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1.
J Thorac Dis ; 13(3): 1922-1944, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33841980

ABSTRACT

During the mid-1990s cardiac surgery started exploring minimally invasive methods for coronary artery bypass grafting (CABG) and has over a 25-year period developed highly differentiated and less traumatic operations. Instead of the traditional sternotomy mini-incisions on the chest or ports are placed, surgery on the beating heart is applied, sophisticated remote access heart lung machine systems as well as videoscopic units are available, and robotic technology enables completely endoscopic approaches. This review describes these methods, reports on the cumulative intra- and postoperative outcome of these procedures, and gives an integrated view on what less invasive coronary bypass surgery can achieve. A total of 74 patient series published on the topic between 1996 and 2019 were reviewed. Six main versions of minimal access and robotically assisted CABG were applied in 11,135 patients. On average 1.3±0.6 grafts were placed and the operative time was 3 hours 42 min ± 1 hour 15 min. The procedures were carried out with a hospital mortality of 1.0% and a stroke rate of 0.6%. The revision rate for bleeding was 2.5% and a renal failure rate of 0.9% was noted. Wound infections occurred at a rate of 1.2% and postoperative hospital stay was 5.6±2.2 days. It can be concluded that less invasive and robotically assisted versions of coronary bypass grafting are carried out with an adequate safety level while surgical trauma is significantly reduced.

2.
Drug Discov Today ; 26(7): 1642-1655, 2021 07.
Article in English | MEDLINE | ID: mdl-33781952

ABSTRACT

Granulocyte colony-stimulating factor (G-CSF) is a cytokine used in pharmaceutical preparations for the treatment of chemotherapy-induced neutropenia. Evidence from experimental studies indicates that G-CSF exerts relevant activities in the central nervous system (CNS) in particular after lesions. In acute, subacute, and chronic CNS lesions, G-CSF appears to have strong anti-inflammatory, antiapoptotic, antioxidative, myelin-protective, and axon-regenerative activities. Additional effects result in the stimulation of angiogenesis and neurogenesis as well as in bone marrow stem cell mobilization to the CNS. There are emerging preclinical and clinical data indicating that G-CSF is a safe and effective drug for the treatment of acute and chronic traumatic spinal cord injury (tSCI), which we summarize in this review.


Subject(s)
Granulocyte Colony-Stimulating Factor/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Drug Repositioning , Granulocyte Colony-Stimulating Factor/pharmacology , Humans , Spinal Cord Injuries/epidemiology
3.
BMC Cardiovasc Disord ; 20(1): 312, 2020 06 30.
Article in English | MEDLINE | ID: mdl-32605611

ABSTRACT

BACKGROUND: An optimal donor work-up to exclude preexisting conditions is recommended, but urgency and technical equipment in donor centers must be considered. We report a case of two coronary stents present in the donor heart and the related long-term outcome. CASE PRESENTATION: A 59-year-old European male patient suffering from dilated cardiomyopathy with severely reduced left ventricular function and presenting with NYHA III underwent cardiac transplantation in 2004. At the one-year follow-up, during routine cardiac catheterization, two stents were found, one in the right coronary artery and one in the circumflex artery, in the patient's transplanted heart. As no stent implantation was performed since transplantation, these were present prior to transplantation and had been transplanted without causing clinical signs. One of the stents showed in-stent restenosis, and the patient received an additional stent 7 years after transplantation. The other stent still showed a good result, and no further intervention has been required so far. The patient is currently in good clinical condition. CONCLUSION: This is the first case report of favorable long-term stented coronary arteries prior to transplantation. This case highlights the importance of the donor work-up and meticulous palpation of the coronary arteries during donor evaluation.


Subject(s)
Donor Selection , Heart Failure/surgery , Heart Transplantation , Percutaneous Coronary Intervention/instrumentation , Stents , Tissue Donors , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/physiopathology , Coronary Restenosis/etiology , Coronary Restenosis/therapy , Heart Failure/diagnosis , Heart Failure/etiology , Heart Failure/physiopathology , Heart Transplantation/adverse effects , Humans , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Treatment Outcome
4.
Neurorehabil Neural Repair ; 34(2): 95-110, 2020 02.
Article in English | MEDLINE | ID: mdl-31971869

ABSTRACT

Objective. To examine (1) if serological or cerebrospinal fluid (CSF) biomarkers can be used as diagnostic and/or prognostic tools in patients with spinal cord injury (SCI) and (2) if literature provides recommendations regarding timing and source of biomarker evaluation. Data Sources. A systematic literature search to identify studies reporting on diagnostic and prognostic blood and/or CSF biomarkers in SCI was conducted in PubMed/MEDLINE, CINAHL, Science Direct, The Cochrane Library, ISI Web of Science, and PEDro. Study Selection. Clinical trials, cohort, and pilot studies on patients with traumatic SCI investigating at least one blood or CSF biomarker were included. Following systematic screening, 19 articles were included in the final analysis. PRISMA guidelines were followed to conduct this review. Data Extraction. Independent extraction of articles was completed by 2 authors using predefined inclusion criteria and study quality indicators. Data Synthesis. Nineteen studies published between 2002 and April 2019 with 1596 patients were included in the systematic review. In 14 studies, blood biomarkers were measured, 4 studies investigated CSF biomarkers, and 1 study used both blood and CSF samples. Conclusions. Serum/CSF concentrations of several biomarkers (S100b, IL-6, GFAP, NSE, tau, TNF-α, IL-8, MCP-1, pNF-H, and IP-10) following SCI are highly time dependent and related to injury severity. Future studies need to validate these markers as true biomarkers and should control for secondary complications associated with SCI. A deeper understanding of secondary pathophysiological events after SCI and their effect on biomarker dynamics may improve their clinical significance as surrogate parameters in future clinical studies.


Subject(s)
Biomarkers/metabolism , Spinal Cord Injuries/diagnosis , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Humans , Spinal Cord Injuries/blood , Spinal Cord Injuries/cerebrospinal fluid
5.
Expert Rev Med Devices ; 17(1): 33-40, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31829047

ABSTRACT

Introduction: Totally endoscopic coronary artery bypass grafting (TECAB) can only be performed in a reproducible manner using robotic technology. This operation has been developed for more than 20 years seeing three generations of surgical robots. TECAB can be carried out beating heart but also on the arrested heart. Single and multiple grafts can be placed and TECAB can be combined with percutaneous coronary intervention in hybrid procedures.Areas covered: This review outlines indications for the procedure, the surgical technique, and the postoperative care. Intra- and postoperative results as available in the literature are reported. Further areas focus on technological development, training methods, learning curves as well as on cost. Finally, we give an outlook on the potential future of this operation.Expert opinion: Robotic TECAB represents a complex, sophisticated but safe, and over-the-years grown procedure. Even though results seem to be in line with conventional coronary surgery worldwide adoption still has been slow probably due to procedure times, costs and learning curves. Main advantages of TECAB are minimized surgical trauma and subsequent reduction of postoperative healing time. With the current introduction of new robotic devices, a new era of procedure development is on its way.


Subject(s)
Coronary Artery Bypass/trends , Coronary Artery Disease/surgery , Endoscopy/trends , Robotic Surgical Procedures/trends , Humans , Postoperative Care , Treatment Outcome
6.
J Neurotrauma ; 34(24): 3362-3371, 2017 12 15.
Article in English | MEDLINE | ID: mdl-28683592

ABSTRACT

Our study aim was to assess the neurological outcomes of surgical decompression and stabilization within 5 and 24 h after injury. We performed a multi-center, retrospective cohort study in adolescents and adults 15-85 years of age presenting cervical spinal cord injury (CSCI) at one of 6 Austrian trauma centers participating in the Austrian Spinal Cord Injury Study (ASCIS). Neurological outcomes were measured using the American Spinal Injury Association Impairment Scale (AIS) grade according to the International Standards For Neurological Classification Of Spinal Cord Injury (ISNCSCI) form after at least 6 months of follow-up (FU). Of the 49 enrolled patients with acute CSCI, 33 underwent surgical decompression within 5 h (mean 3.2 h ± 1.1 h; very early group) after injury, and 16 underwent surgical decompression between 5 and 24 h (mean 8.6 h ± 5.5 h; early group). Significant neurological improvement was observed among the entire study population between the preoperative assessment and the FU. We identified a significant difference in the AIS grade at the last FU between the groups the using Jonckheere-Terpstra test for doubly ordered crosstabs (p = 0.011) and significantly different AIS improvement rates in the early group (Poisson model, p = 0.018). Improvement by one AIS grade was observed in 31% and 42% of the patients in the early and very early groups, respectively (p = 0.54). Improvement by two AIS grades was observed in 31% and 6% of the patients in the early and very early groups, respectively (p = 0.03; relative risk [RR], 5.2; 95% CI, 1.1-35). Improvement by three AIS grades was observed in 6% and 3% of patients in the early and very early groups, respectively (p = 1.0). Decompression of the spinal cord within 24 h after SCI was associated with an improved neurological outcome. No additional neurological benefit was observed in patients who underwent decompression within 5 h of injury.


Subject(s)
Neurosurgical Procedures/methods , Recovery of Function , Spinal Cord Injuries/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Austria , Cervical Vertebrae , Decompression, Surgical/methods , Female , Humans , Male , Middle Aged , Retrospective Studies , Time Factors , Treatment Outcome , Young Adult
7.
Spinal Cord Ser Cases ; 3: 17076, 2017.
Article in English | MEDLINE | ID: mdl-29423282

ABSTRACT

STUDY DESIGN: Establishing the structure of a prospective spinal cord injury (SCI) patient registry. OBJECTIVES: To develop a registry for patients with traumatic spinal cord injury (tSCI) in Austria as a base for addressing research questions, improving patient outcomes, and establishing a platform for future clinical trials. SETTINGS: Coordinating institution: Paracelsus Medical University Salzburg, Austria; participating partners are located in nine states in Austria. METHODS: The Austrian Spinal Cord Injury Study (ASCIS) collects longitudinal data on simple forms within a 7-stage follow-up examination timeline. RESULTS: The implementation of the ASCIS in 2012 created the first nationwide SCI patient registry in Austria. ASCIS is currently implemented in 17 trauma hospitals in 9 Austrian states, and over 150 individuals with acute tSCI have been registered to date. As in Austria, the structure of the health-care system does not involve a specialized SCI center covering the primary health care and the rehabilitation care, major challenges have to be overcome to involve all participating primary centers and rehabilitation centers, which perform tSCI patient care, for ASCIS. Through implementing ASCIS, a network of SCI clinicians and researchers, which is now beginning to support translational research and to initiate clinical trials for patients with tSCI, has formed. CONCLUSIONS: ASCIS is uniquely positioned in Austria to capture detailed information from the early acute to the chronic phases of tSCI, to provide this information also to bigger and translational settings, and to connect researchers and clinicians to facilitate clinical research on tSCI.

8.
Interact Cardiovasc Thorac Surg ; 22(6): 799-805, 2016 06.
Article in English | MEDLINE | ID: mdl-26976130

ABSTRACT

OBJECTIVES: Sutureless and rapid-deployment valves were recently introduced into clinical practice. The Edwards INTUITY valve system is a combination of the Edwards Magna pericardial valve and a subvalvular stent-frame to enable rapid deployment. We performed a parallel cohort study for comparison of the two valve types. METHODS: All patients receiving either an Edwards Magna Ease valve or an Edwards INTUITY valve system due to aortic stenosis from May 2010 until July 2014 were included. Patients undergoing bypass surgery, an additional valve procedure, atrial ablation surgery or replacement of the ascending aorta were excluded. Preoperative characteristics, operative specifications, survival, valve-related adverse events and transvalvulvar gradients were compared. RESULTS: One hundred sixteen patients underwent rapid-deployment aortic valve replacement [mean age 75 years (SD: 8); 62% female] and 132 patients underwent conventional aortic valve replacement [70 years (SD: 9); 31% female; P < 0.001]. Conventional valve patients were taller and heavier. The mean EuroSCORE II was 3.1% (SD: 2.7) and 4.4% (SD: 6.0) for rapid-deployment and conventional valve patients, respectively (P = 0.085). The mean implanted valve size was higher in the conventional group [23.2 mm (SD: 2.0) vs 22.5 mm (SD: 2.2); P = 0.007], but postoperative transvalvular mean gradients were comparable [15 mmHg (SD: 6) vs 14 mmHg (SD: 5); P = 0.457]. A subgroup analysis of the most common valve sizes (21 and 23 mm; implanted in 63% of patients) revealed significantly reduced mean postoperative transvalvular gradients in the rapid-deployment group [14 mmHg (SD: 4) vs 16 mmHg (SD: 5); P = 0.025]. A significantly higher percentage received minimally invasive procedures in the rapid-deployment group (59 vs 39%; P < 0.001). The 1- and 3-year survival rate was 96 and 90% in the rapid-deployment group and 95 and 89% in the conventional group (P = 0.521), respectively. Valve-related pacemaker implantations were more common in the rapid-deployment group (9 vs 2%; P = 0.014) and postoperative stroke was more common in the conventional group (1.6 vs 0% per patient year; P = 0.044). CONCLUSIONS: We conclude that this rapid-deployment valve probably facilitates minimally invasive surgery. Furthermore, a subgroup analysis showed reduced transvalvular gradients in smaller valve sizes compared with the conventionally implanted valve of the same type. The favourable haemodynamic profile and the potentially different spectrum of valve-related adverse events should be addressed in further clinical trials.


Subject(s)
Aortic Valve Stenosis/surgery , Aortic Valve/surgery , Heart Valve Prosthesis Implantation/methods , Minimally Invasive Surgical Procedures/methods , Pericardium/transplantation , Aged , Aortic Valve Stenosis/mortality , Austria/epidemiology , Female , Humans , Male , Prosthesis Design , Survival Rate/trends
9.
Cell Rep ; 12(12): 2072-85, 2015 Sep 29.
Article in English | MEDLINE | ID: mdl-26387951

ABSTRACT

Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily. Here, we show that genetic ablation of Nr2f6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, Nr2f6(-/-) mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor rechallenge. This is paralleled by increased frequencies of both CD4(+) and CD8(+) T cells and higher expression levels of interleukin 2 and interferon γ at the tumor site. Mechanistically, CD4(+) and CD8(+) T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds. Adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COUP Transcription Factors/genetics , Immunologic Surveillance , Immunotherapy, Adoptive/methods , Prostatic Neoplasms/therapy , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/transplantation , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/transplantation , COUP Transcription Factors/deficiency , COUP Transcription Factors/immunology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Immunologic Memory , Interferon-gamma/agonists , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-2/agonists , Interleukin-2/genetics , Interleukin-2/immunology , Lymphocyte Activation , Male , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Prostatic Neoplasms/genetics , Prostatic Neoplasms/immunology , Prostatic Neoplasms/mortality , Repressor Proteins , Signal Transduction , Survival Analysis , Tumor Necrosis Factor-alpha/agonists , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
10.
Front Cell Dev Biol ; 3: 48, 2015.
Article in English | MEDLINE | ID: mdl-26301221

ABSTRACT

Granulocyte-colony stimulating factor (G-CSF) is a growth factor that has originally been identified several decades ago as a hematopoietic factor required mainly for the generation of neutrophilic granulocytes, and is in clinical use for that. More recently, it has been discovered that G-CSF also plays a role in the brain as a growth factor for neurons and neural stem cells, and as a factor involved in the plasticity of the vasculature. We review and discuss these dual properties in view of the neuroregenerative potential of this growth factor.

11.
Eur J Cardiothorac Surg ; 48(4): 557-61, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25527170

ABSTRACT

OBJECTIVES: Outcome of aortic valve replacement may be influenced by the choice of bioprosthesis. Pericardial heart valves are described to have a favourable haemodynamic profile compared with porcine valves, although the clinical notability of this finding is still controversially debated. Herein, we compared the long-term results of two commonly implanted bioprosthesis at a single centre. METHODS: All consecutive patients undergoing isolated aortic valve replacement with either a Carpentier-Edwards Magna pericardial prosthesis or a Medtronic Mosaic porcine prosthesis between 2002 and 2008 were analysed regarding preoperative characteristics, short- and long-term survival, valve-related complications and echocardiographic findings. RESULTS: The Medtronic Mosaic was implanted in 163 patients and the Carpentier-Edwards Magna in 295 patients. The sizes of implanted valves were 22.4 ± 1.5 mm for the Mosaic and 21.8 ± 1.8 mm for the Magna (P = 0.001). The long-term survival rate was 76 and 56% after 5 and 10 years for the Medtronic Mosaic, which was comparable with the Carpentier-Edwards Magna (77 and 57%; P = 0.92). Overall long-term survival was comparable with an age- and sex-matched Austrian general population for both groups. Valve-related adverse events were similar between groups. The postoperative mean transvalvular gradient was significantly increased in the Mosaic group (24 ± 9 mmHg vs 17 ± 7 mmHg; P < 0.001). CONCLUSIONS: Both types of aortic bioprostheses offer excellent results after isolated aortic valve replacement. Despite relevant differences in gradients, long-term survival was comparable with the expected normal survival for both bioprostheses. Patients with a porcine heart valve had a higher postoperative transvalvular gradient.


Subject(s)
Bioprosthesis , Cause of Death , Heart Valve Prosthesis Implantation/mortality , Heart Valve Prosthesis Implantation/methods , Heart Valve Prosthesis , Prosthesis Design/methods , Aged , Aged, 80 and over , Animals , Aortic Valve Insufficiency/diagnostic imaging , Aortic Valve Insufficiency/mortality , Aortic Valve Insufficiency/surgery , Cohort Studies , Echocardiography, Doppler , Female , Humans , Kaplan-Meier Estimate , Male , Pericardium/surgery , Pericardium/transplantation , Prognosis , Proportional Hazards Models , Prosthesis Failure , Retrospective Studies , Risk Assessment , Severity of Illness Index , Survival Rate , Treatment Outcome
12.
Nature ; 507(7493): 508-12, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24553136

ABSTRACT

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Killer Cells, Natural/immunology , Mammary Neoplasms, Experimental/pathology , Melanoma, Experimental/pathology , Neoplasm Metastasis/immunology , Proto-Oncogene Proteins c-cbl/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Ubiquitin-Protein Ligases/metabolism , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Animals , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Female , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Male , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/immunology , Melanoma, Experimental/drug therapy , Melanoma, Experimental/genetics , Melanoma, Experimental/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/prevention & control , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-cbl/deficiency , Proto-Oncogene Proteins c-cbl/genetics , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/genetics , Ubiquitination , Warfarin/pharmacology , Warfarin/therapeutic use , c-Mer Tyrosine Kinase , Axl Receptor Tyrosine Kinase
13.
Clin Breast Cancer ; 13(4): 264-70, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23829892

ABSTRACT

BACKGROUND: The presence of forkhead box protein 3 (FOXP3) in breast cancer cells is a matter of debate. We systematically analyzed expression of FOXP3 in 1574 breast carcinomas. MATERIALS AND METHODS: For nuclear FOXP3 detection in epithelial breast cancer cells, tissue microarray technology was used. In addition, cultured breast cancer cell lines (ZR75-1, MCF7-WH, BT20, T47D, and SKBR3) were tested for FOXP3 expression using real-time polymerase chain reaction and flow cytometry for messenger RNA (mRNA) and protein quantification. RESULTS: We could neither detect any significant levels of mRNA or protein expression of FOXP3 in human breast cancer cell lines, nor in breast cancer specimens. Weak nuclear staining for FOXP3 was detectable in 16 of 1574 breast cancer cases (1%) and was only seen in a small proportion of malignant cells. There was no difference in survival between patients with FOXP3-positive or -negative tumors. CONCLUSION: FOXP3 does most likely not play a significant role in breast cancer biology, because it is only scarcely expressed in a very small proportion of breast cancer samples.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Lobular/metabolism , Epithelial Cells/metabolism , Forkhead Transcription Factors/metabolism , Neoplasm Recurrence, Local/metabolism , T-Lymphocytes/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/genetics , Carcinoma, Lobular/pathology , Cell Nucleus/genetics , Cell Nucleus/metabolism , Cytoplasm/metabolism , Cytoplasm/pathology , Epithelial Cells/pathology , Female , Follow-Up Studies , Forkhead Transcription Factors/genetics , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/pathology , Tumor Cells, Cultured
14.
Blood ; 122(7): 1192-202, 2013 Aug 15.
Article in English | MEDLINE | ID: mdl-23770777

ABSTRACT

The Janus kinase (JAK)-inhibitor ruxolitinib decreases constitutional symptoms and spleen size of myelofibrosis (MF) patients by mechanisms distinct from its anticlonal activity. Here we investigated whether ruxolitinib affects dendritic cell (DC) biology. The in vitro development of monocyte-derived DCs was almost completely blocked when the compound was added throughout the differentiation period. Furthermore, when applied solely during the final lipopolysaccharide-induced maturation step, ruxolitinib reduced DC activation as demonstrated by decreased interleukin-12 production and attenuated expression of activation markers. Ruxolitinib also impaired both in vitro and in vivo DC migration. Dysfunction of ruxolitinib-exposed DCs was further underlined by their impaired induction of allogeneic and antigen-specific T-cell responses. Ruxolitinib-treated mice immunized with ovalbumin (OVA)/CpG induced markedly reduced in vivo activation and proliferation of OVA-specific CD8⁺ T cells compared with vehicle-treated controls. Finally, using an adenoviral infection model, we show that ruxolitinib-exposed mice exhibit delayed adenoviral clearance. Our results demonstrate that ruxolitinib significantly affects DC differentiation and function leading to impaired T-cell activation. DC dysfunction may result in increased infection rates in ruxolitinib-treated patients. However, our findings may also explain the outstanding anti-inflammatory and immunomodulating activity of JAK inhibitors currently used in the treatment of MF and autoimmune diseases.


Subject(s)
Antigen-Presenting Cells/drug effects , Dendritic Cells/drug effects , Janus Kinases/antagonists & inhibitors , Pyrazoles/pharmacology , T-Lymphocytes, Cytotoxic/drug effects , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Apoptosis/drug effects , Blotting, Western , Bone Marrow/drug effects , Bone Marrow/metabolism , Cell Adhesion/drug effects , Cell Differentiation/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Flow Cytometry , Humans , In Vitro Techniques , Mice , Mice, Inbred C57BL , Mice, Transgenic , Monocytes/cytology , Monocytes/drug effects , Monocytes/metabolism , Nitriles , Pyrimidines , Spleen/cytology , Spleen/drug effects , Spleen/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism
15.
PLoS One ; 8(6): e65178, 2013.
Article in English | MEDLINE | ID: mdl-23762309

ABSTRACT

Dendritic cells (DCs) are potent antigen-presenting cells with a promising potential in cancer immunotherapy. Cbl proteins are E3 ubiquitin ligases and have been implicated in regulating the functional activity of various immune cells. As an example, c-Cbl negatively affects DC activation. We here describe that another member of the Cbl-protein family (i.e. Cbl-b) is highly expressed in murine bone-marrow-derived DCs (BMDCs). Differentiation of cblb-/- bone marrow mononuclear cells into classical BMDCs is unaltered, except enhanced induction of DEC-205 (CD205) expression. When tested in mixed-lymphocyte reaction (MLR), cblb-/- BMDCs exhibit increased allo-stimulatory capacity in vitro. BMDCs were next in vitro stimulated by various toll like receptor (TLR)-agonists (LPS, Poly(I:C), CpG) and exposed to FITC-labeled dextran. Upon TLR-stimulation, cblb-/- BMDCs produce higher levels of proinflammatory cytokines (IL-1α, IL-6 and TNF-α) and exhibit a slightly higher level of FITC-dextran uptake. To further characterize the functional significance of cblb-/- BMDCs we tested them in antigen-specific T cell responses against ovalbumin (OVA) protein and peptides, activating either CD8(+) OT-I or CD4(+) OT-II transgenic T cells. However, cblb-/- BMDCs are equally effective in inducing antigen-specific T cell responses when compared to wildtype BMDCs both in vitro and in vivo. The migratory capacity into lymph nodes during inflammation was similarly not affected by the absence of Cbl-b. In line with these observations, cblb-/- peptide-pulsed BMDCs are equally effective vaccines against OVA-expressing B16 tumors in vivo when compared to wildtype BMDCs. We conclude that in contrast to c-Cbl, Cbl-b plays only a limited role in the induction of Ag-specific T cell responses by murine BMDCs in vitro and in vivo.


Subject(s)
Adaptor Proteins, Signal Transducing/immunology , Bone Marrow Cells/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Proto-Oncogene Proteins c-cbl/immunology , Ubiquitin-Protein Ligases/immunology , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Animals , Antigens, CD/genetics , Antigens, CD/immunology , Biological Transport , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation , Cytokines/biosynthesis , Cytokines/immunology , Dendritic Cells/cytology , Dendritic Cells/drug effects , Dextrans/metabolism , Fluorescein-5-isothiocyanate/analogs & derivatives , Fluorescein-5-isothiocyanate/metabolism , Gene Expression , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Lipopolysaccharides/pharmacology , Lymphocyte Culture Test, Mixed , Melanoma, Experimental/drug therapy , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Knockout , Minor Histocompatibility Antigens , Ovalbumin/immunology , Peptides/pharmacology , Poly I-C/pharmacology , Proto-Oncogene Proteins c-cbl/deficiency , Proto-Oncogene Proteins c-cbl/genetics , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , Skin Neoplasms/drug therapy , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/genetics
16.
Clin Dev Immunol ; 2012: 692639, 2012.
Article in English | MEDLINE | ID: mdl-22550535

ABSTRACT

The E3 ubiquitin ligase Cbl-b is an established nonredundant negative regulator of T-cell activation. Cbl-b fine-tunes the activation threshold of T cells and uncouples T cells from their vital need of a costimulatory signal to mount a productive immune response. Accordingly, mice deficient in cblb are prone to autoimmunity and reject tumors. The latter has been described to be mediated via CD8(+) T cells, which are hyperactive and more abundant in shrinking tumors of cblb-deficient animals. This might at least also in part be mediated by resistance of cblb-deficient T cells to negative cues exerted by tumor-associated immuno-suppressive factors, such as TGF-ß and regulatory T cells (Treg). Experiments using cblb-deficient T cells either alone or in combination with vaccines validate the therapeutic concept of enhancing the efficacy of adoptively transferred lymphocytes to treat malignant tumors. This paper summarizes the current knowledge about the negative regulatory role of Cbl-b in T-cell activation and its potential therapeutic implications for cancer immunotherapy.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunotherapy/methods , Neoplasms , Proto-Oncogene Proteins c-cbl/immunology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/metabolism , Cancer Vaccines/administration & dosage , Cancer Vaccines/therapeutic use , Humans , Lymphocyte Activation/immunology , Mice , Mice, Knockout , Neoplasms/immunology , Neoplasms/prevention & control , Neoplasms/therapy , Proto-Oncogene Proteins c-cbl/deficiency , Proto-Oncogene Proteins c-cbl/genetics , Signal Transduction/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/immunology
17.
Immunol Cell Biol ; 90(1): 130-4, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21383769

ABSTRACT

The success of cancer immunotherapy is limited by potent endogenous immune-evasion mechanisms, which are at least in part mediated by transforming growth factor-ß (TGF-ß). The E3 ubiquitin ligase Cbl-b is a key regulator of T cell activation and is established to regulate TGF-ß sensitivity. cblb-deficient animals reject tumors via CD8(+) T cells, which make Cbl-b an ideal target for improvement of adoptive T-cell transfer (ATC) therapy. In this study, we show that cblb-deficient CD8(+) T cells are hyper-responsive to T-cell receptor (TCR)/CD28-stimulation and are in part protected against the negative cues induced by TGF-ß in vitro. Notably, adoptive transfer of polyclonal, non-TCR transgenic cblb-deficient CD8(+) T cells is not sufficient to reject B16-ova or EG7 tumors in vivo. Thus, cblb-deficient ATC requires proper in vivo re-activation by a dendritic cell (DC) vaccine. In strict contrast to ATC monotherapy, this approach delayed tumor outgrowth and significantly increased survival rates, which is paralleled by increased CD8(+) T-cells infiltration to the tumor site and enrichment of ova-specific and interferon-γ (IFN-γ)-secreting CD8(+) T cell in the draining lymph node (LN). Moreover, CD8(+) T cells from cblb-deficient mice vaccinated with the DC vaccine show increased cytolytic activity in vivo. In summary, our data using cblb-deficient polyclonal, non-TCR-transgenic adoptively transferred CD8(+) T cells into immuno-competent non-lymphodepleted recipients suggest that targeting Cbl-b might serve as a novel 'adjuvant approach', suitable to augment the effectiveness of established anti-cancer immunotherapies.


Subject(s)
Adaptor Proteins, Signal Transducing/deficiency , CD8-Positive T-Lymphocytes/transplantation , Cancer Vaccines/therapeutic use , Immunotherapy, Adoptive/methods , Neoplasms, Experimental/therapy , Proto-Oncogene Proteins c-cbl/deficiency , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cancer Vaccines/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cell Survival/immunology , Cells, Cultured , Combined Modality Therapy , Cytokines/immunology , Cytokines/metabolism , Cytotoxicity, Immunologic/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Female , Flow Cytometry , Lymph Nodes/immunology , Lymph Nodes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , Proto-Oncogene Proteins c-cbl/genetics , Proto-Oncogene Proteins c-cbl/immunology , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/pharmacology
18.
J Am Diet Assoc ; 107(8): 1333-8, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17659899

ABSTRACT

OBJECTIVE: To develop and evaluate the efficacy of an online continuing education course for professionals who provide food safety information to high-risk populations. DESIGN: A 2-credit graduate-level class was converted into six web-based modules (overview of foodborne illness, immunology, pregnancy, human immunodeficiency virus, cancer and transplants, and lifecycle) and offered to nutrition and health professionals. Participants had 8 weeks to complete the modules, pre and post questionnaires, and course evaluation. Those who successfully completed the protocol received six continuing education units from one of three professional associations. Change in knowledge was measured using pre and post questionnaires. Course efficacy was evaluated using a post-course questionnaire. SUBJECTS/SETTING: A convenience sample of 140 registered dietitians/dietetic technicians registered, nurses, and extension educators were recruited through professional conferences and electronic mailing lists to take the course. STATISTICAL ANALYSES: Analysis of variance was used to evaluate differences in knowledge scores for all groups across five main effects (attempt, module, profession, age, and education). Course evaluation responses were used to assess course effectiveness. RESULTS: For each module, knowledge scores increased significantly (P<0.001) from pre to post questionnaire. Overall, knowledge scores increased from 67.3% before the modules to 91.9% afterwards. Course evaluation responses were favorable, and participants indicated that course objectives were met. CONCLUSIONS: Online continuing education courses, such as "Food Safety Issues for High Risk Populations," seem to be a convenient, effective option for dietetics professionals, nurses, and extension educators seeking knowledge about food safety issues of high-risk populations. Online learning is a promising delivery approach for the continuing education of health professionals.


Subject(s)
Consumer Product Safety , Dietetics/education , Education, Continuing/standards , Education, Distance/standards , Health Knowledge, Attitudes, Practice , Adolescent , Adult , Analysis of Variance , Education, Continuing/methods , Education, Distance/methods , Female , Food Contamination/prevention & control , Food Handling/standards , Humans , Internet , Male , Middle Aged , Needs Assessment , Reproducibility of Results , Risk Assessment , Sensitivity and Specificity , Surveys and Questionnaires/standards
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