610 Medizin und Gesundheit
Refine
Year of publication
- 2013 (350) (remove)
Document Type
- Article (265)
- Doctoral Thesis (34)
- Conference Proceeding (14)
- Part of Periodical (14)
- Contribution to a Periodical (12)
- Book (3)
- Review (3)
- Part of a Book (2)
- Periodical (2)
- Preprint (1)
Is part of the Bibliography
- no (350)
Keywords
- Video (19)
- Capsule endoscopy (12)
- Small bowel (10)
- Endoscopy (7)
- Balloon enteroscopy (6)
- Enteroscopy (6)
- Endoscopic retrograde cholangiopancreatography (4)
- Apoptosis (3)
- IAP proteins (3)
- Smac (3)
- epigenetics (3)
- Atrial fibrillation (2)
- Begriff (2)
- Begriffsgeschichte <Fach> (2)
- Bile duct stone (2)
- Blog (2)
- Breast cancer (2)
- CBA (2)
- COPD (2)
- Cholangiography (2)
- Cholangiopancreatography (2)
- Colonoscopy (2)
- Colorectal cancer (2)
- Double-balloon enteroscopy (2)
- Endoscopic retrograde (2)
- Enterscopy (2)
- Extended donor criteria (2)
- Gesichtsauflösung (2)
- Hemorrhage (2)
- Herb induced liver injury (2)
- IL-6 (2)
- KGF (2)
- Lymphectasia (2)
- Migration (2)
- PDGFRβ (2)
- ROS (2)
- Rhabdomyosarcoma (2)
- SD-OCT (2)
- Sestrin 2 (2)
- Social Media (2)
- Standard endoscopy (2)
- Stroke (2)
- Thrombolysis (2)
- VEGF (2)
- Web 2.0 (2)
- apoptosis (2)
- cardiac (2)
- cell death (2)
- gamma (2)
- glioblastoma (2)
- immunotherapy (2)
- leukemia (2)
- radiotherapy (2)
- schizophrenia (2)
- signal transduction (2)
- synchrony (2)
- therapy (2)
- ALL (1)
- AML (1)
- Actin (1)
- Adenocarcinoma (1)
- Adhesion (1)
- Adolescence (1)
- Airways (1)
- Allergy (1)
- Angiectasia (1)
- Angiodysplasia (1)
- Antibiotic generic drugs (1)
- Anticoagulation (1)
- Antifungal agents (1)
- Antineoplastic agents (1)
- Antiretrovirals (1)
- Antiviral therapy (1)
- Aortic debranching (1)
- Aortic dissection (1)
- Aromatase inhibitors (1)
- Arteriovenous malformation (1)
- Aspergillosis (1)
- Assessment (1)
- Asthma (1)
- Augenheilkunde (1)
- Augenverletzungen (1)
- Auric nanoparticles (1)
- Autism spectrum disorder (1)
- B-cell (1)
- B16 cells (1)
- BCL2 (1)
- BCR-ABL (1)
- BRVO (1)
- Ballet (1)
- Ballon-assisted enteroscopy (1)
- Bcl-2 (1)
- Befindlichkeit (1)
- Benign disorder (1)
- Bevacizumab (1)
- Bewältigung (1)
- Bildnis (1)
- Billroth II gastroenterostomy (1)
- Billroth papillotome (1)
- Billroth’s operation-II (1)
- Blood-brain barrier (1)
- Bortezomib (1)
- Brain (1)
- Brain development (1)
- Brain repair (1)
- Burnout-Syndrom (1)
- C1-inhibitor deficiency (1)
- CIOMS (1)
- CRVO (1)
- CXCL12 (1)
- CXCR4 (1)
- Cancer (1)
- Cancer stem cells (1)
- Candida (1)
- Capecitabine (1)
- Capsule endoscopy, video (1)
- Cardiac surgery (1)
- Castleman’s disease (1)
- Catheter ablation (1)
- Celiac disease (1)
- Cell Death (1)
- Cell Signaling (1)
- Cell Surface Receptor (1)
- Cellular Immune Response (1)
- Cerasorb (1)
- Cerebral Vasospasm (1)
- Chemoradiotherapy (1)
- Chronic illness (1)
- Chronic obstructive airway disease (1)
- Clip (1)
- Cohort study (1)
- Communication (1)
- Comparative study (1)
- Coordination Of Control Modes (1)
- Core needle biopsy (1)
- Coronary artery disease (CAD) (1)
- Cost And Quality Management (1)
- Crohn’s disease (1)
- Cryoablation (1)
- Cyanoacrylate (1)
- Cytochrome P450 (1)
- Cytokine (1)
- Cytotoxicity (1)
- DNA Adducts (1)
- DR5 (1)
- Dancer (1)
- Delayed Cerebral Ischemia (1)
- Dentin adhesives (1)
- Dermatologie (1)
- Device (1)
- Diabetic nephropathy (1)
- Dieulafoy’s lesion (1)
- Digestive system (1)
- Dilated cardiomyopathy (1)
- Disease management (1)
- Docetaxel (1)
- Doctors In Management (1)
- Double balloon enteroscopy (1)
- Doubling time (1)
- Drug Therapy (1)
- Drug hepatotoxicity (1)
- Drug induced liver injury (1)
- Duodenum (1)
- EEG (1)
- EWS/Fli1 (1)
- Ectopic bone formation (1)
- Ectopic varices (1)
- Effectivity (1)
- Elderly (1)
- Ellipticine (1)
- Endomicroscopy (1)
- Endoscopic papillotomy (1)
- Endoscopic retrograde cholangiography (1)
- Endoscopic sphincterotomy (1)
- Endoscopic treatment (1)
- Endoscopic ultrasound (1)
- Energieumsatz <Medizin> (1)
- Entzündung (1)
- Erschöpfung (1)
- Esophagogastric (1)
- Europe (1)
- European Comparison (1)
- Ewing sarcoma (1)
- Exemestane (1)
- FAP (1)
- FTY720 (1)
- Facet joint osteoarthritis (1)
- Fast-track (1)
- Female (1)
- Fever (1)
- Fibrinolytic (1)
- Fingolimod (1)
- G-CSF (1)
- Gastric adenoma (1)
- Gastric cancer (1)
- Gastritis (1)
- Gastrointestinal bleeding (1)
- Gene polymorphism (1)
- Generic drugs (1)
- Gesicht (1)
- Gesicht <Motiv> (1)
- Gewebedurchblutung (1)
- Gewebetemperatur (1)
- Giant lymph node hyperplasia (1)
- Glivec® (1)
- Glomerulonephritis (1)
- Gold (1)
- Graft function (1)
- Graft survival (1)
- Graz <2013> (1)
- HAE (1)
- HDACi (1)
- HIV therapy (1)
- HNPCC (1)
- HSPC (1)
- Heart (1)
- Hebbian plasticity (1)
- Hematologic malignancies (1)
- Hemobilia (1)
- Hepatitis C (1)
- Herbalife products (1)
- Hexavalent vaccine (1)
- Hormonal (1)
- Hospital Governance (1)
- Hydroxyapatite (1)
- ICU (1)
- IMiD® (1)
- ISO (1)
- Identity (1)
- Identität (1)
- Immunology (1)
- In-vivo (1)
- Infektionsabwehr (1)
- Infektionskrankheit (1)
- Inflammatory bowel disease (1)
- Inflammatory fibroid polyp (1)
- Infrarot (1)
- Innate Immunity (1)
- Innate immunity (1)
- Integrin (1)
- Intestinal fistula (1)
- Intestinal metaplasia (1)
- Intestinal neoplasms (1)
- Invasive candidiasis (1)
- Ischemia (1)
- Ischemia-reperfusion injury (1)
- Kava (1)
- Kidney disease (1)
- Kinderwunsch (1)
- Kommunikation (1)
- Kongress (1)
- Krankheit (1)
- Krankheitsbegriff (1)
- Künste (1)
- Landmark (1)
- Langerhans cell histiocytosis (1)
- Lebensbewältigung (1)
- Lebensgefühl (1)
- Liver biopsy (1)
- Liver histology (1)
- Liver injury (1)
- Liver transplantation (1)
- Lumbar stenosis (1)
- Lung (1)
- Lymphangiectasia (1)
- Lymphoepithelioma (1)
- Lymphoma (1)
- MACE (1)
- MCAO (1)
- MCP (1)
- MCP-1 (1)
- MEG (1)
- MLL (1)
- MTCL (1)
- MTT (1)
- Male (1)
- Marginal grafts (1)
- Medizin (1)
- Medizinische Ausbildung (1)
- Mena/VASP (1)
- Metal clip (1)
- Metapher (1)
- Metastatic (1)
- Mid-intestinal bleeding (1)
- Minimally invasive transforaminal interbody fusion (1)
- Missbildung (1)
- Moderating factors (1)
- Multiple trauma (1)
- Mund-Kiefer-Gesichts-Chirurgie (1)
- Mycoses (1)
- NF-κB (1)
- NK Receptor (1)
- NK cell (1)
- NS3-4A protease inhibitor (1)
- NS5B polymerase inhibitor (1)
- NanoBone (1)
- Nanocrystalline (1)
- Natural Killer (NK) Cell (1)
- Neoadjuvant radiochemotherapy (1)
- Neoadjuvant treatment (1)
- Nerven <Begriff> (1)
- Neural function (1)
- Neural stem cells (1)
- Neurasthenie (1)
- Neuroendocrine tumor (1)
- Neurogenesis (1)
- Neurotransmitter (1)
- New Developments (1)
- Nicht-Ereignis (1)
- Non-Hodgkin lymphoma (1)
- Occupational disease (1)
- Occupational exposure (1)
- Occupational health (1)
- Oesophagogastric cancer oxaliplatin (1)
- Off-pump surgery (1)
- Oncolytic virus (1)
- Oncotargets (1)
- Online-Magazin (1)
- Online-Magazine (1)
- Organ allocation (1)
- Organ rinse (1)
- Organ shortage (1)
- Osteoinduction (1)
- Osteoporosis (1)
- Outcome (1)
- Over-the-scope clip (1)
- Oxaliplatin (1)
- PAX3/FOXO1 (1)
- PET (1)
- Pancreas transplantation (1)
- Paracetamol (1)
- Paraneoplastic syndrome (1)
- Pathologic complete response (1)
- Pelargonium sidoides (1)
- Percutaneous ultrasound (1)
- Peroxidase (1)
- Personality disorder (1)
- Peutz–Jeghers syndrome (1)
- Pharmacodynamic (1)
- Philosophie (1)
- Physical therapist (1)
- Planning target volume (1)
- Platelets (1)
- Pneumococcal conjugate vaccine (1)
- Polyposis syndrome (1)
- Postoperative anatomy (1)
- Preoperative radiochemotherapy (1)
- Professionalism (1)
- Prophylaxis (1)
- Protein Expression (1)
- Psychopathology (1)
- Pulmonary failure (1)
- Pulmonary veins (1)
- Qualitative research (1)
- RAD001 (1)
- RIP1 (1)
- RNA interference (RNAi) (1)
- RUNX1/ETO (1)
- Radiation induced diarrhoea (1)
- Radiotherapy (1)
- Rare disease (1)
- Readmission (1)
- Rectal cancer (1)
- Rejection (1)
- Religiöses Coping (1)
- Restenosis (1)
- S1P1 receptor (1)
- SERS (1)
- SOCS (1)
- Sauerstoffpartialdruck im Gewebe (1)
- Sauerstoffversorgung (1)
- Schmerz (1)
- Schmerzminderung (1)
- Sekretion (1)
- Selenium administration in gynecologic radiation oncology (1)
- Self-expandable metal stents (1)
- Self-expandable metal stents complications (1)
- Self-management support (1)
- Signaling (1)
- Small-bowel endoscopy (1)
- Social skills training (1)
- Spectrin (1)
- Sphingolipid (1)
- Sphingosine 1-phosphate (1)
- Spondylolisthesis (1)
- Sportmedizin (1)
- Sportophthalmologie (1)
- Sportärztekongress (1)
- Stentoplasty (1)
- Study protocol (1)
- Subacute cerebellar degeneration (1)
- Subarachnoid Hemorrhage (1)
- Subfertilität (1)
- Supraventricular arrhythmias (1)
- Syk Kinase (1)
- T cell (1)
- T-cell homeostasis (1)
- T-cell niche (1)
- TEM (1)
- TEVAR (1)
- TKI (1)
- TRAIL (1)
- Tacrolimus (1)
- Tamoxifen (1)
- Temozolomide (1)
- Terminal ileitis (1)
- Thalidomide (1)
- Thoracic trauma (1)
- Thyroid Cancer Cells (1)
- Toll-like receptor (TLR) 6 (1)
- Tonsil (1)
- Toxicology (1)
- Toxins (1)
- Traumatic injury (1)
- Treatment (1)
- Tumor (1)
- Tumor obstruction (1)
- Tumor subtype (1)
- Ultrasonography (1)
- Unfallverletzung (1)
- Ungewollte Kinderlosigkeit (1)
- VEGF receptors (1)
- VIP (1)
- VPAC1 (1)
- Variceal bleeding (1)
- Vertebral augmentation (1)
- Vertebral body stenting (1)
- Vertebral fracture (1)
- Virotherapy (1)
- Vitreous samples (1)
- Western Blotting (1)
- Wilms tumor (1)
- Wissenschaft (1)
- Wunde (1)
- Wundheilung (1)
- Wundinfektion (1)
- YB-1 (1)
- Zivilisationskrankheit (1)
- active perception (1)
- acute leukemia (1)
- acute lymphoblastic leukaemia (1)
- acute myeloid leukaemia (1)
- ageing (1)
- aging (1)
- air pouch (1)
- all-ceramic (1)
- allogeneic hematopoietic stem cell transplantation (1)
- alpha peak (1)
- antifungal agents (1)
- antifungal management (1)
- antifungal prophylaxis (1)
- astrocyte (1)
- astrocytes (1)
- atherosclerosis (1)
- attention (1)
- barriers to implementation (1)
- biocompatibility (1)
- bone morphogenetic protein-2 (1)
- bone substitute material (1)
- bortezomib (1)
- brain injury (1)
- cancer (1)
- cardiovascular (1)
- cardiovascular disease (1)
- chemotherapy (1)
- childhood cancer (1)
- chromosomal translocations (1)
- chronic care (1)
- cigarette (1)
- clinical research (1)
- clinical study (1)
- clinical trials (1)
- cochlear implant (1)
- cognition (1)
- consciousness (1)
- corticomuscular coherence (CMC) (1)
- costs (1)
- crestal bone loss (1)
- critical periods (1)
- crowns (1)
- deconvolution (1)
- development (1)
- directly acting antiviral agents (1)
- distraction (1)
- dual task (1)
- endothelial (1)
- entorhinal cortex lesion (1)
- everolimus (1)
- exercise (1)
- expert review (1)
- fMRI (1)
- finger tapping (1)
- functional MRI (1)
- fungal infection (1)
- gastric (1)
- gastrointestinal (1)
- gene therapy (1)
- glutamate metabolism (1)
- granulocyte (1)
- growth factor (1)
- hand area (1)
- head and neck cancer (1)
- hematopoietic stem and progenitor cells (1)
- hemodialysis (1)
- hepatitis C virus (1)
- hereditary angioedema (1)
- hippocampal volume (1)
- homeostatic synaptic scaling (1)
- iPS (1)
- immune function (1)
- immunocytochemistry (1)
- immunology (1)
- implant (1)
- implant survival (1)
- inflammation (1)
- inhibition of DNA-binding (1)
- interferon-free (1)
- interleukin-10 (1)
- interleukin-22 (1)
- invasive fungal infection (1)
- kidney disease (1)
- lenalidomide (1)
- long-term survival (1)
- mTOR (1)
- magnetoencephalography (1)
- magnetoencephalography (MEG) (1)
- marginal bone loss (1)
- mature T-cell lymphoma (1)
- memory (1)
- metaplasticity (1)
- miRNA (1)
- miRNA-17–92 (1)
- microRNA (1)
- mild cognitive impairment (1)
- mitogen-activated protein kinase (1)
- mitomycin C (1)
- mobilization (1)
- monogenic disorders (1)
- motor control (1)
- motor task (1)
- nanoparticles (1)
- natural killer cell (1)
- necroptosis (1)
- neurobiology (1)
- neuroblastoma (1)
- neurodegeneration (1)
- neurological diseases (1)
- neurooncology (1)
- neuropsychiatric disorders (1)
- next-generation sequencing (1)
- non-invasive brain stimulation (1)
- oligodendrocyte (1)
- organotypic slice cultures (1)
- oscillations (1)
- oxidative stress (1)
- pain (1)
- peptide aptamer (PA) (1)
- perceptual organization (1)
- plasticity (1)
- posaconazole (1)
- pregnancy (1)
- pregnant (1)
- preprocedure prophylaxis (1)
- prevention (1)
- primary motor cortex (1)
- primary motor cortex (M1) (1)
- prognostic value (1)
- progranulin (1)
- prostate and breast cancer cell lines (1)
- prostate cancer (1)
- proteasome inhibitor (1)
- protein transduction (1)
- rat femur defect (1)
- receptor tyrosine kinase (1)
- reduction of pain (1)
- reinforcement learning (1)
- resting state (1)
- robotics (1)
- robustness (1)
- scaffolding proteins (1)
- sciatic nerve injury (1)
- self-management support (1)
- senescence (1)
- signal transducer and activator of transcription (1)
- signal transducer and activator of transcription 5 (Stat5) (1)
- signaling (1)
- single-sided deafness (1)
- sleep (1)
- slowing (1)
- smoking (1)
- sonic hedgehog (1)
- sparse coding (1)
- stem cell therapy (1)
- stem/progenitor cell expansion (1)
- stereo vision (1)
- structural plasticity (1)
- surgical procedures (1)
- survival rate (1)
- thalidomide (1)
- therapeutics (1)
- three point bending test (1)
- tissue blood flow (1)
- tissue oxygen partial pressure (1)
- tissue temperature (1)
- tobacco (1)
- tooth wear (1)
- toxicity (1)
- transcranial alternating current stimulation (tACS) (1)
- translocation partner genes (1)
- tricalcium phosphate (1)
- tumour-infiltrating lymphocytes (1)
- type I interferons (1)
- vascular (1)
- vergence (1)
- viral vectors (1)
- vitreous samples (1)
- wIRA (1)
- wassergefiltertes Infrarot A (1)
- water-filtered infrared-A (wIRA) (1)
- yeast-two-hybrid (Y2H) (1)
- Ätiologie (1)
- ß-tricalciumphosphate (1)
Institute
kurz und kn@pp news : Nr. 27
(2013)
In the absence of apparent mutations, alteration of gene expression patterns represents the key mechanism by which normal cells evolve to cancer cells.
Gene expression is tightly regulated by posttranscriptional processes. Within this context, RNA-binding proteins (RBPs) represent fundamental factors, since they control mechanisms, such as mRNA-stabilization, -translation and -degradation. Human antigen R (HuR) was among the first RBPs that have been directly associated to carcinogenesis. HuR modulates the stability and translation of mRNAs which encode proteins facilitating various ‘hallmarks of cancer’, namely proliferation, evasion of growth suppression, angiogenesis, cell death resistance, invasion and metastasis. Furthermore, it is well established that tumor-promoting inflammation contributes to tumorigenesis. In this process, monocytes are attracted to the site of the tumor and educated towards a tumor-promoting macrophage phenotype. While HuR has been extensively studied in various tumor cell types, little is known about HuR in hepatocellular carcinoma (HCC). Thus, the aim of my work was to characterize the contribution of HuR to the development of cancer characteristics in HCC. I was particularly interested to investigate if HuR facilitates tumor-promoting inflammation, since a role for HuR has not been described in this context. To this end, I depleted HuR in HepG2 cells (HuR k/d) and used a co-culture model of HepG2 tumor spheroids and infiltrating monocytes to study the impact of HuR on the tumor microenvironment. I could show that depletion of HuR resulted in the reduction of cell numbers. Additionally, the expression of proliferation marker KI-67 and proto-oncogene c-Myc was reduced, supporting a proliferative role of HuR. Furthermore, exposure to cytotoxic staurosporine elevated apoptosis in HuR k/d cells compared to control cells. Concomitantly, the expression of the anti-apoptotic mediator B-cell lymphoma protein-2 (Bcl-2) was markedly reduced in the HuR k/d cells, pointing to an involvement of HuR in cell survival processes.
Accordingly, a pro-survival function of HuR was also observed in tumor spheroids, since HuR k/d spheroids exhibited a larger necrotic core region at earlier time points and showed elevated numbers of dead cells compared to control (Ctr.) spheroids. Interestingly, HuR k/d spheroids isplayed reduced numbers of infiltrated macrophages, suggesting that HuR contributes to a tumor-promoting, inflammatory microenvironment by recruiting monocytes/macrophages to the tumor site. Aiming at identifying HuR-regulated factors responsible for the recruitment of monocytes, I found reduced levels of the chemokine interleukin 8 (IL-8) in supernatants of HuR k/d spheroids, supporting a critical involvement of HuR in the chemoattraction of monocytes. Analyzing supernatants of co-cultures of macrophages and HuR k/d or Ctr. spheroids revealed additional differences in chemokine secretion patterns. Interestingly, protein levels of many chemokines were elevated in co-cultures of HuR k/d spheroids compared to control co-cultures. Albeit enhanced chemokine secretion was observed, less monocytes are recruited into HuR k/d spheroids, further underlining the necessity of HuR in cancer related monocyte/macrophage attraction and infiltration. Differences between chemokine profiles of mono- and co-cultured spheroids could be attributable to changes in spheroid-derived chemokines as a result of the crosstalk with the immune cells. Provided the chemokines originate from monocytes/macrophages, the different secretion patterns suggest that HuR contributes to the modulation of the functional phenotype of infiltrated macrophages, since the tumorenvironment is critically involved in the shaping of macrophage phenotypes. Regions of low-oxygen (hypoxia) represent another critical feature of tumors. Therefore, I next analyzed the impact of HuR on the hypoxic response. Loss of HuR attenuated hypoxia-inducible factor (HIF) 2α expression after exposure to hypoxia, while HIF-1α protein levels remained unaltered. Considering previous results of our group, showing that HIF-2α depletion (HIF-2α k/d) resulted in the enhanced expression of HIF-1α protein, I aimed to determine the involvement of HuR in the compensatory upregulation of HIF-1α protein in HIF-2α k/d cells. I could demonstrate that not only total HuR protein levels, but specifically cytoplasmic HuR was elevated in HIF-2α depleted cells pointing to enhanced HuR activity. Silencing HuR in HIF-2α deficient cells attenuated enhanced HIF-1α protein expression, thus confirming a direct role of HuR in the compensatory upregulation of HIF-1α. This as also reflected on HIF-1α target gene expression. I further investigated the mechanism underlying the compensatory HIF-1α expression in HIF-2α deficient cells. Analyzing HIF-1α mRNA expression, I excluded enhanced HIF1-α transcription and stability to account for elevated HIF-1α expression in HIF-2α k/d cells. HIF-1α promoter activity assays confirmed the mRNA data. Furthermore, HIF-1α protein half-life was not elevated in HIF-2α k/d cells compared to control cells, indicating that HIF-1α protein stability is not altered in HIF-2α k/d cells. Analysis of the association of HIF-1α with the translational machinery using polysomal fractionation finally revealed an increased istribution of HIF-1α mRNA in the heavier polysomal fractions in HIF-2α k/d cells compared to control cells. Since augmented ribosome occupancy is an indicator for more efficient translation, I propose enhanced HIF-1α translation as underlying principle of the compensatory increase in HIF-1α protein levels in HIF-2α k/d cells. In summary, my results demonstrate that HuR is critical for the development of cancer characteristics in HCC. Future work analyzing the impact of HuR on tumor-promoting inflammation, specifically macrophage attraction and activation could provide new trategies to inhibit macrophage-driven tumor progression. Furthermore, I provide evidence that HuR contributes to the hypoxic response by regulating the expression of HIF-1α and HIF-2α. Targeting single HIF-isoforms for tumor therapy should be carefully considered, because of their compensatory regulation when one α-subunit is depleted. Thus, therapeutic strategies targeting factors such as HuR that control both α-subunits and at the same time prevent compensation might be more promising.
Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future.
Cataract surgery is one of the oldest and the most frequent outpatient clinic operations in medicine performed worldwide. The clouded human crystalline lens is replaced by an artificial intraocular lens implanted into the capsular bag. During the last six decades, cataract surgery has undergone rapid development from a traumatic, manual surgical procedure with implantation of a simple lens to a minimally invasive intervention increasingly assisted by high technology and a broad variety of implants customized for each patient’s individual requirements. This review discusses the major advances in this field and focuses on the main challenge remaining – the treatment of presbyopia. The demand for correction of presbyopia is increasing, reflecting the global growth of the ageing population. Pearls and pitfalls of currently applied methods to correct presbyopia and different approaches under investigation, both in lens implant technology and in surgical technology, are discussed.
Introduction. Cancellous bone is frequently used for filling bone defects in a clinical setting. It provides favourable conditions for regenerative cells such as MSC and early EPC. The combination of MSC and EPC results in superior bone healing in experimental bone healing models. Materials and Methods. We investigated the influence of osteogenic culture conditions on the endothelial properties of early EPC and the osteogenic properties of MSC when cocultured on cancellous bone. Additionally, cell adhesion, metabolic activity, and differentiation were assessed 2, 6, and 10 days after seeding.
Results. The number of adhering EPC and MSC decreased over time; however the cells remained metabolically active over the 10-day measurement period. In spite of a decline of lineage specific markers, cells maintained their differentiation to a reduced level. Osteogenic stimulation of EPC caused a decline but not abolishment of endothelial characteristics and did not induce osteogenic gene expression. Osteogenic stimulation of MSC significantly increased their metabolic activity whereas collagen-1α and alkaline phosphatase gene expressions declined. When cocultured with EPC, MSC’s collagen-1α gene expression increased significantly. Conclusion. EPC and MSC can be cocultured in vitro on cancellous bone under osteogenic conditions, and coculturing EPC with MSC stabilizes the latter’s collagen-1α gene expression.
While necroptosis has for long been viewed as an accidental mode of cell death triggered by physical or chemical damage, it has become clear over the last years that necroptosis can also represent a programmed form of cell death in mammalian cells. Key discoveries in the field of cell death research, including the identification of critical components of the necroptotic machinery, led to a revised concept of cell death signaling programs. Several regulatory check and balances are in place in order to ensure that necroptosis is tightly controlled according to environmental cues and cellular needs. This network of regulatory mechanisms includes metabolic pathways, especially those linked to mitochondrial signaling events. A better understanding of these signal transduction mechanisms will likely contribute to open new avenues to exploit our knowledge on the regulation of necroptosis signaling for therapeutic application in the treatment of human diseases.
CSF and serum biomarkers focusing on cerebral vasospasm and ischemia after subarachnoid hemorrhage
(2013)
Delayed cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) remain severe complications after subarachnoid hemorrhage (SAH). Although focal changes in cerebral metabolism indicating ischemia are detectable by microdialysis, routinely used biomarkers are missing. We therefore sought to evaluate a panel of possible global markers in serum and cerebrospinal fluid (CSF) of patients after SAH.
CSF and serum of SAH patients were analyzed retrospectively. In CSF, levels of inhibitory, excitatory, and structural amino acids were detected by high-performance liquid chromatography (HPLC). In serum, neuron-specific enolase (NSE) and S100B level were measured and examined in conjunction with CVS and DCI. CVS was detected by arteriography, and ischemic lesions were assessed by computed tomography (CT) scans.
All CSF amino acids were altered after SAH. CSF glutamate, glutamine, glycine, and histidine were significantly correlated with arteriographic CVS. CSF glutamate and serum S100B were significantly correlated with ischemic events after SAH; however, NSE did not correlate neither with ischemia nor with vasospasm. Glutamate, glutamine, glycine, and histidine might be used in CSF as markers for CVS. Glutamate also indicates ischemia. Serum S100B, but not NSE, is a suitable marker for ischemia. These results need to be validated in larger prospective cohorts.
Background: This phase I/II-trial assessed the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of neoadjuvant radiochemotherapy (RCT) with docetaxel and oxaliplatin in patients with locally advanced adenocarcinoma of the oesophagogastric junction.
Methods: Patients received neoadjuvant radiotherapy (50.4 Gy) together with weekly docetaxel (20 mg/m2 at dose level (DL) 1 and 2, 25 mg/m2 at DL 3) and oxaliplatin (40 mg/m2 at DL 1, 50 mg/m2 at DL 2 and 3) over 5 weeks. The primary endpoint was the DLT and the MTD of the RCT regimen. Secondary endpoints included overall response rate (ORR) and progression-free survival (PFS).
Results: A total of 24 patients were included. Four patients were treated at DL 1, 13 patients at DL 2 and 7 patients at DL 3. The MTD of the RCT was considered DL 2 with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2. Objective response (CR/PR) was observed in 32% (7/22) of patients. Eighteen patients (75%) underwent surgery after RCT. The median PFS for all patients (n = 24) was 6.5 months. The median overall survival for all patients (n = 24) was 16.3 months. Patients treated at DL 2 had a median overall survival of 29.5 months.
Conclusion: Neoadjuvant RCT with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2 was effective and showed a good toxicity profile. Future studies should consider the addition of targeted therapies to current neoadjuvant therapy regimens to further improve the outcome of patients with advanced cancer of the oesophagogastric junction.
Trial Registration: NCT00374985
Background: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50–80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells.
Methods: Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8+ T cells.
Results: Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8+ T cells (P = 0.02).
Conclusions: Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8+ T cells.
Apoptosis represents one of the most important forms of cell death in higher organisms and is typically dysregulated in human cancers, including pediatric tumors. This implies that ineffective engagement of cell death programs can contribute to tumor formation as well as tumor progression. In addition, the majority of cytotoxic therapeutic principles rely on the activation of cell death signaling pathways in cancer cells. Blockade of signaling networks that lead to cell death can therefore confer treatment resistance. A variety of genetic and epigenetic events as well as dysfunctional regulation of signaling networks have been identified as underlying causes of cell death resistance in childhood malignancies. Apoptosis pathways can be therapeutically exploited by enhancing proapoptotic signals or by neutralizing antiapoptotic programs. The challenge in the coming years will be to successfully transfer this knowledge into the development of innovative treatment approaches for children with cancer.
Biomarkers and bacterial pneumonia risk in patients with treated HIV infection: a case-control study
(2013)
Background: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist.
Methods: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1:1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls.
Results: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm3. Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively).
Conclusions: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.
Introduction: We aimed at dissociating the neural correlates of memory disorders in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD).
Methods: We included patients with AD (n = 19, 11 female, mean age 61 years) and FTLD (n = 11, 5 female, mean age 61 years) in early stages of their diseases. Memory performance was assessed by means of verbal and visual memory subtests from the Wechsler Memory Scale (WMS-R), including forgetting rates. Brain glucose utilization was measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and brain atrophy by voxel-based morphometry (VBM) of T1-weighted magnetic resonance imaging (MRI) scans. Using a whole brain approach, correlations between test performance and imaging data were computed separately in each dementia group, including a group of control subjects (n = 13, 6 female, mean age 54 years) in both analyses. The three groups did not differ with respect to education and gender.
Results: Patients in both dementia groups generally performed worse than controls, but AD and FTLD patients did not differ from each other in any of the test parameters. However, memory performance was associated with different brain regions in the patient groups, with respect to both hypometabolism and atrophy: Whereas in AD patients test performance was mainly correlated with changes in the parieto-mesial cortex, performance in FTLD patients was correlated with changes in frontal cortical as well as subcortical regions. There were practically no overlapping regions associated with memory disorders in AD and FTLD as revealed by a conjunction analysis.
Conclusion: Memory test performance may not distinguish between both dementia syndromes. In clinical practice, this may lead to misdiagnosis of FTLD patients with poor memory performance. Nevertheless, memory problems are associated with almost completely different neural correlates in both dementia syndromes. Obviously, memory functions are carried out by distributed networks which break down in brain degeneration.
Background: The ability of stroke volume variation (SVV), pulse pressure variation (PPV) and global end-diastolic volume (GEDV) for prediction of fluid responsiveness in presence of pleural effusion is unknown. The aim of the present study was to challenge the ability of SVV, PPV and GEDV to predict fluid responsiveness in a porcine model with pleural effusions.
Methods: Pigs were studied at baseline and after fluid loading with 8 ml kg−1 6% hydroxyethyl starch. After withdrawal of 8 ml kg−1 blood and induction of pleural effusion up to 50 ml kg−1 on either side, measurements at baseline and after fluid loading were repeated. Cardiac output, stroke volume, central venous pressure (CVP) and pulmonary occlusion pressure (PAOP) were obtained by pulmonary thermodilution, whereas GEDV was determined by transpulmonary thermodilution. SVV and PPV were monitored continuously by pulse contour analysis.
Results: Pleural effusion was associated with significant changes in lung compliance, peak airway pressure and stroke volume in both responders and non-responders. At baseline, SVV, PPV and GEDV reliably predicted fluid responsiveness (area under the curve 0.85 (p<0.001), 0.88 (p<0.001), 0.77 (p = 0.007). After induction of pleural effusion the ability of SVV, PPV and GEDV to predict fluid responsiveness was well preserved and also PAOP was predictive. Threshold values for SVV and PPV increased in presence of pleural effusion.
Conclusions: In this porcine model, bilateral pleural effusion did not affect the ability of SVV, PPV and GEDV to predict fluid responsiveness.
Despite the availability of new antifungal compounds, invasive fungal infection remains a significant cause of morbidity and mortality in children and adults undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT recipients suffer from a long lasting defect of different arms of the immune system, which increases the risk for and deteriorates the prognosis of invasive fungal infections. In turn, advances in understanding these immune deficits have resulted in promising strategies to enhance or restore critical immune functions in allogeneic HSCT recipients. Potential approaches include the administration of granulocytes, since neutropenia is the single most important risk factor for invasive fungal infection, and preliminary clinical results suggest a benefit of adoptively transferred donor-derived antifungal T cells. In vitro data and animal studies demonstrate an antifungal effect of natural killer cells, but clinical data are lacking to date. This review summarizes and critically discusses the available data of immunotherapeutic strategies in allogeneic HSCT recipients suffering from invasive fungal infection.
Interleukin (IL)-10 and IL-22 are key members of the IL-10 cytokine family that share characteristic properties such as defined structural features, usage of IL-10R2 as one receptor chain, and activation of signal transducer and activator of transcription (STAT)-3 as dominant signaling mode. IL-10, formerly known as cytokine synthesis inhibitory factor, is key to deactivation of monocytes/macrophages and dendritic cells. Accordingly, pre-clinical studies document its anti-inflammatory capacity. However, the outcome of clinical trials assessing the therapeutic potential of IL-10 in prototypic inflammatory disorders has been disappointing. In contrast to IL-10, IL-22 acts primarily on non-leukocytic cells, in particular epithelial cells of intestine, skin, liver, and lung. STAT3-driven proliferation, anti-apoptosis, and anti-microbial tissue protection is regarded a principal function of IL-22 at host/environment interfaces. In this hypothesis article, hidden/underappreciated pro-inflammatory characteristics of IL-10 and IL-22 are outlined and related to cellular priming by type I interferon. It is tempting to speculate that an inherent inflammatory potential of IL-10 and IL-22 confines their usage in tissue protective therapy and beyond that determines in some patients efficacy of type I interferon treatment.
Background: Candida spp. are a frequent cause of nosocomial bloodstream infections worldwide.
Objective: To evaluate the use patterns and outcomes associated with intravenous (IV) fluconazole therapy in intensive care units in Spain and Germany.
Patients and methods: The research reported here was a prospective multicenter longitudinal observational study in adult intensive care unit patients receiving IV fluconazole. Demographic, microbiologic, therapy success, length of hospital stay, adverse event, and all-cause mortality data were collected at 14 sites in Spain and five in Germany, from February 2004 to November 2005.
Results: Patients (n = 303) received prophylaxis (n = 29), empiric therapy (n = 140), preemptive therapy (n = 85), or definitive therapy (n = 49). A total of 298 patients (98.4%) were treated with IV fluconazole as first-line therapy. The treating physicians judged therapy successful in 66% of prophylactic, 55% of empiric, 45% of preemptive, and 43% of definitive group patients. In the subgroup of 152 patients with proven and specified Candida infection only, 32% suffered from Candida specified as potentially resistant to IV fluconazole. The overall mortality rate was 42%.
Conclusion: Our study informs treatment decision makers that approximately 32% of the patients with microbiological results available suffered from Candida specified as potentially resistant to IV fluconazole, highlighting the importance of appropriate therapy.
In the current event-related potential (ERP) study, we investigated how speech rhythm impacts speech segmentation and facilitates the resolution of syntactic ambiguities in auditory sentence processing. Participants listened to syntactically ambiguous German subject- and object-first sentences that were spoken with either regular or irregular speech rhythm. Rhythmicity was established by a constant metric pattern of three unstressed syllables between two stressed ones that created rhythmic groups of constant size. Accuracy rates in a comprehension task revealed that participants understood rhythmically regular sentences better than rhythmically irregular ones. Furthermore, the mean amplitude of the P600 component was reduced in response to object-first sentences only when embedded in rhythmically regular but not rhythmically irregular context. This P600 reduction indicates facilitated processing of sentence structure possibly due to a decrease in processing costs for the less-preferred structure (object-first). Our data suggest an early and continuous use of rhythm by the syntactic parser and support language processing models assuming an interactive and incremental use of linguistic information during language processing.
Tissue plasminogen activator (tPA) is the only FDA-approved treatment for reperfusing ischemic strokes. But widespread use of tPA is still limited by fears of inadvertently administering tPA in patients with intracerebral hemorrhage (ICH). Surprisingly, however, the assumption that tPA will worsen ICH has never been biologically tested. Here, we assessed the effects of tPA in two models of ICH. In a mouse model of collagenase-induced ICH, hemorrhage volumes and neurological deficits after 24 hrs were similar in saline controls and tPA-treated mice, whereas heparin-treated mice had 3-fold larger hematomas. In a model of laser-induced vessel rupture, tPA also did not worsen hemorrhage volumes, while heparin did. tPA is known to worsen neurovascular injury by amplifying matrix metalloproteinases during cerebral ischemia. In contrast, tPA did not upregulate matrix metalloproteinases in our mouse ICH models. In summary, our experimental data do not support the assumption that intravenous tPA has a deleterious effect in acute ICH. However, due to potential species differences and the inability of models to fully capture the dynamics of human ICH, caution is warranted when considering the implications of these findings for human therapy.
Although motor tasks at most times do not require much attention, there are findings that attention can alter neuronal activity not only in higher motor areas but also within the primary sensorimotor cortex. However, these findings are equivocal as attention effects were investigated only in either the dominant or the nondominant hand; attention was operationalized either as concentration (i.e., attention directed to motor task) or as distraction (i.e., attention directed away from motor task), the complexity of motor tasks varied and almost no left-handers were studied. Therefore, in this study, both right- and left-handers were investigated with an externally paced button press task in which subjects typed with the index finger of the dominant, nondominant, or both hands. We introduced four different attention levels: attention-modulation-free, distraction (counting backward), concentration on the moving finger, and divided concentration during bimanual movement. We found that distraction reduced neuronal activity in both contra- and ipsilateral primary sensorimotor cortex when the nondominant hand was tapping in both handedness groups. At the same time, distraction activated the dorsal frontoparietal attention network and deactivated the ventral default network. We conclude that difficulty and training status of both the motor and cognitive task, as well as usage of the dominant versus the nondominant hand, are crucial for the presence and magnitude of attention effects on sensorimotor cortex activity. In the case of a very simple button press task, attention modulation is seen for the nondominant hand under distraction and in both handedness groups.
Aging is a complex process that is linked to an increased incidence of major diseases such as cardiovascular and neurodegenerative disease, but also cancer and immune disorders. MicroRNAs (miRNAs) are small non-coding RNAs, which post-transcriptionally control gene expression by inhibiting translation or inducing degradation of targeted mRNAs. MiRNAs target up to hundreds of mRNAs, thereby modulating gene expression patterns. Many miRNAs appear to be dysregulated during cellular senescence, aging and disease. However, only few miRNAs have been so far linked to age-related changes in cellular and organ functions. The present article will discuss these findings, specifically focusing on the cardiovascular and neurological systems.
Background and Aims: The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated.
Methods: A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52.
Results: 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52.
Conclusions: Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B.
Trial Registration: ClinicalTrials.gov NCT00651209
Background: Osteoinductive bone substitutes are defined by their ability to induce new bone formation even at heterotopic implantation sites. The present study was designed to analyze the potential osteoinductivity of two different bone substitute materials in caprine muscle tissue.
Materials and methods: One gram each of either a porous beta-tricalcium phosphate (β-TCP) or an hydroxyapatite/silicon dioxide (HA/SiO2)-based nanocrystalline bone substitute material was implanted in several muscle pouches of goats. The biomaterials were explanted at 29, 91 and 181 days after implantation. Conventional histology and special histochemical stains were performed to detect osteoblast precursor cells as well as mineralized and unmineralized bone matrix.
Results: Both materials underwent cellular degradation in which tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells and TRAP-negative multinucleated giant cells were involved. The ß-TCP was completely resorbed within the observation period, whereas some granules of the HA-groups were still detectable after 180 days. Neither osteoblasts, osteoblast precursor cells nor extracellular bone matrix were found within the implantation bed of any of the analyzed biomaterials at any of the observed time points.
Conclusions: This study showed that ß-TCP underwent a faster degradation than the HA-based material. The lack of osteoinductivity for both materials might be due to their granular shape, as osteoinductivity in goat muscle has been mainly attributed to cylindrical or disc-shaped bone substitute materials. This hypothesis however requires further investigation to systematically analyze various materials with comparable characteristics in the same experimental setting.
Background: Regulatory T cells (Treg) expressing the transcription factor forkhead-box protein P3 (Foxp3) have been identified to counteract anti-tumor immune responses during tumor progression. Besides, Foxp3 presentation by cancer cells itself may also allow them to evade from effector T-cell responses, resulting in a survival benefit of the tumor. For colorectal cancer (CRC) the clinical relevance of Foxp3 has not been evaluated in detail. Therefore the aim of this study was to study its impact in colorectal cancer (CRC).
Methods and Findings: Gene and protein analysis of tumor tissues from patients with CRC was performed to quantify the expression of Foxp3 in tumor infiltrating Treg and colon cancer cells. The results were correlated with clinicopathological parameters and patients overall survival. Serial morphological analysis demonstrated Foxp3 to be expressed in cancer cells. High Foxp3 expression of the cancer cells was associated with poor prognosis compared to patients with low Foxp3 expression. In contrast, low and high Foxp3 level in tumor infiltrating Treg cells demonstrated no significant differences in overall patient survival.
Conclusions: Our findings strongly suggest that Foxp3 expression mediated by cancer cells rather than by Treg cells contribute to disease progression.
Background: Group-based social skills training (SST) has repeatedly been recommended as treatment of choice in high-functioning autism spectrum disorder (HFASD). To date, no sufficiently powered randomised controlled trial has been performed to establish efficacy and safety of SST in children and adolescents with HFASD. In this randomised, multi-centre, controlled trial with 220 children and adolescents with HFASD it is hypothesized, that add-on group-based SST using the 12 weeks manualised SOSTA–FRA program will result in improved social responsiveness (measured by the parent rated social responsiveness scale, SRS) compared to treatment as usual (TAU). It is further expected, that parent and self reported anxiety and depressive symptoms will decline and pro-social behaviour will increase in the treatment group. A neurophysiological study in the Frankfurt HFASD subgroup will be performed pre- and post treatment to assess changes in neural function induced by SST versus TAU.
Methods/design: The SOSTA – net trial is designed as a prospective, randomised, multi-centre, controlled trial with two parallel groups. The primary outcome is change in SRS score directly after the intervention and at 3 months follow-up. Several secondary outcome measures are also obtained. The target sample consists of 220 individuals with ASD, included at the six study centres.
Discussion: This study is currently one of the largest trials on SST in children and adolescents with HFASD worldwide. Compared to recent randomised controlled studies, our study shows several advantages with regard to in- and exclusion criteria, study methods, and the therapeutic approach chosen, which can be easily implemented in non-university-based clinical settings.
Trial registration: ISRCTN94863788 – SOSTA – net: Group-based social skills training in children and adolescents with high functioning autism spectrum disorder.
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup.
Targeted drugs have significantly improved the therapeutic options for advanced renal cell carcinoma (RCC). However, resistance often develops, negating the benefit of these agents. In the present study, the molecular mechanisms of acquired resistance towards the histone deacetylase (HDAC) inhibitor valproic acid (VPA) in a RCC in vivo model were investigated. NMRI:nu/nu mice were transplanted with Caki-1 RCC cells and then treated with VPA (200 mg/kg/day). Controls remained untreated. Based on tumor growth dynamics, the mice were divided into “responders” and “non-responders” to VPA. Histone H3 and H4 acetylation and expression of cell signaling and cell cycle regulating proteins in the RCC mouse tumors were evaluated by Western blotting. Tumor growth of VPA responders was significantly diminished, whereas that of VPA non-responders even exceeded control values. Cdk1, 2 and 4 proteins were strongly enhanced in the non-responders. Importantly, Akt expression and activity were massively up-regulated in the tumors of the VPA non-responders. Chronic application (12 weeks) of VPA to Caki-1 cells in vitro evoked a distinct elevation of Akt activity and cancer cells no longer responded with cell growth reduction, compared to the short 2 week treatment. We assume that chronic use of an HDAC-inhibitor is associated with (re)-activation of Akt, which may be involved in resistance development. Consequently, combined blockade of both HDAC and Akt may delay or prevent drug resistance in RCC.
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
The information processing abilities of neural circuits arise from their synaptic connection patterns. Understanding the laws governing these connectivity patterns is essential for understanding brain function. The overall distribution of synaptic strengths of local excitatory connections in cortex and hippocampus is long-tailed, exhibiting a small number of synaptic connections of very large efficacy. At the same time, new synaptic connections are constantly being created and individual synaptic connection strengths show substantial fluctuations across time. It remains unclear through what mechanisms these properties of neural circuits arise and how they contribute to learning and memory. In this study we show that fundamental characteristics of excitatory synaptic connections in cortex and hippocampus can be explained as a consequence of self-organization in a recurrent network combining spike-timing-dependent plasticity (STDP), structural plasticity and different forms of homeostatic plasticity. In the network, associative synaptic plasticity in the form of STDP induces a rich-get-richer dynamics among synapses, while homeostatic mechanisms induce competition. Under distinctly different initial conditions, the ensuing self-organization produces long-tailed synaptic strength distributions matching experimental findings. We show that this self-organization can take place with a purely additive STDP mechanism and that multiplicative weight dynamics emerge as a consequence of network interactions. The observed patterns of fluctuation of synaptic strengths, including elimination and generation of synaptic connections and long-term persistence of strong connections, are consistent with the dynamics of dendritic spines found in rat hippocampus. Beyond this, the model predicts an approximately power-law scaling of the lifetimes of newly established synaptic connection strengths during development. Our results suggest that the combined action of multiple forms of neuronal plasticity plays an essential role in the formation and maintenance of cortical circuits.
Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato complex differ in their resistance to complement-mediated killing, particularly in regard to human serum. In the present study, we elucidate the serum and complement susceptibility of B. valaisiana, a genospecies with the potential to cause Lyme disease in Europe as well as in Asia. Among the investigated isolates, growth of ZWU3 Ny3 was not affected while growth of VS116 and Bv9 was strongly inhibited in the presence of 50% human serum. Analyzing complement activation, complement components C3, C4 and C6 were deposited on the surface of isolates VS116 and Bv9, and similarly the membrane attack complex was formed on their surface. In contrast, no surface-deposited components and no aberrations in cell morphology were detected for serum-resistant ZWU3 Ny3. While further investigating the protective role of bound complement regulators in mediating complement resistance, we discovered that none of the B. valaisiana isolates analyzed bound complement regulators Factor H, Factor H-like protein 1, C4b binding protein or C1 esterase inhibitor. In addition, B. valaisiana also lacked intrinsic proteolytic activity to degrade complement components C3, C3b, C4, C4b, and C5. Taken together, these findings suggest that certain B. valaisiana isolates differ in their capability to resist complement-mediating killing by human serum. The molecular mechanism utilized by B. valaisiana to inhibit bacteriolysis appears not to involve binding of the key host complement regulators of the alternative, classical, and lectin pathways as already known for serum-resistant Lyme disease or relapsing fever borreliae.