Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential

Reduced migratory function of circulating angiogenic progenitor cells (CPCs) has been associated with impaired neovascularization in patients with cardiovascular disease (CVD). Previous findings underline the role of the kallikrein-kinin system in angiogenesis. We now demonstrate the involvement of the kinin B2 receptor (B(2)R) in the recruitment of CPCs to sites of ischemia and in their proangiogenic action. In healthy subjects, B(2)R was abundantly present on CD133(+) and CD34(+) CPCs as well as cultured endothelial progenitor cells (EPCs) derived from blood mononuclear cells (MNCs), whereas kinin B1 receptor expression was barely detectable. In transwell migration assays, bradykinin (BK) exerts a potent chemoattractant activity on CD133(+) and CD34(+) CPCs and EPCs via a B(2)R/phosphoinositide 3-kinase/eNOS-mediated mechanism. Migration toward BK was able to attract an MNC subpopulation enriched in CPCs with in vitro proangiogenic activity, as assessed by Matrigel assay. CPCs from cardiovascular disease patients showed low B(2)R levels and decreased migratory capacity toward BK. When injected systemically into wild-type mice with unilateral limb ischemia, bone marrow MNCs from syngenic B(2)R-deficient mice resulted in reduced homing of sca-1(+) and cKit(+)flk1(+) progenitors to ischemic muscles, impaired reparative neovascularization, and delayed perfusion recovery as compared with wild-type MNCs. Similarly, blockade of the B(2)R by systemic administration of icatibant prevented the beneficial effect of bone marrow MNC transplantation. BK-induced migration represents a novel mechanism mediating homing of circulating angiogenic progenitors. Reduction of BK sensitivity in progenitor cells from cardiovascular disease patients might contribute to impaired neovascularization after ischemic complications.     

A counterpoint paper: Comments on the electrocardiographic part of the 2018 Fourth Universal Definition of Myocardial Infarction endorsed by the International Society of Electrocardiology and the International Society for Holter and Noninvasive Electrocardiology

The Fourth Universal Definition of Myocardial Infarction (FUDMI) focuses on the distinction between nonischemic myocardial injury and myocardial infarction (MI), along with the role of cardiovascular magnetic resonance, in order to define the etiology of myocardial injury. As a consequence, there is less emphasis on updating the parts of the definition concerning the electrocardiographic (ECG) changes related to MI. Evidence of myocardial ischemia is a prerequisite for the diagnosis of MI, and the ECG is the main available tool for (a) detecting acute ischemia, (b) triage, and (c) risk stratification upon presentation. This review focuses on multiple aspects of ECG interpretation that we firmly believe should be considered for incorporation in any future update to the Universal Definition of MI.     

Antitumor Effects of Recombinant Antivascular Protein ABRaA-VEGF121 Combined with IL-12 Gene Therapy

Development and neoplastic progression strongly rely on tumor microenvironment cells. Various kinds of cells that form such tumor milieu play substantial roles in angiogenesis and immunosuppression. Attempts to inhibit tumor vascularization alter tumor milieu and enhance immune response against the tumor. Anticancer therapeutic strategy bringing together antiangiogenic and immunostimulating agents has emerged as a promising approach. We here investigated whether therapy directed against preexisting vessels, combined with an immunomodulatory factor would be equally effective in arresting tumor growth. To this goal, we investigated the effectiveness of ABRaA-vascular endothelial growth factor isoform 121 (VEGF₁₂₁), an antivascular drug constructed by us. It is a fusion protein composed of VEGF₁₂₁, and abrin A chain (translation-inhibiting toxin). We used it in combination with interleukin (IL-12) gene therapy and tried to inhibit B16-F10 melanoma tumor growth. ABRaA-VEGF₁₂₁ is a chimeric recombinant protein capable of destroying tumor vasculature and triggering necrosis in the vicinity of damaged vessels. IL-12 cytokine, in turn, activates both specific and non-specific immune responses. Our results demonstrate that combination of ABRaA-VEGF₁₂₁ antivascular agent with immunostimulatory cytokine IL-12 indeed inhibits tumor growth more effectively than either agent alone, leading to complete cure of ca. 20 % mice. Post-therapeutic analysis of tumors excised from mice treated with combination therapy showed decreased numbers of blood microvessels in the tumor microenvironment, lowered numbers of regulatory T lymphocytes, as well as showed higher levels of CD4⁺ and CD8⁺ as compared to control mice. It seems that bringing together antivascular strategy and the action of immunostimulating agents indeed inhibits growth of tumors.     

The Role of Sex Differences in Autophagy in the Heart During Coxsackievirus B3-Induced Myocarditis

Under normal conditions, autophagy maintains cardiomyocyte health and integrity through turnover of organelles. During stress, oxygen and nutrient deprivation, or microbial infection, autophagy prolongs cardiomyocyte survival. Sex differences in induction of cell death may to some extent explain the disparity between the sexes in many human diseases. However, sex differences in gene expression, which regulate cell death and autophagy, were so far not taken in consideration to explain the sex bias of viral myocarditis. Coxsackievirus B3 (CVB3)-induced myocarditis is a sex-biased disease, with females being substantially less susceptible than males and sex hormones largely determine this bias. CVB3 was shown to induce and subvert the autophagosome for its optimal viral RNA replication. Gene expression analysis on mouse and human, healthy and CVB3-infected, cardiac samples of both sexes, suggests sex differences in autophagy-related gene expression. This review discusses the aspects of sex bias in autophagy induction in cardiomyocytes.     

t(X;14)(p11.4;q32.33) is recurrent in marginal zone lymphoma and up-regulates GPR34

Genetic events underlying pathogenesis of nodal and extranodal marginal zone lymphoma are not completely understood. We report here a novel t(X;14)(p11.4;q32.33) identified in 4 lymphoma cases: 2 with a mucosa-associated lymphoid tissue lymphoma, one with a nodal marginal zone lymphoma and one with gastric diffuse large B-cell lymphoma. In all cases, lymphoma evolved from a previous auto-immune disorder. Fluorescence in situ hybridization and molecular studies showed that t(X;14), which is mediated by immunoglobulin heavy chain locus, targets the GPR34 gene at Xp11.4. Upregulation of GPR34 mRNA and aberrant expression of GPR34 protein has been demonstrated in 3 presented cases by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. GPR34 belongs to the largest family of cell surface molecules involved in signal transmission that play important roles in many physiological and pathological processes, including tumorigenesis. Although functional consequences of t(X;14) have not been identified, our studies suggest that up-regulated GPR34 activate neither nuclear factor-κB nor ELK-related tyrosine kinase.     

EGFR mutation testing on cytological and histological samples in non-small cell lung cancer: a Polish,single institution study and systematic review of European incidence

The targeted treatment of advanced non-small-cell lung cancer (NSCLC) depends on confirmation of activating somatic EGFR mutation. The aim of the study was to evaluate the incidence of EGFR mutations in NSCLC detected in cytological and histological material and present literature review on European EGFR mutation incidence. 273 patients with confirmed NSCLC were entered into the study: 189 histological, paraffin-embedded materials, 12 fresh and 72 fixed cytological specimens. DNA was extracted from both types of material and the EGFR mutation in exons 18-21 was analyzed by direct sequencing. In addition the EGFR gene copy number in cases with sufficient histological material (110 patients) was evaluated by fluorescent in situ hybridization (FISH) technique. The percentage of EGFR somatic mutations was 10.62%. FISH positive results (amplification or high polysomy of EGFR gene) were identified in 33 patients (30.0%). The strongest clinicopathological correlation with the EGFR mutation was found for histological type (adenocarcinoma; p < 0.01), gender (females; p < 0.01) and FISH positive result (p < 0.05). This is the first, single institution study that estimates the EGFR mutation incidence in the Polish population. Cytological material recovered from fixed preparations and stained with hematoxylin and eosin showed DNA quality comparable to fresh tumor cells and histological samples.     

Bone graft incorporation after revision hip arthroplasty in patients with rheumatoid arthritis, seventy eight revisions using bone allografts with or without metal reinforcements

Purpose

The aim of the study was to assess bone graft incorporation after revision hip arthroplasty in patients with rheumatoid arthritis (RA).

Methods

We report an acetabular reconstruction using impacted, morselized, frozen, radiation sterilized bone allografts in 71 patients suffering from RA. There were sixty-six women and five men at a mean age of 57.5 years. Reconstruction was performed in 78 revision total hip arthroplasties (THAs) for aseptic loosening of acetabular component. The mean follow-up was five years and four months. In 38 cases, a revision was done with use of reinforcement devices.

Results

In four revised hips (10 %) without reinforcement implants, resorption of the allografts was noticed. All Mueller rings and 50 % of unscrews cages (Link, Howmedica) were revised because of aseptic loosening and bone graft resorption. In all of 17 hips with the Burch-Schneider cage, no measurable migration or bone allografts resorption occurred. There were no major general complications.

Conclusions

Acetabular reconstruction with use of morselized, frozen, radiation sterilized bone allografts and the Burch-Schneider cage can be highly successful in managing massive deficiency of acetabular bone stock in revision hip arthroplasty in RA patients.