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Sonstige beteiligte Institutionen
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
- Bavarian Center for Applied Energy Research (ZAE Bayern), 97074 Würzburg, Germany (1)
- Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut fuer biophysikalische Chemie (1)
- Blindeninstitut, Ohmstr. 7, 97076, Wuerzburg, Germany (1)
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany (1)
- DNA Analytics Core Facility, Biocenter, University of Wuerzburg, Wuerzburg, Germany (1)
- Deakin University, Australia (1)
- Department of Pediatrics, Pediatrics I, Innsbruck Medical University, Anichstr. 35, 6020, Innsbruck, Austria (1)
- EMBL, Structural and Computational Biology Unit, Heidelberg, Germany (1)
- Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, Suite 310, San Diego, California 92109, USA (1)
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- D-1250-2010 (1)
Background
The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact.
Methodology and Principal Findings
We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples.
Conclusion
Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.
Background
The standard clinical protocol of image-guided IMRT for prostate carcinoma introduces isocenter relocation to restore the conformity of the multi-leaf collimator (MLC) segments to the target as seen in the cone-beam CT on the day of treatment. The large interfractional deformations of the clinical target volume (CTV) still require introduction of safety margins which leads to undesirably high rectum toxicity. Here we present further results from the 2-Step IMRT method which generates adaptable prostate IMRT plans using Beam Eye View (BEV) and 3D information.
Methods
Intermediate/high-risk prostate carcinoma cases are treated using Simultaneous Integrated Boost at the Universitätsklinkum Würzburg (UKW). Based on the planning CT a CTV is defined as the prostate and the base of seminal vesicles. The CTV is expanded by 10 mm resulting in the PTV; the posterior margin is limited to 7 mm. The Boost is obtained by expanding the CTV by 5 mm, overlap with rectum is not allowed. Prescription doses to PTV and Boost are 60.1 and 74 Gy respectively given in 33 fractions.
We analyse the geometry of the structures of interest (SOIs): PTV, Boost, and rectum, and generate 2-Step IMRT plans to deliver three fluence steps: conformal to the target SOIs (S0), sparing the rectum (S1), and narrow segments compensating the underdosage in the target SOIs due to the rectum sparing (S2). The width of S2 segments is calculated for every MLC leaf pair based on the target and rectum geometry in the corresponding CT layer to have best target coverage. The resulting segments are then fed into the DMPO optimizer of the Pinnacle treatment planning system for weight optimization and fine-tuning of the form, prior to final dose calculation using the collapsed cone algorithm.
We adapt 2-Step IMRT plans to changed geometry whilst simultaneously preserving the number of initially planned Monitor Units (MU). The adaptation adds three further steps to the previous isocenter relocation: 1) 2-Step generation for the geometry of the day using the relocated isocenter, MU transfer from the planning geometry; 2) Adaptation of the widths of S2 segments to the geometry of the day; 3) Imitation of DMPO fine-tuning for the geometry of the day.
Results and conclusion
We have performed automated 2-Step IMRT adaptation for ten prostate adaptation cases. The adapted plans show statistically significant improvement of the target coverage and of the rectum sparing compared to those plans in which only the isocenter is relocated. The 2-Step IMRT method may become a core of the automated adaptive radiation therapy system at our department.
Background
Referring to individuals with reactivity to honey bee and Vespula venom in diagnostic tests, the umbrella terms “double sensitization” or “double positivity” cover patients with true clinical double allergy and those allergic to a single venom with asymptomatic sensitization to the other. There is no international consensus on whether immunotherapy regimens should generally include both venoms in double sensitized patients.
Objective
We investigated the long-term outcome of single venom-based immunotherapy with regard to potential risk factors for treatment failure and specifically compared the risk of relapse in mono sensitized and double sensitized patients.
Methods
Re-sting data were obtained from 635 patients who had completed at least 3 years of immunotherapy between 1988 and 2008. The adequate venom for immunotherapy was selected using an algorithm based on clinical details and the results of diagnostic tests.
Results
Of 635 patients, 351 (55.3%) were double sensitized to both venoms. The overall re-exposure rate to Hymenoptera stings during and after immunotherapy was 62.4%; the relapse rate was 7.1% (6.0% in mono sensitized, 7.8% in double sensitized patients). Recurring anaphylaxis was statistically less severe than the index sting reaction (P = 0.004). Double sensitization was not significantly related to relapsing anaphylaxis (P = 0.56), but there was a tendency towards an increased risk of relapse in a subgroup of patients with equal reactivity to both venoms in diagnostic tests (P = 0.15).
Conclusions
Single venom-based immunotherapy over 3 to 5 years effectively and long-lastingly protects the vast majority of both mono sensitized and double sensitized Hymenoptera venom allergic patients. Double venom immunotherapy is indicated in clinically double allergic patients reporting systemic reactions to stings of both Hymenoptera and in those with equal reactivity to both venoms in diagnostic tests who have not reliably identified the culprit stinging insect.
Background
Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention.
Methods
Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles.
Results
We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD.
Conclusions
Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.
Human herpesvirus-6 (HHV-6) exists in latent form either as a nuclear episome or integrated into human chromosomes in more than 90% of healthy individuals without causing clinical symptoms. Immunosuppression and stress conditions can reactivate HHV-6 replication, associated with clinical complications and even death. We have previously shown that co-infection of Chlamydia trachomatis and HHV-6 promotes chlamydial persistence and increases viral uptake in an in vitro cell culture model. Here we investigated C. trachomatis-induced HHV-6 activation in cell lines and fresh blood samples from patients having Chromosomally integrated HHV-6 (CiHHV-6). We observed activation of latent HHV-6 DNA replication in CiHHV-6 cell lines and fresh blood cells without formation of viral particles. Interestingly, we detected HHV-6 DNA in blood as well as cervical swabs from C. trachomatis-infected women. Low virus titers correlated with high C. trachomatis load and vice versa, demonstrating a potentially significant interaction of these pathogens in blood cells and in the cervix of infected patients. Our data suggest a thus far underestimated interference of HHV-6 and C. trachomatis with a likely impact on the disease outcome as consequence of co-infection.
This article reviews experimental and clinical data on the use of magnesium as a neuroprotective agent in various conditions of cerebral ischemia. Whereas magnesium has shown neuroprotective properties in animal models of global and focal cerebral ischemia, this effect could not be reproduced in a large human stroke trial. These conflicting results may be explained by the timing of treatment. While treatment can be started before or early after ischemia in experimental studies, there is an inevitable delay of treatment in human stroke. Magnesium administration to women at risk for preterm birth has been investigated in several randomized controlled trials and was found to reduce the risk of neurological deficits for the premature infant. Postnatal administration of magnesium to babies after perinatal asphyxia has been studied in a number of controlled clinical trials. The results are promising but the trials have, so far, been underpowered. In aneurysmal subarachnoid hemorrhage (SAH), cerebral ischemia arises with the onset of delayed cerebral vasospasm several days after aneurysm rupture. Similar to perinatal asphyxia in impending preterm delivery, treatment can be started prior to ischemia. The results of clinical trials are conflicting. Several clinical trials did not show an additive effect of magnesium with nimodipine, another calcium antagonist which is routinely administered to SAH patients in many centers. Other trials found a protective effect after magnesium therapy. Thus, it may still be a promising substance in the treatment of secondary cerebral ischemia after aneurysmal SAH. Future prospects of magnesium therapy are discussed.
The phyllosphere of plants is inhabited by diverse microorganisms, however, the factors shaping their community composition are not fully elucidated. The plant cuticle represents the initial contact surface between microorganisms and the plant. We thus aimed to investigate whether mutations in the cuticular wax biosynthesis would affect the diversity of the phyllosphere microbiota. A set of four Arabidopsis thaliana eceriferum mutants (cer1, cer6, cer9, cer16) and their respective wild type (Landsberg erecta) were subjected to an outdoor growth period and analysed towards this purpose. The chemical distinctness of the mutant wax phenotypes was confirmed by gas chromatographic measurements. Next generation amplicon pyrosequencing of the bacterial communities showed distinct community patterns. This observation was supported by denaturing gradient gel electrophoresis experiments. Microbial community analyses revealed bacterial phylotypes that were ubiquitously present on all plant lines (termed “core” community) while others were positively or negatively affected by the wax mutant phenotype (termed “plant line-specific“ community). We conclude from this study that plant cuticular wax composition can affect the community composition of phyllosphere bacteria.
Introduction
There is mounting evidence for the influence of emotional content on working memory performance. This is particularly important in light of the emotion processing that needs to take place when emotional content interferes with executive functions. In this study, we used emotional words of different valence but with similar arousal levels in an n-back task.
Methods
We examined the effects on activation in the prefrontal cortex by means of functional near-infrared spectroscopy (fNIRS) and on the late positive potential (LPP). FNIRS and LPP data were examined in 30 healthy subjects.
Results
Behavioral results show an influence of valence on the error rate depending on the difficulty of the task: more errors were made when the valence was negative and the task difficult. Brain activation was dependent both on the difficulty of the task and on the valence: negative valence of a word diminished the increase in activation, whereas positive valence did not influence the increase in activation, while difficulty levels increased. The LPP also differentiated between the different valences, and in addition was influenced by the task difficulty, the more difficult the task, the less differentiation could be observed.
Conclusions
Summarized, this study shows the influence of valence on a verbal working memory task. When a word contained a negative valence, the emotional content seemed to take precedence in contrast to words containing a positive valence. Working memory and emotion processing sites seemed to overlap and compete for resources even when words are carriers of the emotional content.
Many pathogenic bacteria cause local infections but occasionally invade into the blood stream, often with fatal outcome. Very little is known about the mechanism underlying the switch from local to invasive infection. In the case of Neisseria gonorrhoeae, phase variable type 4 pili (T4P) stabilize local infection by mediating microcolony formation and inducing anti-invasive signals. Outer membrane porin PorBIA, in contrast, is associated with disseminated infection and facilitates the efficient invasion of gonococci into host cells. Here we demonstrate that loss of pili by natural pilus phase variation is a prerequisite for the transition from local to invasive infection. Unexpectedly, both T4P-mediated inhibition of invasion and PorBIA-triggered invasion utilize membrane rafts and signaling pathways that depend on caveolin-1-Y14 phosphorylation (Cav1-pY14). We identified p85 regulatory subunit of PI3 kinase (PI3K) and phospholipase Cγ1 as new, exclusive and essential interaction partners for Cav1-pY14 in the course of PorBIA-induced invasion. Active PI3K induces the uptake of gonococci via a new invasion pathway involving protein kinase D1. Our data describe a novel route of bacterial entry into epithelial cells and offer the first mechanistic insight into the switch from local to invasive gonococcal infection.
The interplay of specific leukocyte subpopulations, resident cells and proalgesic mediators results in pain in inflammation. Proalgesic mediators like reactive oxygen species (ROS) and downstream products elicit pain by stimulation of transient receptor potential (TRP) channels. The contribution of leukocyte subpopulations however is less clear. Local injection of neutrophilic chemokines elicits neutrophil recruitment but no hyperalgesia in rats. In meta-analyses the monocytic chemoattractant, CCL2 (monocyte chemoattractant protein-1; MCP-1), was identified as an important factor in the pathophysiology of human and animal pain. In this study, intraplantar injection of CCL2 elicited thermal and mechanical pain in Wistar but not in Dark Agouti (DA) rats, which lack p47phox, a part of the NADPH oxidase complex. Inflammatory hyperalgesia after complete Freund's adjuvant (CFA) as well as capsaicin-induced hyperalgesia and capsaicin-induced current flow in dorsal root ganglion neurons in DA were comparable to Wistar rats. Macrophages from DA expressed lower levels of CCR2 and thereby migrated less towards CCL2 and formed limited amounts of ROS in vitro and 4-hydroxynonenal (4-HNE) in the tissue in response to CCL2 compared to Wistar rats. Local adoptive transfer of peritoneal macrophages from Wistar but not from DA rats reconstituted CCL2-triggered hyperalgesia in leukocyte-depleted DA and Wistar rats. A pharmacological stimulator of ROS production (phytol) restored CCL2-induced hyperalgesia in vivo in DA rats. In Wistar rats, CCL2-induced hyperalgesia was completely blocked by superoxide dismutase (SOD), catalase or tempol. Likewise, inhibition of NADPH oxidase by apocynin reduced CCL2-elicited hyperalgesia but not CFA-induced inflammatory hyperalgesia. In summary, we provide a link between CCL2, CCR2 expression on macrophages, NADPH oxidase, ROS and the development CCL2-triggered hyperalgesia, which is different from CFA-induced hyperalgesia. The study further supports the impact of CCL2 and ROS as potential targets in pain therapy.