth factor production, prolonged inflammation, tissue hypoxia, reduced cellular migration and ECM deposition, and impaired revascularization, making the wound more susceptible to infection. Adult pluripotent cells have been proposed as a therapy for multiple dis-orders because they have been shown to decrease inflammation and pro-mote host tissue preservation and angiogenesis. Adipose-derived stromal cells (ASC) are a population of mesenchymal, pluripotent cells derived from adipose tissue. Compared to bone marrow derived MSC, ASC can be easily obtained thru minimally invasive procedures. It has been shown in previous studies that ASC improved wound closure in normal and diabetic mice and stimulated proliferation of human dermal fibroblasts, increasing the epitheli-alization of cutaneous wounds. The next challenge is to find a clinically relevant cell-delivery method. In light of this, we propose the use of current clinical wound healing scaf-folds as a delivery vehicle for ASC in combination with endothelial cell (EC) and keratinocytes. We hypothesize that that ASC will promote keratinocyte and EC survival (both are used clinically), thus promoting epithelialization and neovascularization of graft. The use of ASC, EPC and keratinocytes in combination with wound healing scaffolds currently used by physicians, such as Integra is a novel combination and will provide a faster transition to clinic if it is found to be efficacious. Our lab has shown that ASC promote survival of EC on Integra and sup-port the formation of vascular-like cord structures. Factors secreted by ASC promote keratinocytes ingrowth in a wound closure assay. Keratinocytes also showed increased survival when cultured with ASC

A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPreviously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.info:eu-repo/grantAgreement/EC/FP7/21807

Adipose stromal cells enhance keratinocyte survival and migration in vitro, and graft revascularization in mouse wound healing model

In the US, more than 1 million burn injuries are reported annually. About 45,000 injuries due to fires and burns result in hospitalization and ten percent of these result in death every year. Advances in burn treatment have led to a reduction in mortality rate over the last decades. Since more patients are surviving the initial resuscitation phase even with very large areas of skin being burned away, wound care has become increasingly important to ensure continued patient survival and improvement. While currently a common treatment for third degree burn wounds, skin grafts have several drawbacks. The availability of donor sites for autografts may be limited, especially in incidences of extensive skin loss. The rejection associated with the use of allografts and xenografts may render them inadequate or undesirable. Even if a suitable graft is found, poor retention due to infection, hematoma, and low vascularity at the recipient site are other drawbacks associated with the use of skin grafts as a primary treatment for severe burn wounds. As such, research has been done into alternative treatments, which include but are not limited to artificial skin, cell therapy, and growth factor application. We propose the delivery of adipose derived stem cells (ASC) in combination with endothelial progenitor cells (EC) via Integra Dermal Regenerative Template (DRT) to promote faster graft vascularization and thus faster healing of wounds. Integra DRT is an acellular skin substitute that consists of a dermal layer composed of bovine collagen and chondroitin-6-sulfate glycosaminoglycan, and an epidermal layer, which consists of silicone polymer. This silicone layer is removed after the collagen matrix is adequately vascularized (usually takes 2-3 weeks), and then a thin layer autograft is applied to the top of the neo-dermis. ASC are derived from the stromal-vascular fraction (SVF) of adipose tissue and are a readily available, pluripotent, mesenchymal cell known to promote angiogenesis. They are being explored as a treatment for a myriad of diseases and conditions, including wound healing. In combination with ECs, they form stable microvessel networks in vitro and in vivo. In our work, we found that ASC+EC form stable microvessel networks when cultured on Integra DRT. Also, ASC and ASC+EC conditioned media promoted both survival and migration of human epidermal keratinocytes compared to control medium. In a full thickness wound healing model, using healthy NSG mice, the ASC+EC case showed a significantly higher rate of wound closure compared to control. Based on best linear unbiased estimates (BLUE), the difference between the healing rates of ASC alone treatment and the Control treatment group is -0.45 +/- 0.22 mm2/day (p=0.041), which is not less than 0.025 and thus not statistically significant (Bonferroni Adjusted). However, the BLUE for the difference between the ASC+EC group and the Control group healing rates is -0.55 +/- 0.28 mm2/day (p = 0.017 \u3c 0.025, Bonferroni Adjusted), which is statistically significant. Histology revealed a significantly higher number of vessels compared to control in both ASC alone and ASC+EC case. CD31 staining revealed the presence of human vessels in ASC+EC treatment scaffolds. We conclude that the combination of ASC and EC can be used to accelerate healing of full-thickness wounds when delivered to site of the wound via Integra. This result is especially compelling due to the fact that the mice used were all healthy. Thus our treatment shows an improvement in healing rate even compared to normal wound healing

A novel operator-independent noninvasive device for assessing arterial reactivity.

Background: Endothelial dysfunction is associated with increased risk of cardiovascular disease (CVD). Currently available noninvasive methods of measuring endothelial function have limitations. We tested a novel device that provides an automated measurement of the difference between baseline and post-ischemic, hyperemia-induced, brachial arterial compliance, a phenomenon known to be endothelium-dependent. The association between the calculated index, Flow-mediated Compliance Response (FCR), and established CVD risk indices was determined. Methods: Adults with CVD risk factors or known coronary artery disease (CAD) were enrolled. Framingham Risk Score (FRS) was calculated and presence of metabolic syndrome (MetSyn) was assessed. Carotid artery plaques were identified by ultrasound. Cardiorespiratory fitness was assessed by 6-minute walk test (6MWT). FCR was measured using the device. Results: Among 135 participants, mean age 49.3 +/- 17.9 years, characteristics included: 48% female, 7% smokers, 7% CAD, 10% type 2 diabetes, 34% MetSyn, and 38% with carotid plaque. Those with MetSyn had 24% lower FCR than those without (p \u3c 0.001). Lower FCR was associated with higher FRS percentile (r = -0.29, p \u3c 0.001), more MetSyn factors (r = -0.30, p \u3c 0.001), more carotid plaques (r = -0.22, p = 0.01), and lower 6MWT (r = 0.34, p \u3c 0.0001). Conclusion: FCR, an index of arterial reactivity obtained automatically using a novel, operator-independent device, was inversely associated with established CVD risk indices, increased number of carotid plaques, and lower cardiorespiratory fitness. Whether measuring FCR could play a role in screening for CVD risk and assessing whether endothelial function changes in response to treatments aimed at CVD risk reduction, warrants further study

Clinicians for CARE: A Systematic Review and Meta‐Analysis of Interventions to Support Caregivers of Patients With Heart Disease

Background Caregivers provide critical support for patients with chronic diseases, including heart disease, but often experience caregiver stress that negatively impacts their health, quality of life, and patient outcomes. We aimed to inform health care teams on an evidence‐based approach to supporting the caregivers of patients with heart disease. Methods and Results We conducted a systematic review and meta‐analysis of randomized controlled trials written in English that evaluated interventions to support caregivers of patients with heart disease. We identified 15,561 articles as of April 2, 2020 from 6 databases; of which 20 unique randomized controlled trials were evaluated, representing a total of 1570 patients and 1776 caregivers. Most interventions focused on improving quality of life, and reducing burden, depression, and anxiety; 85% (17 of 20) of the randomized controlled trials provided psychoeducation for caregivers. Interventions had mixed results, with moderate non‐significant effects observed for depression (Hedges’ g=−0.64; 95% CI, −1.34 to 0.06) and burden (Hedges’ g=−0.51; 95% CI, −2.71 to 1.70) at 2 to 4 months postintervention and small non‐significant effects observed for quality of life and anxiety. These results were limited by the heterogeneity of outcome measures and intervention delivery methods. A qualitative synthesis of major themes of the interventions resulted in clinical recommendations represented with the acronym “CARE” (Caregiver‐Centered, Active engagement, Reinforcement, Education). Conclusions This systematic review highlights the need for greater understanding of the challenges faced by caregivers and the development of guidelines to help clinicians address those challenges. More research is necessary to develop clinical interventions that consistently improve caregiver outcomes

Sequence variant on 8q24 confers susceptibility to urinary bladder cancer

We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7))

A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UB