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Background: Glioblastoma (GBM) is a lethal brain tumor without effective treatment options. The aim of this study was to characterize longitudinal tumor immune microenvironment (iTME) changes in order to find potential actionable targets to prevent GBM-induced immune evasion mechanisms.Methods: This study included 15 patient-matched treatment-naïve WHO grade 4 primary (pGBM) and recurrent (rGBM) tumors. RNA and proteins extracted from fresh frozen tumor samples from matched pGBM and rGBM were profiled via transcriptomics and proteomics, respectively. A tissue microarray containing paired formalin-fixed paraffin-embedded tumor samples was processed for spatial transcriptomics analysis.Results: Differentially expressed genes and proteins between pGBM and rGBM were involved in pathways responsible for synapse development and myelination which have been shown to play a role in GBM recurrence. By categorizing patients into short and long time-to-relapse (STTR vs LTTR), we identified genes positively or negatively associated with TTR. Expression of Fcγ receptors and complement system genes such asFCGR1A(CD64),FCGR3AandC3in rGBM samples were negatively correlated with TTR, whereas expression ofDNMT1/3A, andSMARCA4, involved in DNA methylation, were positively correlated with TTR. Spatial transcriptomic analysis of the tumor cell compartment showed enrichment of oligodendrocytes in rGBM, whereas the myeloid cell compartment switched from quiescent to activated microglia, was enriched in B and T cells, specifically in rGBM with STTR.Conclusions:Our results uncover a role for CD64-expressing activated microglia in GBM recurrence and suggest that interfering with these cells may represent a therapeutic option for hindering GBM relapse.Key points:Transcriptomic and proteomic differences exist between patient-paired primary and recurrent GBM tumorsHigh expression of Fcy receptors genes on activated microglia at tumor recurrence is associated with shorter time to relapse.Importance of this study:In glioblastoma (GBM), the tumor recurs in almost all cases after standard treatment such as surgery and chemo-radiotherapy. In this study, we longitudinally evaluated the immune- and neoplastic compartments using transcriptomic, proteomic, and spatial transcriptomics in patient-matched treatment-naive and recurrent tumor samples. By correlating gene expression with time-to-relapse, we identified a geneset associated with treatment resistance and faster tumor recurrence. Moreover, this study highlighted the plasticity of the myeloid compartment during disease progression and an unfavorable role of activated microglia in tumor recurrence.

Nnedi Okorafor’s Binti series (2015–2017) weaves advanced mathematics, multi-species entanglements, and futuristic modes of communication into Africanfuturist narratives; the series’ devotion to ma...

Ichthyosis with confetti (IWC) is a genodermatosis associated with dominant‐negative variants in keratin 10 (KRT10) or keratin 1 (KRT1). These frameshift variants result in extended aberrant proteins, localized to the nucleus rather than the cytoplasm. This mislocalization is thought to occur as a result of the altered carboxy (C)‐terminus, from poly‐glycine to either a poly‐arginine or ‐alanine tail. Previous studies on the type of C‐terminus and subcellular localization of the respective mutant protein are divergent. In order to fully elucidate the pathomechanism of IWC, a greater understanding is critical. This study aimed to establish the consequences for localization and intermediate filament formation of altered keratin 10 (K10) C‐termini. To achieve this, plasmids expressing distinct KRT10 variants were generated. Sequences encoded all possible reading frames of the K10 C‐terminus as well as a nonsense variant. A keratinocyte line was transfected with these plasmids. Additionally, gene editing was utilized to introduce frameshift variants in exon 6 and exon 7 at the endogenous KRT10 locus. Cellular localization of aberrant K10 was observed via immunofluorescence using various antibodies. In each setting, immunofluorescence analysis demonstrated aberrant nuclear localization of K10 featuring an arginine‐rich C‐terminus. However, this was not observed with K10 featuring an alanine‐rich C‐terminus. Instead, the protein displayed cytoplasmic localization, consistent with wild‐type and truncated forms of K10. This study demonstrates that, of the various 3′ frameshift variants of KRT10, exclusively arginine‐rich C‐termini lead to nuclear localization of K10.

The ‘nonhuman’ encompasses such a vast variety of different agents that it seems difficult to collect them all under the same term. However, insisting on a strict division between them may still be rooted firmly in a Western-centric need to classify and categorise. Based partly on the Aboriginal concept of ‘country,’ Ambelin Kwaymullina’s young adult (YA) The Tribe trilogy endeavours to make varied nonhuman voices audible by representing multiple nonhuman agents, which, on the surface, seem vastly different from one another but are similar in their value and dignity. This chapter explores Kwaymullina’s strategies for making the nonhuman heard as a collective without denying the individuality of each nonhuman agent. It also strives to explain how Kwaymullina uses the genre of YA speculative fiction to reach a wider audience without denying the reality of the beliefs Kwaymullina holds and represents. The concept of a sentient nonhuman world is thus not weakened because of its framing within speculative fiction; instead, it is reconfirmed as a futuristic but very much possible human-nonhuman dynamic, which requires not magic but merely human awareness to come into being.

The opening chapter will introduce and contextualise new forms, contents, tropes, and genres that characterise novel writing in the twenty-first century. Characteristics central to the novel as a form play an important role in providing the imaginative space to explore human-nonhuman relations. Our aim is twofold: first, we want to contextualise our literary approach within wider conversations about nature, globalisation, the Anthropocene, the digital turn, and the concomitant rise in awareness of nonhuman agents. We will situate our volume within existing discourses in the field, relating our volume to approaches from the paradigms of ecocriticism, new materialism, posthumanism, object-oriented philosophy, and actor-network theory. Bringing together different ideas and approaches from these fields, we will show how nonhuman agency emerges in literature where traditional means of meaning-making no longer suffice and categories of the ‘known’ are surpassed. Second, we will provide a general overview over the variety of different approaches that have been established to discuss literary texts and to envision the potential of the nonhuman beyond traditional dualisms. In this section, we will reflect upon the affordances of the novel as a form and its potential to trigger cultural and political change by connecting ethical questions and aesthetic expressions. The introduction will conclude with a short overview of the approaches presented in the following chapters.

International audience; Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to β-HPVs of EV patients.

Background The ability to differentiate patient-specific human induced pluripotent stem cells in cardiac myocytes (hiPSC-CM) offers novel perspectives for cardiovascular research. A number of studies, that reported mainly on current-voltage curves used hiPSC-CM to model voltage-gated Na + channel (Na v ) dysfunction. However, the expression patterns and precise biophysical and pharmacological properties of Na v channels from hiPSC-CM remain unknown. Our objective was to study the characteristics of Na v channels from hiPSC-CM and assess the appropriateness of this novel cell model. Methods We generated hiPSC-CM using the recently described monolayer-based differentiation protocol. Results hiPSC-CM expressed cardiac-specific markers, exhibited spontaneous electrical and contractile activities, and expressed distinct Na v channels subtypes. Electrophysiological, pharmacological, and molecular characterizations revealed that, in addition to the main Na v 1.5 channel, the neuronal tetrodotoxin (TTX)-sensitive Na v 1.7 channel was also significantly expressed in hiPSC-CM. Most of the Na + currents were resistant to TTX block. Therapeutic concentrations of lidocaine, a class I antiarrhythmic drug, also inhibited Na + currents in a use-dependent manner. Na v 1.5 and Na v 1.7 expression and maturation patterns of hiPSC-CM and native human cardiac tissues appeared to be similar. The 4 Na v β regulatory subunits were expressed in hiPSC-CM, with β3 being the preponderant subtype. Conclusions The findings indicated that hiPSC-CM robustly express Na v 1.5 channels, which exhibited molecular and pharmacological properties similar to those in native cardiac tissues. Interestingly, neuronal Na v 1.7 channels were also expressed in hiPSC-CM and are likely to be responsible for the TTX-sensitive Na v current.

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency. We thank the patients that participated in the study, the flow sorting team and the microscopy core facility of the Department of Biomedicine, University and University Hospital of Basel, the Blood Donor Center affiliated with the University Hospital of Basel, as well as G. Hoenger, U. Duthaler, C. Gasser, J. Hirsiger, C. Berger, T. Daikeler, F. Marquardsen and F. Baldin for technical support and/or help with the clinical management of patients. Funding was provided by Gebert Rüf Foundation (grant no. GRS-058/14 to C.H. and M.R.); Swiss National Science Foundation (SNSF) (grant nos. 31003A_172848 to C.H. and PP00P3_181038 to M.R.). This work was further supported by a grant from the Swiss National Supercomputing Center (project ID SM09). Sí

Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers and impairs cardiac contractility. The SCN5A gene encodes Nav1.5, the predominant cardiac sodium channel alpha subunit. SCN5A mutations have been identified in patients with arrhythmic disorders associated with DCM. The characterization of Nav1.5 mutations located in the voltage sensor domain (VSD) and associated with DCM revealed divergent biophysical defects that do not fully explain the pathologies observed in these patients. The purpose of this study was to characterize the pathological consequences of a gating pore in the heart arising from the Nav1.5/R219H mutation in a patient with complex cardiac arrhythmias and DCM. We report its properties using cardiomyocytes derived from patient-specific human induced pluripotent stem cells. We showed that this mutation generates a proton leak (called gating pore current). We also described disrupted ionic homeostasis, altered cellular morphology, electrical properties, and contractile function, most probably linked to the proton leak. We thus propose a novel link between SCN5A mutation and the complex pathogenesis of cardiac arrhythmias and DCM. Furthermore, we suggest that leaky channels would constitute a common pathological mechanism underlying several neuronal, neuromuscular, and cardiac pathologies.

Background: Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancer, mainly cutaneous squamous cell carcinoma (cSCC). Two genes (TMC6/EVER1 and TMC8/EVER2), mutated in epidermodysplasia verruciformis (EV) patients with an increased risk of cSCC development, contain numerous single-nucleotide polymorphisms (SNPs). Aim: To evaluate the effect of SNPs in both TMC/EVER genes on the different susceptibilities of RTRs to cSCC. Method: We determined the occurrence of cSCC in 105 RTRs who were transplanted at least 7 years previously and investigated the frequency of 26 SNPs within both TMC/EVER genes in severely affected (n = 16) as well as in nonaffected RTRs (n = 25). Results: Our data did not indicate a significant association between any SNP genotype and risk of cSCC development in RTRs. Conclusion: To clarify the correlation between SNPs in both TMC genes and cSCC development in RTRs, integrated investigations of large cohorts including both RTRs and immunocompetent individuals with consideration of cSCC status, SNP genotype and human papillomavirus status might be necessary.

Background Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative. Objective The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described EV patients. Patients and methods We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood and β-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types. Results Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described EV patients. Around 40% of EV patients analysed for genetic alterations carried no mutation in TMC6/8. While β-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals. Conclusion The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in EV patients, but HPV-3, HPV-14, and HPV-20 were unexpectedly identified more frequently than HPV-8. This article is protected by copyright. All rights reserved.

SummaryBackground Autosomal dominant adermatoglyphia (ADG) is characterized by lack of palmoplantar epidermal ridges. Recently, ADG was found to be caused in one family by a mutation in SMARCAD1, a member of the SNF subfamily of the helicase protein superfamily. Objectives To investigate the genetic basis of ADG. Methods We used direct sequencing and global gene expression analysis. Results We identified three novel heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) in a total of six patients. Surprisingly, all four ADG-causing mutations identified to date disrupt a single conserved donor splice site adjacent to the 3′ end of a noncoding exon and are predicted to result in haploinsufficiency for a skin-specific isoform of SMARCAD1. These data indicate a pivotal role for the SMARCAD1-skin specific isoform in dermatoglyph formation. In order to better understand the consequences of ADG-associated mutations, we ascertained the global transcription profiles of primary keratinocytes downregulated for SMARCAD1 and of patient-derived keratinocytes. A total of eight genes were found to be differentially expressed in both patient-derived and knocked down keratinocytes. Of interest, these differentially expressed genes have been implicated in epidermal ontogenesis and differentiation, and in psoriasis, which is characterized by abnormal finger ridge patterns. Conclusions The present data suggest that ADG is genetically homogeneous and result from perturbed expression of epidermal differentiation-associated genes.

Ichthyosis with confetti (IWC) was first described as ichthyose en confettis and subsequently as congenital reticular ichthyosiform erythroderma. Because of the development of hundreds to thousands of pale, normal-appearing confetti-like spots during childhood, the disease was named IWC. Patients with IWC show erythroderma, prominent scaling and palmoplantar keratoderma. Our female index patient was described in 1990 as the fourth patient reported worldwide; at that time she did not show any confetti-like spots. She was periodically examined at our clinic from birth until adulthood; hence we are able to describe the natural course of IWC in detail for the first time. We furthermore identified two novel deletions in KRT10, one of them leading to a frameshift and consequently to an arginine tail of keratin 10. Our report is the first independent confirmation of the KRT10 gene defect and revertant mosaicism mechanism in patients with IWC and it expands the clinical findings.

Background and Aims. Benign skin tumors such as lipomas, fibromas, and epidermal cysts are among the extracolonic manifestations of familial adenomatous polyposis (FAP). Readily detectable by inspection, they could serve as presymptomatic diagnostic markers to identify FAP patients. We therefore prospectively determined the prevalence of cutaneous lesions in genetically confirmed adenomatous polyposis coli (APC) mutation carriers and assessed their potential usefulness in the identification of FAP patients. Methods. Whole-skin examination was performed in 56 adult APC mutation carriers, compared with a control group (n = 116). In addition, FAP patients were investigated for the presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE), an established clinical marker for FAP, and a detailed review of medical records was performed. Results. Nearly half of all FAP patients (48.2%) had at least one FAP-associated skin lesion, compared with one third (34.5%) of controls. Only multiple lipomas and combined skin lesions were significantly more prevalent in APC mutation carriers. CHRPE was observed in 22 (43.1%) of 51 FAP patients, including 14 (37.8%) of 37 individuals with APC mutations outside the CHRPE-associated region between codons 311 and 1465. Conclusions. Despite a significantly higher prevalence of multiple lipomas, occurring at younger age, and combined skin lesions in APC mutation carriers, the low diagnostic sensitivity of FAP-associated skin lesions precludes their use as markers for FAP in clinical practice. Based on our findings, the common CHRPE-associated region should be extended to APC codons 148-2043.

Rabbits absorb more calcium (Ca) from their diet than they require, and excrete surplus via urine, which therefore contains a typical 'sludge'. This makes rabbits susceptible to Ca-containing uroliths. But given the Ca content of diets of free-ranging specimens, and the limited reports of urinary sludge and Ca contents in free-ranging lagomorphs, we can suspect that rabbits are naturally adapted to high urinary Ca loads. We fed four groups of New Zealand hybrid rabbits [n = 28, age at start 5-6 weeks) pelleted diets consisting of lucerne hay only (L, Ca 2.32% dry matter (DM)], lucerne:oats 1:1 (LG, Ca 1.36%), grass hay only (G, Ca 1.04%), or grass:oats 1:1 (GG, 0.83%) for 25 weeks, with water available ad libitum. Diets were not supplemented with Ca, phosphorus, or vitamin D. Rabbits on diets LG and GG had lower food and water intakes, lower faeces and urine output, grew faster and had higher body mass at slaughter (mainly attributable to adipose tissue). Apparent Ca digestibility decreased in the order L-LG-G/GG. Rabbits on L had larger and heavier kidneys, more urinary sediment at sonography, and a higher urinary Ca content than the other groups. No animal showed signs of urolithiasis/calcinosis at X-ray, sonography, or gross pathology. Kidney/aorta histology only sporadically indicated Ca deposits, with no systematic difference between groups. Under the conditions of the experiment, dietary Ca loads in legume hay do not appear problematic for rabbits, and other factors, such as water supply and level of activity may be important contributors to urolithiasis development in veterinary patients. However, due to the lower Ca content of grass hay, the significantly lower degree of urinary sludge formation, and the significantly higher water intake related with grass hay feeding, grass hay-dominated diets are to be recommended for rabbits in which urolithiasis prevention is an issue.

In the digital age, personal identification by fingerprints (epidermal ridges) has become more frequent and is often required for biometric passports. The more fingerprints are analyzed, the more variants in their formation are documented. Individuals completely missing fingerprints as an isolated finding are extremely rare. Only 4 kindreds have been described to date, with additional clinical features in most cases. We describe a female patient with missing epidermal ridges on the fingers, palms, toes, and soles as an isolated feature. Absent fingerprints, or adermatoglyphia, were inherited over 4 generations of her family in an autosomal dominant fashion. We present the clinical features of the index patient, and compare the case with previous reports in the literature. Because of problems in personal identification, this embryologic malformation caused the patient significant difficulties when traveling to other countries, which is why we name it the immigration delay disease.

Background: Epidermodysplasia verruciformis (EV) is a rare genodermatosis that is characterized by susceptibility to infection with specific human papillomavirus (HPV) genotypes. Among polyomaviruses, the novel Merkel cell polyomavirus (MCPyV) has been found in different epithelial skin neoplasias. Objective: To examine whether EV is associated with cutaneous MCPyV infection. Methods: We used MCPyV-specific PCR to study skin neoplasms of 6 congenital EV patients and of 1 patient with acquired EV. Results: In all congenital EV patients, MCPyV DNA was found in carcinomas in situ, in invasive squamous cell carcinomas and in common warts. In 4 of these patients, the MCPyV-positive skin lesions were from different anatomic locations. In addition, 1 immunosuppressed patient suffering from acquired EV harbored MCPyV DNA in 2 common warts. In contrast, 7 normal skin samples tested negative for MCPyV DNA. Only 2 out of 24 carcinomas in situ (8.3%) and 2 out of 30 common warts (6.7%) from immunocompetent individuals were positive for MCPyV DNA. Conclusions: The strong association of EV-associated skin neoplasms with MCPyV suggests a unique susceptibility of EV patients to infections with MCPyV. Both MCPyV and EV-HPV may act as synergistic oncogenic cofactors in the development of EV-associated skin neoplasms.

The early diagnosis of colorectal cancer (CRC) is central for effective treatment, as prognosis is directly related to the stage of the disease. Development of tumor markers found in the blood from patients, which can detect CRC at an early stage, should have a major impact in morbidity and mortality of this disease. The nuclear matrix is the structural scaffolding of the nucleus and specific nuclear matrix proteins (NMPs) have been identified as an "fingerprint" for various cancer types. Previous studies from our laboratory have identified four colon cancer associated NMPs termed colon cancer-specific antigen (CCSA)-2 to (CCSA)-5. The objective of the present study was to analyze the expression of one of these proteins, CCSA-2 in serum from various patient populations and to determine whether CCSA-2 antibodies could be used in a clinically applicable serum-based immunoassay specifically to detect colon cancer. Using an indirect ELISA, which detects CCSA-2, the protein was measured in the serum from 174 individuals, including healthy individuals, patients with colon cancer, patients with diverticulosis, colon polyps, inflammatory bowel disease (IBD) as well as other cancer types. With a predetermined cutoff absorbance of 0.6 OD we have successfully utilized this approach to develop an immunoassay that detected colon cancer. The immunoassay showed a sensitivity of 88.8% (24/27) and an overall specificity of 84.2% (106/127). This initial study showed the potential of CCSA-2 to serve as a highly specific blood based marker for colon cancer. Although potentially promising, the results of this study must be confirmed in larger independent validation studies.

Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers, impairs cardiac contractility and systolic function leading to heart failure. SCN5A gene encodes the cardiac sodium channel (Nav1.5) in which mutations have been identified in patients with arrhythmic disorders associated with DCM. However, it is not understood how a dysfunction in SCN5A may cause very atypical cardiac arrhythmias associated with dilatation remodeling of the heart. We generated control and patient specific human induced pluripotent cells (hiPS) carrying the Nav1.5/R219H mutation. hiPS were differentiated to obtain cardiomyocytes derived from hiPS (hiPS-CM). Molecular dynamic simulations experiments revealed that the R219H mutation opens up a pathway directly through the voltage sensitive domain (VSD) of Nav1.5 channels. We hypothesized that such a proton leak through the VSD caused by the R219H mutation may be responsible for the clinical phenotypes observed in our index patient. We unraveled the underlying mechanism responsible for the association of SCN5A and DCM. Indeed, the data shows the presence of a gating pore or omega current that is responsible of the observed abnormal ionic homeostasis, absent in control hiPS-CM. Action potential recordings showed abnormal electrical activities in both atrial and ventricular hiPS-CM. Myocytes stemmed from the index patient exhibited dilatation. Single cardiomyocytes contractility probed using atomic force microscopy revealed a higher frequency of contractility with reduced force compared to control myocytes. This could be attributed to the observed contractile protein dysfunction uncovered using immunofluorescence. Overall, the results support the hypothesis that the Nav1.5/R219H mutation creates a proton leak. This leak then causes electrical, structural and contractile disturbances that may explain the related cardiac arrhythmias associated with myocytes dilatation. We concluded that gating pore current, a novel cardiac channelopathy is directly related to the association of SCN5A and DCM. We suggest that this aberrant leak current should be investigated to characterize similar SCN5A mutations with similar clinical phenotypes.

Wo und wie moderne Wirtschaftsförderung am besten funktioniert und wie Unternehmen bestehende Förderpotenziale optimal heben, erfährt man in diesem Buch. Versierte Spezialisten und sehr erfolgreiche Wirtschaftsförderer geben einen hervorragenden Ein- und Überblick über Organisation und Strukturen der deutschen und europäischen Wirtschaftsförderung. Unterschiedliche Fördermodelle und die Antragstellung bei EU, der Bundesgesellschaft GTAI, sowie Länder- und kommunalen Wirtschaftsfördergesellschaften werden ausführlich erläutert. Sie finden Erfolgsbeispiele und Best Practices, viele Tipps und praktische Gestaltungsempfehlungen: die gesamte Welt der Wirtschaftsförderung in einem kompakten Band.

Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancer, mainly cutaneous squamous cell carcinoma (cSCC). Two genes (TMC6/EVER1 and TMC8/EVER2), mutated in epidermodysplasia verruciformis (EV) patients with an increased risk of cSCC development, contain numerous single-nucleotide polymorphisms (SNPs).To evaluate the effect of SNPs in both TMC/EVER genes on the different susceptibilities of RTRs to cSCC.We determined the occurrence of cSCC in 105 RTRs who were transplanted at least 7 years previously and investigated the frequency of 26 SNPs within both TMC/EVER genes in severely affected (n = 16) as well as in nonaffected RTRs (n = 25).Our data did not indicate a significant association between any SNP genotype and risk of cSCC development in RTRs.To clarify the correlation between SNPs in both TMC genes and cSCC development in RTRs, integrated investigations of large cohorts including both RTRs and immunocompetent individuals with consideration of cSCC status, SNP genotype and human papillomavirus status might be necessary.

IMPORTANCE Ichthyosis with confetti (IWC) is a genodermatosis caused by dominant negative mutations in the gene encoding keratin 10 (KRT10). We investigated clinical and genetic details of a substantial number of patients with IWC in order to define major and minor criteria for diagnosis of this rare disorder. OBSERVATIONS Parallel clinical investigation of 6 patients with IWC revealed a novel spectrum of phenotypes. We found several features that qualify as major criteria for diagnosis, which are clearly and consistently associated with the condition. These included malformation of ears, hypoplasia of mammillae, and dorsal acral hypertrichosis. Genetic analysis of patients revealed several different frameshift mutations in intron 6 or exon 7 of KRT10. Analysis of this locus in 17 unrelated control individuals revealed 2 novel polymorphisms of KRT10. CONCLUSIONS AND RELEVANCE We present for the first time to our knowledge the spectrum of clinical variability of IWC in 6 patients with confirmed mutations in KRT10. From this, we have extracted major and minor criteria to aid early and correct clinical diagnosis. Ectodermal malformations, present in all patients, suggest a novel classification of IWC as a syndrome. There is remarkable genetic variation at the IWC disease locus within control individuals from the general population.

Juvenile polyposis syndrome (JPS) is an autosomal dominant predisposition to multiple juvenile polyps in the gastrointestinal tract. Germline mutations in the MADH4 or BMPR1A genes have been found to be causative of the disease in a subset of JPS patients. So far, no genotype-phenotype correlation has been reported. We examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A genes and identified MADH4 mutations in seven (24%) and BMPR1A mutations in five patients (17%). A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. This is the first genotype-phenotype correlation observed in JPS.

Background and Aims: Up to now, various tumor markers have been proposed for the detection of the onset of malignant cell transformation or the better follow-up of cancer patients. The aim of the present study is to investigate the diagnostic value of systemic lipid peroxidation as an additional evaluative tool in the follow-up of surgical patients with colorectal cancer in combination to the clinically routine tumor markers carcinoembryonic antigen (CEA) and carcinoantigen 19-9 (CA 19-9). Patients and Methods: 36 patients with a colorectal carcinoma were included in this study. Blood samples were collected 1 day prior to the operation, 10 days and 1 year after the operation. Oxygen free radical mediated lipid peroxidation was determined by measurement of thiobarbituric acid-reactive substances in the same serum that were used for the determination of tumor markers. Results: Compared to control values, a highly significant increase of lipid peroxidation was found in the serum of all colorectal carcinoma patients up to the first 10 postoperative days. Differentiation of the patients, according to the T-stage, showed a marked and more obvious tendency towards higher serum lipid peroxides with increased tumor stage when compared to the conventional tumor markers. One year postoperatively the serum levels of lipid peroxidation returned to nearly normal values. Also the conventional tumor markers CEA and CA 19-9 showed a relative rise in the levels with the respective tumor stage, but differences were only statistically significant in the highest T-categories. Conclusion: After curative resection of the tumor, the level of systemic lipid peroxides decreases to normal values. We conclude from these results that the tumor is the primary cause of the increased systemic lipid peroxides.

Every disease is a mirror of interactions between genes and the environment. In monogenic disorders only one mutation can lead to a specific phenotype. However the spectrum and the degree of manifestations depend on numerous factors from the environment. Ichthyosis vulgaris is caused by a mutation in the filaggrin gene. However the phenotype is much more pronounced in the winter months. In polygenic disorders such as atopic dermatitis numerous modifying genes influence the phenotype including a mutation in filaggrin. The skin is the organ of the human body which is most commonly involved in monogenic diseases. More than one third of all genetic diseases affect the integument. At the very moment more than 350 genodermatoses are identified with functional insights. The Human Genome Project was finished in 2001 with the aim that all genes can be identified for diagnostics, pharmacogenomics potential gene therapy and to understand the principle basis of diseases. The next project called ENCODE for Enzyclopedia of DNA Elements targets to identify all functional elements in the human genome sequence. MicroRNAs seem to have great importance for the regulation of genefunctions in the skin. At the moment epigenetics is at the epicentre of modern medicine. Epigenetics is the study of non-DNA sequence-related heredity. Epigenetics is an important tool to study the relationship between the genome and the environment. In the second part cases will be presented and the way of diagnosis making will be shown. It will be shown that it is very important to find clinical key features which may allow an allocation to a genetic pathway.

Globalization and regionalization seem like contradictory concepts. However, they present the framework for economic activity, innovation, and cooperation in our time. Under these circumstances, regions are, to an increasing extent, in an entrepreneurial position. They must compete among each other for: enterprises, investments, highly skilled personnel, and jobs. The extent to which a region is competitive depends on several factors, the most important of which are knowledge, social capital, networks, and supporting structures. These factors may be self-organized or government-based. In reality, there is no single recipe known that guarantees success in all cases. However, in view of the relevance of knowledge and learning, the cluster approach can offer an explanation as to why some regions manage to develop their knowledge-based industries more successfully than others. When we talk about globalization we have a new economic setting in mind, one in which profit-oriented multinational strategies of large business corporations lead to an international division of labor. The resulting post-Fordist concept of flexible production is comprised of a formation of independent units within large corporations. These units are integrated into regional networks, instead of being hierarchically sub-ordered into the centralized corporation. To local communities, this situation poses a challenge but also provides new opportunities concerning the task of directing their development to the advantage of the region. M. E. Porter (1990, 1998, 2000) is one of the prominent writers to draw attention to the relevance of regions in a globalized economy. The first part of this chapter gives greater insight into the concept of regional cluster development, its characteristics, and its meaning for regional policy. Very often, Science or Technology Parks are seen as a suitable means to form clusters of modern high technological industries. The second part deals with the example of the City of Dortmund, Germany, since the recent history of this city is a perfect example for successful regional development and the key ingredients involved. Special attention is given to the role of research and higher education within the structural policy that helped Dortmund to overcome a severe crisis. The technology park in Dortmund demonstrates how active cluster development can help improve the economic development of a region, thus improving its competitiveness and the life of its population.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers, but the influence of microRNA (miRNA) expression has only been sporadically analysed. We hypothesized that miRNAs are differentially expressed in cSCC and hence influence its development. We therefore isolated total miRNA from well-differentiated cSCCs and from controls without SCC. Expression analyses of 12 miRNAs showed three significantly differentially expressed miRNAs. We identified a significant upregulation of the miR-21 and the miR-31, a proto-oncogene like miR-21. While the upregulated expression of miR-21 has been known for some time, the increased expression of miR-31 was never shown so clearly. Furthermore, we showed the upregulation of miRNA-205, which has never been described before. The miR-205 induces specific keratinocyte migration and could be a characteristic marker for cSCC. It has to be determined in following studies whether these upregulated expressions are specific for cSCC and if so, for which cSCC stages.