T‐regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these ...responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini‐review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg‐dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform‐selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.
Biochemical and molecular studies show that the functions of Foxp3+ regulatory T cells can be pharmacologically enhanced with isoform‐specific histone/protein deacetylase inhibitors, providing real‐world options for sustained therapy in transplant recipients.
Induced Forkhead box P3-positive (Foxp3(+)) T-regulatory cells (iTregs) are essential to gastrointestinal immune homeostasis, and loss of the ability to develop iTregs may lead to autoimmune colitis. ...We previously showed a role for sirtuin-1 (Sirt1) in control of Treg function and hypothesized that targeting of Sirt1 might enhance iTreg development and thereby represent a potential therapy for inflammatory bowel disease (IBD). We adoptively transferred CD4(+)CD25(-)Foxp3(-) T effector (TE) cells from wild-type (WT) (C57BL/6) or fl-Sirt1/CD4cre mice into B6/Rag1(-/-) mice and monitored the mice until they lost 10-15% of their weight. Adoptive transfer of TE cells lacking Sirt1 to B6/Rag1(-/-) mice resulted in a 2.8-fold increase in iTreg formation compared with mice receiving WT TE cells and correlated with attenuated colitis and reduced weight loss (1.04±1.4% vs. 13.97±2.2%, respectively, P<0.001). In a second model of IBD, we used pharmacologic Sirt1 targeting of mice receiving multiple cycles of dextran sodium sulfate (DSS) in their drinking water, alternated with fresh water. Likewise, WT mice receiving cyclic DSS and a Sirt1 inhibitor, EX-527, had reduced weight loss (5.8±5.9% vs. 13.2±6.9%, respectively, P=0.03) and increased iTreg formation compared with controls. Sirt1 appears a promising target for pharmacologic therapy of IBD as a result of promoting iTreg development.
Expression profiles of CXC- and CC-chemokines in various forms of tonsillar disease were studied to evaluate whether certain chemokines play a predominant role in a specific subset of tonsillar ...disease. Total RNA was isolated from 89 biopsies (21 hyperplastic palatine tonsils, 25 adenoids, 16 chronic inflammatory palatine tonsils and 27 chronic inflammatory palatine tonsils with histological prove of acute inflammation), reverse transcribed and subjected to PCR amplifying IL-8, Gro-alpha, eotaxin-1, eotaxin-2, MCP-3, MCP-4 and RANTES. 2% agarose gel electrophoresis revealed a predominance of IL-8 in the chronic inflammatory palatine tonsil group compared to tonsillar hyperplasia. Furthermore, eotaxin-2 was strongly overexpressed in adenoid samples compared to chronic inflammatory specimens. Our data suggest that the majority of diseases related to adenoid formation are mediated via an eotaxin-2 expression, whereas chronic inflammatory tonsillitis is associated with IL-8 upregulation. These data imply that adenoids are related to a Th-2, and chronic inflammatory tonsillitis to a Th-1 based immune response.
This report serves to publicize the research of academic institutions for Plastic Surgery within our society DGPRÄC in 2017/2018 and sequels the funding report of 2015/2016. Applications to public, ...non-public, or industrial funding organizations were evaluated. At the same time, this paper analyses the number of approved DFG applications in Plastic, Thoracic and Vascular Surgery in the GEPRIS system. Contrary to these specialties, Plastic Surgery is not classified as an independent speciality in the subject structure of the DFG review board which results in a lack of transparency concerning Plastic Surgery research work.
Our previously established online database (https://docs.google.com/forms/d/1OaSnHyKTysawiI1ie7kfUxDf7nJP_RiTUJTsnb7Mq_E/edit) for reporting requested/ approved and rejected research applications to public, non-public and industrial funding organizations was continued and evaluated together with applications found in the DFG's public database GEPRIS.
Compared to the previous year's report, the number of approved applications from public research organizations (DFG, BMBF, BMWi, EU) was increased from 23 to 27. We identified 19 approved DFG applications from Plastic Surgery, as compared to 9 and 8 applications by Thoracic and Vascular Surgery, respectively.
Taken together, this data emphasizes that our research is at least equal to that of other newly established surgical specialties within the framework of the DFG. Accordingly, we hope to provide further arguments for an adaptation of the DFG review boards subject structure to include Plastic Surgery as an independent specialty as it is for Vascular Surgery and Thoracic Surgery.
Abstract Background Cold ischemia and clamping of the renal artery contribute to acute tubular necrosis and renal dysfunction of transplant grafts. The mechanism of ischemic injury is not fully ...understood, but endothelin (ET)-1 and -2 have been found to participate in reperfusion injury. ET receptor blockade has been shown to have renoprotective effects in both warm and cold reperfusion injury. Objective We sought to assess the effect of tezosentan, a competitive ET antagonist, on piglet renal function during cold ischemia and renal artery clamping. Design/Methods Sixteen piglets (7 to 10 days old) were prepped and assigned to three experimental groups: piglets with kidneys clamped ( KCLAMP ), with kidneys wrapped in ice ( KICE ), and piglets treated with tezosentan injected after 45 minutes of clamping and ice ( KTEZO ). Preexperiment parameters including vital signs, urine volume, glomerular filtration rate (GFR), paraaminohippuric acid clearance (CPAH), fractional excretion of sodium and potassium (FeNa, FeK), and renal blood flow (RBF) were measured at baseline, then at 1- and 2-hour intervals. Results The decrease in urine volume was comparable in both KCLAMP and KICE groups, but no UV decrease was observed in KTEZO group. RBF and GFR were similar (26% to 52% decrease) in all three groups. FeNa decreased by >50% in KICE , whereas it increased by 60% in KTEZO when compared with baseline. A similar increase in FeK was observed in all three groups. Conclusions Cold ischemia and clamping have deleterious effects on RBF, GFR, and FeNa. ET blockade did not have a renoprotective effect except on urine volume when given soon after the injury.
T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these ...responses involves changes in post-translational modifications (PTMs) of histones and many non-histone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg-dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.
Despite ongoing developments of treatment protocols head and neck squamous cell carcinomas (HNSCC) show only marginal improvement in outcome, which has been attributed to a lack of therapy ...individualized to tumor biological properties. We compared mRNA expression profiles of HNSCC and normal epithelial cells using differential display to identify gene fragments showing differential expression in HNSCC cells. We identified a 127-bp long fragment to be overexpressed in HNSCC cells that revealed a 98.4% homology with the Pim-1 mRNA. The differential expression was confirmed by Northern hybridization. Immunohistochemistry showed overexpression of the Pim-1 protein in 98% (41/42) of invasive HNSCC. Analysis of Pim-1 protein expression in relation to TNM stage and histological grade of the tumors exhibited no significant correlation. However, when samples of primary tumor and metastasis retrieved from the same patients (n=26) were analyzed, nearly significant correlation of Pim-1 expression with histological grade was found (p=0.06). The high frequency of the Pim-1 expression of HNSCC of different grades and stages in conjunction with its absence in non-neoplastic head and neck squamous cell epithelium underlines the functional role of Pim-1 in molecular processes of HNSCC.
Zusammenfassung
Hintergrund
Dieser Bericht baut auf dem Forschungsförderungsbericht aus
dem Jahr 2015/2016 auf und dient der Bekanntmachung der akademischen
Forschungsleistung an Universitätskliniken ...der Deutschen Gesellschaft der
Plastischen, Rekonstruktiven und Ästhetischen Chirurgen (DGPRÄC) für 2017/2018.
Berücksichtigt wurden dabei Anträge auf Forschungsförderung bei öffentlichen,
nicht-öffentlichen, oder industriellen Förderinstituten. Gleichzeitig soll
dieser Beitrag die Anzahl der genehmigten Anträge bei der Deutschen
Forschungsgemeinschaft (DFG) aus der Plastischen Chirurgie, Thorax- und
Gefäßchirurgie gegenüberstellen. Innerhalb dieser jüngeren selbständigen
chirurgischen Fachgebiete wird das seit 1993 eigenständige Fachgebiet Plastische
Chirurgie in der Fächerstruktur der DFG Fachkollegien immer noch nicht separat
geführt, sondern dem Fachkollegium Orthopädie und Unfallchirurgie zugeordnet.
Dies führt dazu, dass die Anträge nicht fachspezifisch begutachtet werden.
Material und Methoden
Die bereits etablierte online Datenbank (
https://docs.google.com/forms/d/1OaSnHyKTysawiI1ie7kfUxDf7nJP_RiTUJTsnb7Mq_E/edit
)
zur Meldung beantragter/ genehmigter und abgelehnter Forschungsförderungen
öffentlicher, nicht-öffentlicher und industrieller Förderinstitutionen wurde
fortgeführt und gemeinsam mit den Anträgen aus der öffentlichen Datenbank der
DFG, das Geförderte Projekte Informationssystem (GEPRIS), ausgewertet.
Ergebnisse
Im Vergleich zum letzten Beobachtungszeitraum von 2015/2016
nahm die Anzahl genehmigter Anträge aus öffentlichen Einrichtungen (DFG, BMBF,
BMWi, EU) von 23 auf 27 zu. Aus den chirurgischen Fachgebieten Thorax- und
Gefäßchirurgie waren jeweils 9 bzw. 8 DFG Anträge im GEPRIS dokumentiert,
wohingegen 19 Bewilligungen von Anträgen der Plastischen Chirurgie identifiziert
wurden.
Schlussfolgerung
Durch die vorliegende Auswertung konnten wir zeigen, dass
das Aufkommen an Anträgen aus dem Fachgebiet der Plastischen Chirurgie denen der
anderen eigenständig geführten Fachgebiete entspricht, wobei sogar eine höhere
Anzahl zu verzeichnen ist. Vor diesem Hintergrund ist die gegenwärtige
Subsummierung seitens der DFG, auch im Hinblick auf eine öffentlich
nachvollziehbare Vergabe der Fördersummen, nicht zu akzeptieren.
Since 2015/16 the DGPRÄC collects, evaluates and publishes the research activities of academic sections, departments and clinics for plastic surgery at university hospitals in Germany, in order to ...raise the awareness of plastic surgical research performance.
The directors of plastic surgical academic institutions were contacted via the DGPRÄC and asked to report any requested/approved and rejected research applications to public, non-public and industrial funding organizations. Data was collected in our previously established online database: https://docs.google.com/forms/d/e/1FAIpQLSe6F5xmTyw-k7VKJx_2jkPA4LBXsA0sgBGMrC3rx_4bHj6uzQ/viewform?usp=sf_link. In addition, applications were identified via the DFG's public database GEPRIS.
A total of 41 funding applications to the public funding institutes DFG, BMBF, BMWi, BMG and EU were identified. 75.6 % (31/41) of the applications had already been approved at the time of data collection, of which 77.4 % (24/31) were DFG, 9.7 % (3/31) were BMWi, 6.5 % (2/31) were EU and 3.2 % (1/31) were BMBF or BMG applications. The average funding amounted to 358 301 Euro. In 50.0 % (12/24) of the cases, the approved DFG proposals were assigned to the subject review board 205-27 Orthopedics, Trauma Surgery, Reconstructive Surgery.
The continuous publication of plastic surgical research funding reports submitted by the convention of university plastic surgeons of the DGPRÄC portraits the excellent, collaborative research activity in the field of plastic surgery.
To compare gene expression patterns between laryngeal squamous cell carcinoma (SCC) cells and their normal phenotypes to identify genes showing differential expression.
Messenger RNA was isolated ...from both kinds of cells, reversely transcribed and subjected to differential display reverse transcription (DDRT)-PCR. Gene fragments showing difference in the expression were recovered, reamplified, cloned and sequenced, enabling homology search. Total RNA was isolated from laryngeal SCC cells and adjacent normal mucosa and subjected to Northern hybridization.
A 159 bp gene fragment was detected, revealing 96% homology with the human myosin-binding protein-C1 (MYBPC-1) gene. Compared to the benign phenotypes the expression of MYBPC-1 was particularly increased in SCC cells, confirmed by Northern hybridization.
The results presented in this work may help to extend the diagnostic panoply available for the evaluation of laryngeal tissue conspicuous for malignancy.
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