Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

Radiation and reprogramming in pluripotent Stem Cell of tissue-resident mesenchymal stem cells in the head and neck region

Im ersten Teil der Arbeit wurden erfolgreich mesenchymale Stammzellen (MSCs) aus der humanen nasalen Mukosa (mMSC) und der Glandula Parotis (pMSC) isoliert. Die mMSCs und pMSCs wiesen alle MSC-typische Charakteristika wie Plastikadhärenz, fibroblastenartige Morphologie, reges Proliferationsverhalten, typische Oberflächenantigen-Expression und adipogenes, osteogenes und chondrogenes Differenzierungspotenzial auf. Anschließend wurden mMSCs von vier gesunden Spendern induziert pluripotente Stammzellen (iPS-Zellen) reprogrammiert. Pro Patient wurden zwei Zelllinien etabliert und charakterisiert. Sowohl das morphologische Bild der Kolonien pluripotenter Zellen als auch die Färbung für die aktive alkalische Phosphataseaktivität gaben Hinweise auf das Vorhandensein von Pluripotenz. Eine weitere Bestätigung erfolgte durch die Expression der entsprechenden Pluripotenzgene (u. a. NANOG, OCT4 und SOX2). Die Differenzierung in die drei Keimblätter Mesoderm, Endoderm und Ektoderm bestätigte die Pluripotenz und die Selbsterneuerungsfähigkeit der Zellen. Aus den iPS-Zellen wurden im nächsten Schritt induzierte pluripotente abhängige mesenchymale Stammzellen (iP-MSCs) differenziert. Diese MSC-ähnlichen Zellen wiesen ebenfalls die stammzellspezifischen Charakteristika auf: Die Morphologie der Zellen stimmte mit dem morphologischen Bild der mMSCs überein, die Oberflächenantigen-Expression der iP-MSCs glich den mMSCs und die iP-MSCs wiesen ein adipogenes, osteogenes und chondrogenes Differenzierungspotenzial auf. Das Proliferationsverhalten von mMSCs in vitro nimmt mit zunehmender Kultivierungsdauer ab, während iPS-Zellen eine annähernd unendliche Zellquelle darstellen. Somit stellen iP-MSCs eine vielversprechende Alternative dar. Erstmalig wurden in dieser Studie iP-MSCs aus humanen mMSCs differenziert und morphologische und genetische Gemeinsamkeiten zwischen den isolierten mMSCs und den differenzierten iP-MSCs gefunden. Basierend auf den in dieser Studie erzielten Ergebnissen müssen weitere vergleichende Studien hinsichtlich Proliferationsverhalten, immunologischen Fähigkeiten und Einsatzmöglichkeiten durchgeführt werden. Im zweiten Teil der Arbeit wurde das Verhalten von MSCs aus der Kopf-Hals-Region auf ionisierende Bestrahlung untersucht. Wie Patienten, die eine Bestrahlungstherapie erhalten, wurden die isolierten pMSCs und mMSCs fraktioniert bestrahlt. Sowohl morphologisch als auch durchflusszytometrisch konnten bis zu einer Dosis von zehn Gray keine Unterschiede zu unbestrahlten Kontrollzellen erkannt werden. Die Fähigkeit, Kolonien zu bilden, nahm mit steigender Bestrahlung ab, während die Apoptoserate mit zunehmender Bestrahlungsdosis zunahm. Des Weiteren wurde in der Arbeit festgestellt, dass ionisierende Bestrahlung weder Einfluss auf das Migrationsverhalten der Zellen noch auf die Interaktion mit anderen Immunzellen mittels Zytokinen und Chemokinen hatte, sondern dass diese Fähigkeiten auch nach Bestrahlung beibehalten wurde. Mesenchymale Stammzellen nehmen Einfluss auf das Regenerationsverhalten und den Wundheilungsprozess und stellen einen therapeutischen Ansatz für die Behandlung strahleninduzierter Xerostomie und Mukositis dar. Die in dieser Arbeit erhobenen Daten geben erstmalig Einblicke, wie MSCs aus der Kopf-Hals-Region auf Bestrahlung reagieren. Gegenstand weiterer Forschung sollten beispielsweise In-vivo-Experimente oder eine Erweiterung durch iP-MSCs sein.Mesenchymal stem cells (MSCs) exhibit a promising therapeutic potential in the field of cell-based tissue engineering and regenerative medicine due to their immunomodulatory properties and differentiation capacity. In the first section, mesenchymal stem cells (MSCs) were successfully isolated from human nasal mucosa (mMSC) and parotid gland (pMSC). The MSCs showed a plastic adherent and fibroblast-like morphology and were able to form colonies. They expressed the typical bone marrow MSC marker antigens CD29, CD44, CD73, CD90, and CD105 and were able to differentiate along the adipogenic, chondrogenic, and osteogenic pathways. Subsequently, mMSCs from four healthy donors were reprogrammed into induced pluripotent stem cells (iPSCs) by non-integrative chromosomal technologies. Two cell lines were established and characterized. Both the morphological picture of the colonies of pluripotent cells and the staining for active alkaline phosphatase activity indicated the presence of pluripotency. Further confirmation was obtained by expression of the corresponding pluripotency genes (including NANOG, OCT4, and SOX2). Differentiation into the three germ layers mesoderm, endoderm and ectoderm confirmed pluripotency and self-renewal ability of the cells. Induced pluripotent dependent mesenchymal stem cells (iP-MSCs) were differentiated from the iPS cells in the next step. These MSC-like cells also exhibited the stem cell-specific characteristics. It was demonstrated that mMSCs and iP-MSCs show similar cell characteristics in terms of morphology, clonogenic potential, differentiation, and surface phenotype. Moreover, iP-MSCs demonstrated related immunosuppressive capacity as mMSCs including the secretion of cytokines, and T cell inhibition. Therefore, generating iP-MSCs in an autologous manner may be a novel personalized treatment option in regenerative medicine. In the second section, the mMSCs and pMSCs were cultured and exposed to single radiation dosages of 2 Gy/day up to 10 days. Effects on morphology, colony forming ability, apoptosis, chemokine receptors, cytokine secretion, and cell migration were analyzed. It was shown that the ability to form colonies decreased with increasing irradiation, while the apoptosis rate increased with increasing irradiation dose. Furthermore, it was demonstrated that ionizing irradiation did not affect cell migration behavior or interaction with other immune cells via cytokines and chemokines. In summary, MSCs exhibited robustness and activation upon radiation for the support of tissue regeneration, but lost their potential to replicate.2022-10-2

Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Show Comparable Functionality to Their Autologous Origin

A multimodal therapeutic approach involving radiotherapy is required when treating head and neck squamous cell carcinoma. However, radiotherapy is restricted due to its high risk for damages to the surrounding healthy tissue of the treated area. Tissue regeneration and wound healing is promoted by the survival and regenerative capacities of tissue-resident or invading stem cells. Mesenchymal stem cells (MSCs) exhibit a promising therapeutic potential in the field of cell-based tissue engineering and regenerative medicine due to their immunomodulatory properties and differentiation capacity. However, the generation of MSCs for therapeutic applications is still a major challenge. We aimed to produce highly homogeneous induced pluripotent stem cell-derived mesenchymal stem cells (iP-MSCs) in an autologous manner from initially isolated human mucosa mesenchymal stem cells (mMSCs) of the upper respiratory tract. Therefore, mMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) by non-integrative chromosomal technologies and differentiated into corresponding iP-MSCs. We demonstrated that mMSCs and iP-MSCs show similar cell characteristics in terms of morphology, clonogenic potential, differentiation, and surface phenotype. Moreover, iP-MSCs demonstrated related immunosuppressive capacity as mMSCs including the secretion of cytokines, and T cell inhibition. Therefore, generating iP-MSCs in an autologous manner may be a novel personalized treatment option in regenerative medicine

A High-Throughput Method as a Diagnostic Tool for HIV Detection in Patient-Specific Induced Pluripotent Stem Cells Generated by Different Reprogramming Methods

Induced pluripotent stem cells (iPSCs) provide a unique opportunity for generation of patient-specific cells for use in translational purposes. We aimed to compare iPSCs generated by different reprogramming methods regarding their reprogramming efficiency, pluripotency capacity, and the possibility to use high-throughput PCR-based methods for detection of human pathogenic viruses. iPSCs from skin fibroblasts (FB), peripheral blood mononuclear cells (PBMCs), or mesenchymal stem cells (MSCs) were generated by using three different reprogramming systems including chromosomal integrating and nonintegrating methods. Reprogramming efficiencies were in accordance with the literature, indicating that the parental cell type and the reprogramming method play a major role for the reprogramming efficiencies (FB: STEMCCA: 1.30 +/- 0.18, Sendai virus: 1.37 +/- 0.01, and episomal plasmids: 0.04 +/- 0.02; PBMCs: Sendai virus: 0.002 +/- 0.001, episomal plasmids: 0) but result in the same characteristics of pluripotency. We found the highest reprogramming efficiencies for MSC with 3.32 +/- 1.2 by using episomal plasmids. Since GMP standard working procedures and screening units need virus contamination-free cell lines, we studied HIV-1 contamination in the generated iPSCs. We used the high-throughput cobas (R) 6800/8800 system, which is normally used for detection of HIV-1 in plasma of patients, and found that footprint-free reprogramming methods as episomal plasmids and Sendai virus are useful for the described virus detection method. This fast, cost-effective, robust, and reliable assay demonstrates the feasibility to use high-throughput PCR-based methods for detection of human pathogenic viruses in ps-iPSC lines that were generated with nongenome integrating reprogramming methods

Exercise modalities and endothelial function: a systematic review and dose-response meta-analysis of randomized controlled trials.

Background: Regular exercise is associated with enhanced nitric oxide (NO) bioavailability. Flow-mediated dilation (FMD) is used widely to assess endothelial function (EF) and NO release. Objectives: The aims of this systematic review and meta-analysis were to (i) investigate the effect of exercise modalities (aerobic, resistance or combined) on FMD; and (ii) determine which exercise and participant characteristics are most effective in improving FMD. Methods: We searched the MEDLINE, Embase, Cochrane Library, and Scopus databases for studies that met the following criteria: (i) randomized controlled trials of exercise with comparative non-exercise, usual care or sedentary groups; (ii) duration of exercise intervention ≥4 weeks; (iii) age ≥18 years; and (iv) EF measured by FMD before and after the intervention. Weighted mean differences (WMDs) with 95 % confidence interval were entered into a random effect model to estimate the pooled effect of the exercise interventions. Results: All exercise modalities enhanced EF significantly: aerobic (WMD 2.79, 95 % CI 2.12–3.45, p = 0.0001), resistance (WMD 2.52, 95 % CI 1.11–3.93, p = 0.0001) and combined (WMD 2.07, 95 % CI 0.70–3.44, p = 0.003). A dose–response relationship was observed between aerobic exercise intensity and improvement in EF. A 2 metabolic equivalents (MET) increase in absolute exercise intensity or a 10 % increase in relative exercise intensity resulted in a 1 % unit improvement in FMD. There was a positive relationship between frequency of resistance exercise sessions and improvement in EF (β 1.14, CI 0.16–2.12, p = 0.027). Conclusions: All exercise modalities improve EF significantly and there was a significant, positive relationship between aerobic exercise intensity and EF. Greater frequency, rather than intensity, of resistance exercise training enhanced EF