Der Stellenwert der transartiellen Chemoembolisation beim hepatozellulärem Karzinom vor einer Lebertransplantation: eine retrospektive Studie des patientengutes der Universitätsklinik Jena in den Jahren 1996 - 2008

Nach heutigem Kenntnisstand bietet eine Lebertransplantation für Patienten mit einem HCC auf dem Boden einer Zirrhose die beste Chance auf ein Langzeitüberleben (Baccarani et al. 2007) (Vennarecci et al. 2007). Bei unseren Patienten ist in Übereinstimmung mit der Literatur das Langzeitüberleben besser, wenn sich das hepatozelluläre Karzinom innerhalb der Milan Kriterien befindet, d.h. ein singulärer Tumor ist ≤ 5 cm im Durchmesser bzw. es liegen maximal 3 Tumore mit einem jeweiligen Durchmesser von ≤ 3 cm vor. Die transarterielle Chemoembolisation (TACE) ist neben der palliativen Therapieoption ein Verfahren im Rahmen des „bridging“-Konzeptes vor einer Lebertransplantation, um eine weitere Tumorprogression zu vermeiden oder im Idealfall eine Tumorregression herbeizuführen. Damit soll verhindert werden, dass Patienten durch einen Tumorprogress außerhalb der Milan-Kriterien geraten und von der Warteliste genommen werden müssen oder dass Patienten durch ein „down sizing“ von primär Milan out zu Milan in durch exceptional MELD eine deutlich kürzere Wartezeit und somit bessere Überlebenschancen erhalten

Repression of anti-proliferative factor Tob1 in osteoarthritic cartilage

Osteoarthritis is the most common degenerative disorder of the modern world. However, many basic cellular features and molecular processes of the disease are poorly understood. In the present study we used oligonucleotide-based microarray analysis of genes of known or assumed relevance to the cellular phenotype to screen for relevant differences in gene expression between normal and osteoarthritic chondrocytes. Custom made oligonucleotide DNA arrays were used to screen for differentially expressed genes in normal (n = 9) and osteoarthritic (n = 10) cartilage samples. Real-time polymerase chain reaction (PCR) with gene-specific primers was used for quantification. Primary human adult articular chondrocytes and chondrosarcoma cell line HCS-2/8 were used to study changes in gene expression levels after stimulation with interleukin-1β and bone morphogenetic protein, as well as the dependence on cell differentiation. In situ hybridization with a gene-specific probe was applied to detect mRNA expression levels in fetal growth plate cartilage. Overall, more than 200 significantly regulated genes were detected between normal and osteoarthritic cartilage (P < 0.01). One of the significantly repressed genes, Tob1, encodes a protein belonging to a family involved in silencing cells in terms of proliferation and functional activity. The repression of Tob1 was confirmed by quantitative PCR and correlated to markers of chondrocyte activity and proliferation in vivo. Tob1 expression was also detected at a decreased level in isolated chondrocytes and in the chondrosarcoma cell line HCS-2/8. Again, in these cells it was negatively correlated with proliferative activity and positively with cellular differentiation. Altogether, the downregulation of the expression of Tob1 in osteoarthritic chondrocytes might be an important aspect of the cellular processes taking place during osteoarthritic cartilage degeneration. Activation, the reinitiation of proliferative activity and the loss of a stable phenotype are three major changes in osteoarthritic chondrocytes that are highly significantly correlated with the repression of Tob1 expression

Both systemic and local application of Granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy

<p>Abstract</p> <p>Background</p> <p>The hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which was recently found to be expressed also in the central nervous system. In addition, G-CSF provided neuroprotection in models of neuronal cell death. Here we used the retinal ganglion cell (RGC) axotomy model to compare effects of local and systemic application of neuroprotective molecules.</p> <p>Results</p> <p>We found that the <it>G-CSF receptor </it>is robustly expressed by RGCs <it>in vivo </it>and <it>in vitro</it>. We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously. As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application. Both routes of application reduced retinal ganglion cell death to a comparable extent. Moreover, G-CSF enhanced the survival of immunopurified RGCs <it>in vitro</it>.</p> <p>Conclusion</p> <p>We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma.</p

Trophic Dynamics of Mercury in the Baltic Archipelago Sea Food Web: The Impact of Ecological and Ecophysiological Traits

We investigated trophic dynamics of Hg in the polluted Baltic Archipelago Sea using established trophic magnification (TMFs) and biomagnification factors (BMFs) on a comprehensive set of bird, fish, and invertebrate species. As different ecological and ecophysiological species traits may affect trophic dynamics, we explored the effect of food chain (benthic, pelagic, benthopelagic) and thermoregulatory strategy on trophic total Hg (THg) dynamics, using different approaches to accommodate benthopelagic species and normalize for trophic position (TP). We observed TMFs and most BMFs greater than 1, indicating overall THg biomagnification. We found significantly higher pelagic TMFs (3.58-4.02) compared to benthic ones (2.11-2.34) when the homeotherm bird species were excluded from models, but not when included. This difference between the benthic and pelagic TMFs remained regardless of how the TP of benthopelagic species was modeled, or whether TMFs were normalized for TP or not. TP-corrected BMFs showed a larger range (0.44-508) compared to BMFs representing predator-prey concentration ratios (0.05-82.2). Overall, the present study shows the importance of including and evaluating the effect of ecological and ecophysiological traits when investigating trophic contaminant dynamics

PID Network Deutschland: Netzwerk für die Förderung von persistenten Identifikatoren in Wissenschaft und Kultur

[No abstract available

Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.

IMPORTANCE Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. OBJECTIVE To identify a new gene for nsBAV. DESIGN, SETTING, AND PARTICIPANTS This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. MAIN OUTCOMES AND MEASURES To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. RESULTS A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. CONCLUSIONS AND RELEVANCE This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.This study was supported in part by grants PID2019-104776RB-I00 and CB16/ 11/00399 (Dr de la Pompa) from the Spanish Ministerio de Ciencia e Innovación (MCIN/ AEI/ 10.13039/501100011033/); a grant from Hadassah France Association (Drs Gilon and Tessler); a grant from the Center for Interdisciplinary Data Science Research of the Hebrew University of Jerusalem (Dr Tessler); grant R35 CA220340 from the National Institutes of Health (Dr Blacklow), and grants R21HL150373, R01HL114823 (Dr Body); BSF grants 2013269 and 2017245 (Drs. Sprinzak and Blacklow); a consolidator grant from the European Research Council (Genomia – ERC-COG-2017-771945; Dr Loeys); the European Reference Network on rare multisystemic vascular disorders (VASCERN - project ID: 769036 partly cofunded by the European Union Third Health Programme (Drs Loeys and Verstraeten); funding from the Outreach project (Dutch Heart Foundation; Dr Luyckx); funding from Heart and Stroke Foundation of Canada/Robert M Freedom Chair of Cardiovascular Science (Dr Mital); sample biobanking and sequencing from Canada were supported by grants from the Leducq Foundation Transatlantic Networks of Excellence grant, and the Ted Rogers Centre for Heart Research; ISF grant 1053/12 (Dr Durst); and grant R01HL150401 from National Heart, Lung, and Blood Institute (Dr Muehlschlegel).S

AMP kinase–mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis

Disturbances in cellular ion gradients by excitotoxicity promote apoptosis through activation of the Bcl-2 family member Bim

Symptom Burden and Palliative Care Needs of Patients with Incurable Cancer at Diagnosis and During the Disease Course

Background Although current guidelines advocate early integration of palliative care, symptom burden and palliative care needs of patients at diagnosis of incurable cancer and along the disease trajectory are understudied. Material and Methods We assessed distress, symptom burden, quality of life, and supportive care needs in patients with newly diagnosed incurable cancer in a prospective longitudinal observational multicenter study. Patients were evaluated using validated self-report measures (National Comprehensive Cancer Network Distress Thermometer [DT], Functional Assessment of Cancer Therapy [FACT], Schedule for the Evaluation of Individual Quality of Life [SEIQoL-Q], Patients Health Questionnaire-4 [PHQ-4], modified Supportive Care Needs Survey [SCNS-SF-34]) at baseline (T0) and at 3 (T1), 6 (T2), and 12 months (T3) follow-up. Results From October 2014 to October 2016, 500 patients (219 women, 281 men; mean age 64.2 years) were recruited at 20 study sites in Germany following diagnosis of incurable metastatic, locally advanced, or recurrent lung (217), gastrointestinal (156), head and neck (55), gynecological (57), and skin (15) cancer. Patients reported significant distress (DT score >= 5) after diagnosis, which significantly decreased over time (T0: 67.2%, T1: 51.7%, T2: 47.9%, T3: 48.7%). The spectrum of reported symptoms was broad, with considerable variety between and within the cancer groups. Anxiety and depressiveness were most prevalent early in the disease course (T0: 30.8%, T1: 20.1%, T2: 14.7%, T3: 16.9%). The number of patients reporting unmet supportive care needs decreased over time (T0: 71.8 %, T1: 61.6%, T2: 58.1%, T3: 55.3%). Conclusion Our study confirms a variable and mostly high symptom burden at the time of diagnosis of incurable cancer, suggesting early screening by using standardized tools and underlining the usefulness of early palliative care. Implications for Practice A better understanding of symptom burden and palliative care needs of patients with newly diagnosed incurable cancer may guide clinical practice and help to improve the quality of palliative care services. The results of this study provide important information for establishing palliative care programs and related guidelines. Distress, symptom burden, and the need for support vary and are often high at the time of diagnosis. These findings underscore the need for implementation of symptom screening as well as early palliative care services, starting at the time of diagnosis of incurable cancer and tailored according to patients' needs

Fachkräftebedarf: Analyse und Handlungsstrategien

Mit der verbesserten Lage am Arbeitsmarkt und dem aus demografischen Gründen zu erwartenden Rückgang des Erwerbspersonenpotenzials gewinnt auch das Thema Fachkräftesicherung immer mehr an Bedeutung. Dieses Thema wird in Kapitel D ("Fachkräftebedarf: Analyse und Handlungsstrategien") eingehend behandelt. Dabei wird deutlich: Die Folgen des demografischen Wandels für den Arbeitsmarkt sind erheblich und es muss an vielen Stellschrauben gedreht werden, um diese abzumildern. Sowohl die Mobilisierung inländischer Potenziale als auch die verstärkte Zuwanderung von Fachkräften ist notwendig, um den Rückgang des Erwerbspotenzials spürbar abzufedern