Enhanced Integrin α4β1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes.

Diabetes is associated with a deficit of circulating endothelial progenitor cells (EPCs), which has been attributed to their defective mobilization from the bone marrow. The basis for this mobilization defect is not completely understood, and we sought to determine if hyperglycemic conditions enhanced EPC adhesion. We found that culturing EPCs in high glucose media increased adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1β (PRKAR1β), activation of protein kinase A (PKA), and phosphorylation of α4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1β, or expression of a phosphorylation-defective α4-integrin variant (α4[S988A]). Using a model of type 1 diabetes, we showed that α4(S988A)-expressing mice have more circulating EPCs than their wild-type counterparts. Moreover, diabetic α4(S988A) mice demonstrate enhanced revascularization after hind limb ischemia. Thus, we have identified a novel signaling mechanism activating PKA in diabetes (downregulation of an inhibitory regulatory subunit) that leads to deficits of circulating EPCs and impaired vascular repair, which could be reversed by α4-integrin mutation

Antitumor activity of an anti-CD98 antibody.

CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors

Peritoneal perfusion with oxygenated perfluorocarbon augments systemic oxygenation.

BACKGROUND: Despite maximal ventilatory support, many patients die from hypoxia in the setting of potentially reversible pulmonary failure. There remains a pressing need for additional pulmonary supportive care measures, especially techniques that do not require systemic anticoagulation. The objective of our experiments was to determine whether systemic oxygenation could be increased in a large animal, with induced hypoxia, by perfusing the abdominal cavity with oxygenated perfluorocarbons. METHODS: Fifteen pigs with a mean (+/- SD) weight of 45 +/- 5 kg were intubated and rendered hypoxic by ventilating them with a blend of nitrogen and oxygen to achieve subatmospheric concentrations of inspired oxygen ranging from 18 to 10%, resulting in baseline mean Pao(2) range of 65.9 +/- 9.7 to 26.6 +/- 2.8 mm Hg, respectively. Peritoneal perfusion was performed in eight animals with oxygenated perfluorocarbon and in seven control animals with oxygenated saline solution. RESULTS: The average increase in Pao(2) with oxygenated perfluorocarbon perfusion, compared to oxygenated saline solution perfusion, ranged from 8.1 to 18.2 mm Hg. A common treatment effect was estimated across all fraction of inspired oxygen (Fio(2)) values, representing the average mean difference in oxygen uptake between oxygenated perfluorocarbon and saline solution, irrespective of the level of Fio(2). This average was 12.8 mm Hg (95% confidence interval, 7.4 to 18.2; p \u3c 0.001). The most clinically relevant results occurred at an Fio(2) of 14%, resulting in a baseline mean Pao(2) of 39.4 +/- 5.0 mm Hg with oxygenated saline solution perfusion, and a mean Pao(2) of 55.3 +/- 7.6 mm Hg with oxygenated perfluorocarbon perfusion. This corresponded to an increase in arterial oxygen saturation from 73 to 89%. CONCLUSION: These results of our principle experiments demonstrate that the peritoneal cavity can be used for gas exchange and, in our model, yielded clinically relevant increases in systemic arterial oxygen levels. This technique may have the potential for the supportive care of patients dying from hypoxia in the setting of reversible lung injury

Atrazine and cancer incidence among pesticide applicators in the agricultural health study (1994-2007).

Atrazine is a triazine herbicide used widely in the United States. Although it is an animal carcinogen, the mechanism in rodents does not appear to operate in humans. Few epidemiologic studies have provided evidence for an association

CRS Issue Briefs

This is one report in the series of reports that discuss the campaign finance practices and related issues. Concerns over financing federal elections have become a seemingly perennial aspect of our political system, centered on the enduring issues of high campaign costs and reliance on interest groups for needed campaign funds. The report talks about the today’s paramount issues such as perceived loopholes in current law and the longstanding issues: overall costs, funding sources, and competition

CRS Issue Briefs

This is one report in the series of reports that discuss the campaign finance practices and related issues. Concerns over financing federal elections have become a seemingly perennial aspect of our political system, centered on the enduring issues of high campaign costs and reliance on interest groups for needed campaign funds. The report talks about the today’s paramount issues such as perceived loopholes in current law and the longstanding issues: overall costs, funding sources, and competition

CRS Issue Briefs

This is one report in the series of reports that discuss the campaign finance practices and related issues. Concerns over financing federal elections have become a seemingly perennial aspect of our political system, centered on the enduring issues of high campaign costs and reliance on interest groups for needed campaign funds. The report talks about the today’s paramount issues such as perceived loopholes in current law and the longstanding issues: overall costs, funding sources, and competition

CRS Issue Briefs

This is one report in the series of reports that discuss the campaign finance practices and related issues. Concerns over financing federal elections have become a seemingly perennial aspect of our political system, centered on the enduring issues of high campaign costs and reliance on interest groups for needed campaign funds. The report talks about the today’s paramount issues such as perceived loopholes in current law and the longstanding issues: overall costs, funding sources, and competition

Campaign Financing: Highlights and Chronology of Current Federal Law

Current law governing financial activity of campaigns for federal office is based on two principal statutes: the Federal Election Campaign Act (FECA) of 1971, as amended in 1974, 1976, and 1979, and the Revenue Act of 1971. These laws were enacted to remedy widely perceived shortcomings of existing law, the Corrupt Practices Act of 1925, and in response to reports of campaign finance abuses over the years, culminating in the 1972-1974 Watergate scandal. This report provides a summary of major provisions of federal law and a chronology of key legislative and judicial actions