Publications by authors named "Thomas Vogt"

384 Publications

Epidermolysis bullosa dystrophica prätibialis - Klinischer Schnappschuss und Management einer seltenen Erkrankung.

J Dtsch Dermatol Ges 2021 Jul;19(7):983-986

Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum des Saarlandes, Homburg/Saar.

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http://dx.doi.org/10.1111/ddg.14446_gDOI Listing
July 2021

Engineering Betalain Biosynthesis in Tomato for High Level Betanin Production in Fruits.

Front Plant Sci 2021 9;12:682443. Epub 2021 Jun 9.

Department of Cell and Metabolic Biology, Leibniz Institute of Plant Biochemistry, Halle, Germany.

Betalains are pigments found in plants of the Caryophyllales order, and include the red-purple betacyanins and the yellow-orange betaxanthins. The red pigment from red beets, betanin, is made from tyrosine by a biosynthetic pathway that consists of a cytochrome P450, a L-DOPA dioxygenase, and a glucosyltransferase. The entire pathway was recently reconstituted in plants that do not make betalains naturally including potato and tomato plants. The amount of betanin produced in these plants was however not as high as in red beets. It was recently shown that a plastidic arogenate dehydrogenase gene involved in biosynthesis of tyrosine in plants is duplicated in and other betalain-producing plants, and that one of the two encoded enzymes, BvADHα, has relaxed feedback inhibition by tyrosine, contributing to the high amount of betanin found in red beets. We have reconstituted the complete betanin biosynthetic pathway in tomato plants with or without a gene, and with all genes expressed under control of a fruit-specific promoter. The plants obtained with a construct containing produced betanin at a higher level than plants obtained with a construct lacking this gene. These results show that use of BvADHα can be useful for high level production of betalains in heterologous hosts. Unlike red beets that produce both betacyanins and betaxanthins, the transformed tomatoes produced betacyanins only, conferring a bright purple-fuschia color to the tomato juice.
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http://dx.doi.org/10.3389/fpls.2021.682443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220147PMC
June 2021

Vernachlässigung der histologischen Diagnostik der Onychomykose - dabei wäre das Beste so einfach.

J Dtsch Dermatol Ges 2021 Jun;19(6):885-888

Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum des Saarlandes, Homburg/Saar.

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http://dx.doi.org/10.1111/ddg.14382_gDOI Listing
June 2021

Granuloma anulare und maligne kutane Lymphome: Gibt es eine Assoziation beider Erkrankungen?

J Dtsch Dermatol Ges 2021 Jun;19(6):803-814

Klinik für Dermatologie, Allergologie und Venerologie, Universitätsklinikum des Saarlandes, Homburg/Saar.

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http://dx.doi.org/10.1111/ddg.14401_gDOI Listing
June 2021

Epidermolysis bullosa dystrophica pretibialis - Clinical snapshot and management of a rare orphan disease.

J Dtsch Dermatol Ges 2021 07 5;19(7):983-986. Epub 2021 May 5.

Department of Dermatology, Venereology and Allergology, Saarland University Medical Center, Homburg/Saar, Germany.

If blistering occurs in childhood, the possibility of hereditary epidermolysis bullosa should be considered even if the symptoms are mild. Besides clinical and histological examination, molecular genetic screening is diagnostically relevant. For localized forms, symptomatic, topical therapy options are currently still the primary choice. Of particular interest is the new option of topical therapy with diacerein 1 % cream. In the case of a pronounced clinical picture with extracutaneous organ involvement, multidisciplinary management is required. In the future, new forms of therapy such as autologous epidermal stem cell transplantation and gene therapeutic procedures may be applied. Human genetic counselling is indispensable.
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http://dx.doi.org/10.1111/ddg.14446DOI Listing
July 2021

Granuloma annulare - is it a paraneoplastic condition for malignant lymphoma?

J Dtsch Dermatol Ges 2021 06 5;19(6):803-812. Epub 2021 May 5.

Department of Dermatology, Allergology and Venereology, Saarland University Hospital, Homburg/Saar.

In recent years, an association between granuloma annulare and the occurrence of malignant cutaneous lymphomas in the sense of a facultative paraneoplasia has been observed several times. The aim of the present work is to provide an overview of the currently available literature on granuloma annulare as well as an analysis of its association with cutaneous lymphomas. Using the example of two patients with granuloma annulare and associated cutaneous lymphomas, we would like to sensitize clinically active dermatologists and dermatopathologists to the possible association between these two diseases. Characteristic features and clinicopathological signs are discussed, which should raise suspicion of an associated malignant lymphoma. It is recommended to rule out an underlying cutaneous and/or extracutaneous lymphoma in unusual clinical constellations (for instance distribution pattern, subjective complaints, age at first manifestation, lack of response to conventional therapy), especially in the absence of other known clinical triggers of granuloma annulare such as insect bites, trauma or varicella-zoster infections, among others. However, in individual cases the criteria mentioned here justify lymphoma screening.
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http://dx.doi.org/10.1111/ddg.14401DOI Listing
June 2021

Identification and characterization of piperine synthase from black pepper, Piper nigrum L.

Commun Biol 2021 Apr 8;4(1):445. Epub 2021 Apr 8.

Leibniz Institute of Plant Biochemistry, Dept. Cell and Metabolic Biology, Halle (Saale), Germany.

Black pepper (Piper nigrum L.) is the world's most popular spice and is also used as an ingredient in traditional medicine. Its pungent perception is due to the interaction of its major compound, piperine (1-piperoyl-piperidine) with the human TRPV-1 or vanilloid receptor. We now identify the hitherto concealed enzymatic formation of piperine from piperoyl coenzyme A and piperidine based on a differential RNA-Seq approach from developing black pepper fruits. This enzyme is described as piperine synthase (piperoyl-CoA:piperidine piperoyl transferase) and is a member of the BAHD-type of acyltransferases encoded by a gene that is preferentially expressed in immature fruits. A second BAHD-type enzyme, also highly expressed in immature black pepper fruits, has a rather promiscuous substrate specificity, combining diverse CoA-esters with aliphatic and aromatic amines with similar efficiencies, and was termed piperamide synthase. Recombinant piperine and piperamide synthases are members of a small gene family in black pepper. They can be used to facilitate the microbial production of a broad range of medicinally relevant aliphatic and aromatic piperamides based on a wide array of CoA-donors and amine-derived acceptors, offering widespread applications.
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http://dx.doi.org/10.1038/s42003-021-01967-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032705PMC
April 2021

X-ray Free Electron Laser-Induced Synthesis of ε-Iron Nitride at High Pressures.

J Phys Chem Lett 2021 Apr 25;12(12):3246-3252. Epub 2021 Mar 25.

Department of Earth Sciences, University of Oxford, South Parks Road, OX1 3AN Oxford, United Kingdom.

The ultrafast synthesis of ε-FeN in a diamond-anvil cell (DAC) from Fe and N under pressure was observed using serial exposures of an X-ray free electron laser (XFEL). When the sample at 5 GPa was irradiated by a pulse train separated by 443 ns, the estimated sample temperature at the delay time was above 1400 K, confirmed by transformation of α- to γ-iron. Ultimately, the Fe and N reacted uniformly throughout the beam path to form FeN, as deduced from its established equation of state (EOS). We thus demonstrate that the activation energy provided by intense X-ray exposures in an XFEL can be coupled with the source time structure to enable exploration of the time-dependence of reactions under high-pressure conditions.
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http://dx.doi.org/10.1021/acs.jpclett.1c00150DOI Listing
April 2021

Adjuvant Therapy of High-Risk (Stages IIC-IV) Malignant Melanoma in the Post Interferon-Alpha Era: A Systematic Review and Meta-Analysis.

Front Oncol 2020 18;10:637161. Epub 2021 Feb 18.

Department of Hematology, Oncology, Clinical Immunology and Rheumatology, Medical School, University of Saarland, Homburg, Germany.

Introduction: Multiple agents are approved in the adjuvant setting of completely resected high-risk (stages IIC-IV) malignant melanoma. Subgroups may benefit differently depending on the agent used. We performed a systematic review and meta-analysis to evaluate the efficiency and tolerability of available options in the post interferon era across following subgroups: patient age, stage, ulceration status, lymph node involvement, BRAF status.

Methods: The PubMed and Cochrane Library databases were searched without restriction in year of publication in June and September 2020. Data were extracted according to the PRISMA Guidelines from two authors independently and were pooled according to the random-effects model. The predefined primary outcome was recurrence-free survival (RFS). Post-data extraction it was noted that one trial (BRIM8) reported disease-free survival which was defined in the exact same way as RFS.

Results: Five prospective randomized placebo-controlled trials were included in the meta-analysis. The drug regimens included ipilimumab, pembrolizumab, nivolumab, nivolumab/ipilimumab, vemurafenib, and dabrafenib/trametinib. Adjuvant treatment was associated with a higher RFS than placebo (HR 0.57; 95% CI= 0.45-0.71). Nivolumab/ipilimumab in stage IV malignant melanoma was associated with the highest RFS benefit (HR 0.23; 97.5% CI= 0.12-0.45), followed by dabrafenib/trametinib in stage III BRAF-mutant melanoma (HR 0.49; 95% CI= 0.40-0.59). The presence of a BRAF mutation was associated with higher RFS rates (HR 0.30; 95% CI= 0.11-0.78) compared to the wildtype group (HR 0.60; 95% CI= 0.44-0.81). Patient age did not influence outcomes (≥65: HR 0.50; 95% CI= 0.36-0.70, <65: HR 0.58; 95% CI= 0.46-0.75). Immune checkpoint inhibitor monotherapy was associated with lower RFS in non-ulcerated melanoma. Patients with stage IIIA benefited equally from adjuvant treatment as those with stage IIIB/C. Nivolumab/ipilimumab and ipilimumab monotherapy were associated with higher toxicity.

Conclusion: Adjuvant therapy should not be withheld on account of advanced age or stage IIIA alone. The presence of a BRAF mutation is prognostically favorable in terms of RFS. BRAF/MEK inhibitors should be preferred in the adjuvant treatment of BRAF-mutant non-ulcerated melanoma.
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http://dx.doi.org/10.3389/fonc.2020.637161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930562PMC
February 2021

Neglect of the histological diagnostics of onychomycosis - the best would be so easy.

J Dtsch Dermatol Ges 2021 06 26;19(6):885-888. Epub 2021 Feb 26.

Saarland University Medical Center, Dept. of Dermatology, Homburg/Saar, Germany.

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http://dx.doi.org/10.1111/ddg.14382DOI Listing
June 2021

Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin.

Elife 2021 Feb 23;10. Epub 2021 Feb 23.

Sorbonne Université, Centre National de la Recherche Scientifique UMR 8256, INSERM ERL U1164, Paris, France.

Loss of cellular homeostasis has been implicated in the etiology of several neurodegenerative diseases (NDs). However, the molecular mechanisms that underlie this loss remain poorly understood on a systems level in each case. Here, using a novel computational approach to integrate dimensional RNA-seq and in vivo neuron survival data, we map the temporal dynamics of homeostatic and pathogenic responses in four striatal cell types of Huntington's disease (HD) model mice. This map shows that most pathogenic responses are mitigated and most homeostatic responses are decreased over time, suggesting that neuronal death in HD is primarily driven by the loss of homeostatic responses. Moreover, different cell types may lose similar homeostatic processes, for example, endosome biogenesis and mitochondrial quality control in -expressing neurons and astrocytes. HD relevance is validated by human stem cell, genome-wide association study, and post-mortem brain data. These findings provide a new paradigm and framework for therapeutic discovery in HD and other NDs.
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http://dx.doi.org/10.7554/eLife.64984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901871PMC
February 2021

CYP719A37 Catalyzes the Decisive Methylenedioxy Bridge Formation in Piperine Biosynthesis.

Plants (Basel) 2021 Jan 9;10(1). Epub 2021 Jan 9.

Leibniz Institute of Plant Biochemistry, Department Cell and Metabolic Biology, Weinberg 3, D-06120 Halle (Saale), Germany.

Black pepper () is among the world's most popular spices. Its pungent principle, piperine, has already been identified 200 years ago, yet the biosynthesis of piperine in black pepper remains largely enigmatic. In this report we analyzed the characteristic methylenedioxy bridge formation of the aromatic part of piperine by a combination of RNA-sequencing, functional expression in yeast, and LC-MS based analysis of substrate and product profiles. We identified a single cytochrome P450 transcript, specifically expressed in black pepper immature fruits. The corresponding gene was functionally expressed in yeast () and characterized for substrate specificity with a series of putative aromatic precursors with an aromatic vanilloid structure. Methylenedioxy bridge formation was only detected when feruperic acid (5-(4-hydroxy-3-methoxyphenyl)-2,4-pentadienoic acid) was used as a substrate, and the corresponding product was identified as piperic acid. Two alternative precursors, ferulic acid and feruperine, were not accepted. Our data provide experimental evidence that formation of the piperine methylenedioxy bridge takes place in young black pepper fruits after a currently hypothetical chain elongation of ferulic acid and before the formation of the amide bond. The partially characterized enzyme was classified as CYP719A37 and is discussed in terms of specificity, storage, and phylogenetic origin of CYP719 catalyzed reactions in magnoliids and eudicots.
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http://dx.doi.org/10.3390/plants10010128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826766PMC
January 2021

Ancient friends, revisited: Systematic review and case report of pyoderma gangrenosum-associated autoinflammatory syndromes.

J Transl Autoimmun 2020 20;3:100071. Epub 2020 Nov 20.

Department of Dermatology, The Saarland University Hospital, 66421, Homburg, Germany.

In the last decade, new scientific findings significantly improved our understanding of the molecular pathogenesis of autoinflammation and have resulted in the identification and definition of several pyoderma gangrenosum-associated autoinflammatory syndromes (PGAAIS) as new and distinct clinical entities. These different clinical entities include PAPA (pyogenic arthritis, pyoderma gangrenosum and acne conglobata), PASH (pyoderma gangrenosum, acne and suppurative hidradenitis), PAPASH (pyoderma gangrenosum, acne, suppurative hidradenitis and pyogenic arthritis), PsAPASH (pyoderma gangrenosum, acne, suppurative hidradenitis and psoriatic arthritis), PASS (pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis) and PAC (pyoderma gangrenosum, acne and ulcerative colitis), which can be distinguished by their clinical presentation and the presence or absence of mutations in several genes, such as the genes encoding proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1), nicastrin (NCSTN), Mediterranean fever (MEFV) and nucleotide-binding oligomerization domain-containing protein (NOD). In this systematic review, we summarize the present knowledge of this rapidly developing hot topic and provide a guide to enable the easy diagnosis of these syndromes in everyday clinical practice. Moreover, we report a rare case of PASS syndrome demonstrating successful treatment with adalimumab and another case of a previously unreported combination of symptoms, including psoriatic arthritis, pyoderma gangrenosum, suppurative hidradenitis and Crohn's disease (newly coined PsAPSC), as examples. Because of the identification of similar genetic and pathogenic mechanisms of PGAAIS, we think the wide variety of seemingly different syndromes may represent distinct phenotypes of one disease.
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http://dx.doi.org/10.1016/j.jtauto.2020.100071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718158PMC
November 2020

Tofacitinib Loaded Squalenyl Nanoparticles for Targeted Follicular Delivery in Inflammatory Skin Diseases.

Pharmaceutics 2020 Nov 24;12(12). Epub 2020 Nov 24.

Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), 66123 Saarbrücken, Germany.

Tofacitinib (TFB), a Janus kinase inhibitor, has shown excellent success off-label in treating various dermatological diseases, especially alopecia areata (AA). However, TFB's safe and targeted delivery into hair follicles (HFs) is highly desirable due to its systemic adverse effects. Nanoparticles (NPs) can enhance targeted follicular drug delivery and minimize interfollicular permeation and thereby reduce systemic drug exposure. In this study, we report a facile method to assemble the stable and uniform 240 nm TFB loaded squalenyl derivative (SqD) nanoparticles (TFB SqD NPs) in aqueous solution, which allowed an excellent loading capacity (LC) of 20%. The SqD NPs showed an enhanced TFB delivery into HFs compared to the aqueous formulations of plain drug in an pig ear model. Furthermore, the therapeutic efficacy of the TFB SqD NPs was studied in a mouse model of allergic dermatitis by ear swelling reduction and compared to TFB dissolved in a non-aqueous mixture of acetone and DMSO (7:1 /). Whereas such formulation would not be acceptable for use in the clinic, the TFB SqD NPs dispersed in water illustrated a better reduction in inflammatory effects than plain TFB's aqueous formulation, implying both encouraging good efficacy and safety. These findings support the potential of TFB SqD NPs for developing a long-term topical therapy of AA.
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http://dx.doi.org/10.3390/pharmaceutics12121131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760822PMC
November 2020

Update: Solar UV Radiation, Vitamin D, and Skin Cancer Surveillance in Organ Transplant Recipients (OTRs).

Adv Exp Med Biol 2020 ;1268:335-353

Center for Clinical and Experimental Photodermatology and Department of Dermatology, Saarland University Medical Center, Homburg, Germany.

Although great progress has been achieved during the last decades, the clinical management of organ transplant recipients (OTRs) remains a challenge. OTRs need in general lifelong immunosuppressive therapy that is associated with an increased risk to develop skin cancer and with an unfavorable clinical outcome of these malignancies. Skin cancer prevention measures, including regular full-body examinations, are therefore necessary in OTRs to detect and treat suspicious lesions at an early stage. The frequency of aftercare depends on the individual risk factors of the patient. Patients should apply consistent sun protection with sunscreens and clothing, as well as a monthly self-examination. On the other hand, the need of UVR avoidance increases the risk of vitamin D deficiency, which itself is associated with an increased risk for many diseases, including malignancies. OTRs should therefore be monitored for 25(OH)D status and/or should take vitamin D supplements. It has to be emphasized that an interdisciplinary approach, coordinated by the transplant center, that includes regular skin examinations by a dermatologist, is needed to ensure the best care for the OTRs.
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http://dx.doi.org/10.1007/978-3-030-46227-7_17DOI Listing
September 2020

Crosstalk Between Vitamin D and p53 Signaling in Cancer: An Update.

Adv Exp Med Biol 2020 ;1268:307-318

José Carreras Centre and Internal Medicine I, University of Saarland Medical Centre, Homburg (Saar), Germany.

It has now been convincingly shown that vitamin D and p53 signaling protect against spontaneous or carcinogen-induced malignant transformation of cells. The vitamin D receptor (VDR) and the p53/p63/p73 proteins (the p53 family hereafter) exert their effects as receptors/sensors that turn into transcriptional regulators upon stimulus. While the p53 clan, mostly in the nucleoplasm, responds to a large and still growing number of alterations in cellular homeostasis commonly referred to as stress, the nuclear VDR is transcriptionally activated after binding its naturally occurring biologically active ligand 1,25-dihydroxyvitamin D with high affinity. Interestingly, a crosstalk between vitamin D and p53 signaling has been demonstrated that occurs at different levels, has genome-wide implications, and is of high importance for many malignancies, including non-melanoma skin cancer. These interactions include the ability of p53 to upregulate skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Increased pigmentation protects the skin against UV-induced DNA damage and skin photocarcinogenesis, but also inhibits cutaneous synthesis of vitamin D. A second level of interaction is characterized by binding of VDR and p53 protein, an observation that may be of relevance for the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well-established role as a key negative regulator of p53 activity. Finally, p53 and its family members have been implicated in the direct regulation of the VDR. This review gives an update on some of the implications of the crosstalk between vitamin D and p53 signaling for carcinogenesis in the skin and other tissues, focusing on a genome-wide perspective.
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http://dx.doi.org/10.1007/978-3-030-46227-7_15DOI Listing
September 2020

DNA methylation study of Huntington's disease and motor progression in patients and in animal models.

Nat Commun 2020 09 10;11(1):4529. Epub 2020 Sep 10.

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Although Huntington's disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10) and in the transgenic sheep model (p = 2.4 × 10). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10), GRIK4 (p = 3.0 × 10), and COX4I2 (p = 6.5 × 10). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.
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http://dx.doi.org/10.1038/s41467-020-18255-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484780PMC
September 2020

Kikuchi-Fujimoto Disease Triggered by Systemic Lupus Erythematosus and Mycoplasma pneumoniae Infection-A Report of a Case and a Review of the Literature.

Am J Dermatopathol 2021 Mar;43(3):202-208

Institute of Medical Microbiology and Hygiene, Saarland University Medical Center, Homburg/Saar, Germany.

Abstract: Kikuchi-Fujimoto disease (KFD) is a necrotizing histiocytic lymphadenitis that was described for the first time in 1972 in Japan. Its etiology is still not fully understood. It has been reported in association with many different agents, diseases, and triggering factors without any conclusive result. To the best of our knowledge, we report for the first time a case of KFD with systemic lupus erythematosus in a child in association with a polymerase chain reaction (PCR)-positive throat swab for Mycoplasma pneumoniae. Although difficult to prove, the acute M. pneumoniae infection might have served as a triggering event for the development of KFD in our case. We encourage further studies to investigate a potential relationship between KFD and M. pneumoniae, which should also use PCR-based testing for this pathogen in patients with KFD.
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http://dx.doi.org/10.1097/DAD.0000000000001764DOI Listing
March 2021

Pressure-induced assemblies and structures of graphitic-carbon sheet encapsulated Au nanoparticles.

Nanoscale 2020 Aug;12(33):17462-17469

Department of Earth System Sciences, Yonsei University, Seoul 120749, Korea.

A novel strategy of using hydrostatic pressures to synthesize gold-carbon (Au-C) nanohybrid materials is explored. The stable face-centered-cubic (fcc) Au undergoes a structural phase transition to a mixture of primitive orthorhombic and cubic phases as the carbon phase acquires a highly ordered onion-like carbon (OLC) structure which encapsulates the Au nanoparticles, thereby exerting an additional pressure. Increasing the pressure results in a one dimensional (1-D) chain-like structure with the primitive cubic Au nanoparticles contained in an amorphous carbon matrix. The OLC structure allows the formation of quenchable Au nanoparticle phases with the primitive close packing and Au-C hybrids with new mesoscopic structures. Under pressure, we observe the formation of a hybrid material composed of a poorly conducting matrix made of amorphous carbon and conducting OLC-encapsulated Au nanoparticles. The electrical conductivity of this hybrid material under pressure reveals a percolation threshold. We present a new synthesis approach to explore the interplay between atomic and mesoscopic structures and the electrical conductivity of metal hybrid structures.
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http://dx.doi.org/10.1039/d0nr04443aDOI Listing
August 2020

Immunizations in immunocompromised patients: a guide for dermatologists.

J Dtsch Dermatol Ges 2020 Jul;18(7):699-723

Department of Dermatology, Venereology and Allergology, University Hospital, Würzburg, Germany.

The increasingly frequent use of immunomodulatory agents in dermatology requires the observance of specific recommendations for immunization. These recommendations are developed and regularly updated by the German Standing Committee on Vaccination (STIKO), an independent advisory group at the Robert Koch Institute. Dermatological patients on immunosuppressive treatment should ideally receive all vaccinations included in the standard immunization schedule. Additionally, it is recommended that they also undergo vaccination against the seasonal flu, pneumococci, and herpes zoster (inactivated herpes zoster subunit vaccine for patients ≥ 50 years). Additional immunizations against Haemophilus influenzae type B, hepatitis B and meningococci may be indicated depending on individual comorbidities and exposure risk. Limitations of use, specific contraindications and intervals to be observed between vaccination and immunosuppression depend on the immunosuppressive agent used and its dosing. Only under certain conditions may live-attenuated vaccines be administered in patients on immunosuppressive therapy. Given its strong suppressive effect on the humoral immune response, no vaccines - except for flu shots - should be given within six months after rituximab therapy. This CME article presents current recommendations on immunization in immunocompromised individuals, with a special focus on dermatological patients. Its goal is to enable readers to provide competent counseling and to initiate necessary immunizations in this vulnerable patient group.
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http://dx.doi.org/10.1111/ddg.14156DOI Listing
July 2020

Impfen bei Immunsuppression: ein Leitfaden für die dermatologische Praxis.

J Dtsch Dermatol Ges 2020 Jul;18(7):699-725

Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg.

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http://dx.doi.org/10.1111/ddg.14156_gDOI Listing
July 2020

Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation.

Neuron 2020 09 17;107(5):891-908.e8. Epub 2020 Jul 17.

Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington's disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.
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http://dx.doi.org/10.1016/j.neuron.2020.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486278PMC
September 2020

Pressure-Induced Enhancement of Broad-Band White Light Emission in Butylammonium Lead Bromide.

J Phys Chem Lett 2020 May 8;11(10):4131-4137. Epub 2020 May 8.

Department of Earth System Sciences, Yonsei University, Seoul 03722, Korea.

Two-dimensional (2D) perovskites with inorganic layers sandwiched between hydrophobic organic cations possess excellent lighting properties and moisture stability. However, broad-band white light (BWL) is limited to a selected class of perovskites. Our understanding of the intrinsic relationship of BWL and structure and the systemic study of their mechanism of photoluminescence (PL) emission caused by self-trapped excitons in 2D perovskites are still lacking. Here, we show a pressure-induced PL enhancement (PIPE) and a remarkable BWL emission covering the whole visible spectrum in BAPbBr. Synchrotron X-ray diffraction shows cooperative octahedral tilting below 1 GPa and a Jahn-Teller-like octahedral distortion above 5.3(1) GPa driving the PIPE and BWL emission, respectively. The BWL and structural distortion are retained down to 1.8(1) GPa. Our study provides important insights into the intrinsic correlation between optical properties and structural changes and establishes pressure as a new means for tailoring the use of perovskites in lighting devices.
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http://dx.doi.org/10.1021/acs.jpclett.0c01160DOI Listing
May 2020

The Tapetal Major Facilitator NPF2.8 Is Required for Accumulation of Flavonol Glycosides on the Pollen Surface in .

Plant Cell 2020 05 10;32(5):1727-1748. Epub 2020 Mar 10.

Department of Cell and Metabolic Biology, Leibniz Institute of Plant Biochemistry, D-06120 Halle (Saale), Germany

The exine of angiosperm pollen grains is usually covered by a complex mix of metabolites including pollen-specific hydroxycinnamic acid amides (HCAAs) and flavonoid glycosides. Although the biosynthetic pathways resulting in the formation of HCAAs and flavonol glycosides have been characterized, it is unclear how these compounds are transported to the pollen surface. In this report we provide several lines of evidence that a member of the nitrate/peptide transporter family is required for the accumulation and transport of pollen-specific flavonol 3-o-sophorosides, characterized by a glycosidic -,-linkage, to the pollen surface of Arabidopsis (). Ectopic, transient expression in epidermal leaf cells demonstrated localization of this flavonol sophoroside transporter (FST1) at the plasmalemma when fused to green fluorescent protein (GFP). We also confirmed the tapetum-specific expression of by reporter lines driven by the promoter. In vitro characterization of FST1 activity was achieved by microbial uptake assays based on C-labeled flavonol glycosides. Finally, rescue of an insertion mutant by complementation with an genomic fragment restored the accumulation of flavonol glycosides in pollen grains to wild-type levels, corroborating the requirement of FST1 for transport of flavonol-3-o-sophorosides from the tapetum to the pollen surface.
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http://dx.doi.org/10.1105/tpc.19.00801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203936PMC
May 2020

Association of Vitamin D Receptor Gene Polymorphisms With Melanoma Risk: A Meta-analysis and Systematic Review.

Anticancer Res 2020 Feb;40(2):583-595

Department of Dermatology, Saarland University, Campus Homburg, Homburg, Germany

Background/aim: Increasing evidence indicates a relevance of the vitamin D endocrine system for pathogenesis of malignant melanoma. We performed a systematic review and meta-analysis to update previous reports that investigated the association between vitamin D receptor (VDR) gene polymorphisms and melanoma risk.

Materials And Methods: A comprehensive literature search (PubMed, ISI Web of Science) identified a total of 14 studies that were eligible for inclusion in our meta-analysis. In the statistical analysis, the ORs and the 95% CIs were calculated for the dominant and recessive models for seven VDR gene polymorphisms, namely rs2228570 (FokI), rs731236 (TaqI), rs1544410 (BsmI), rs4516035 (A-1012G), rs11568820 (Cdx2), rs7975232 (ApaI) and rs739837 (BglI). Results were illustrated in Forest Plots. Publication bias was tested using Funnel Plots and the Egger's test.

Results: Our meta-analysis showed in the dominant model (Bb + BB vs. bb) a significant association of a 15% risk reduction in malignant melanoma incidence for carriers of the rarer allele B of rs1544410 (Bsml). Notably, the dominant model (Ff + ff vs. FF) of rs2228570 (FokI) demonstrates that carriers of the rarer allele f are 22% more likely to develop malignant melanoma. For rs7975232 (ApaI), there is a 20% higher risk of melanoma for carriers of the rarer a allele (Aa + aa vs. AA). The results of the meta-analysis revealed no significant association between melanoma risk and the other investigated VDR polymorphisms.

Conclusion: The VDR variants FokI, ApaI and BsmI may influence the susceptibility to developing melanoma. These findings support the concept, that the vitamin D endocrine system is of importance for pathogenesis of malignant melanoma.
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http://dx.doi.org/10.21873/anticanres.13988DOI Listing
February 2020

Probing Compositional Order in Atomic Columns: STEM Simulations Beyond the Virtual Crystal Approximation.

Microsc Microanal 2020 Feb;26(1):46-52

Department of Chemistry and Biochemistry and NanoCenter, University of South Carolina, 631 Sumter St., Columbia, SC29208, USA.

Taking advantage of recent advances in parallel computing, we studied compositional disorder along metal-oxygen atomic columns in a complex Mo,V-oxide bronze using multislice frozen-phonon calculations. Commonly, the virtual crystal approximation (VCA) is used to model compositional disorder at crystallographic sites in a unit cell for a number of different theoretical and experimental techniques. In the VCA, a weighted linear sum of atomic properties is used to approximate the model structure. When using the VCA, the extracted V content of Mo,V-O columns from experimental high-angle annular dark-field (HAADF) images will be about half the V content estimated from simulations, considering the distinct cation ordering. This discrepancy is larger than the spread of HAADF signals of different configurational orders at a given V concentration, which can be up to 20%. Certain "isophilic" atomic arrangements along the column can be distinguished from more random ones using HAADF-STEM imaging. The trends and ratios of the simulated intensity spreads due to different compositional ordering along 11 M-O columns along the c-axis of the Mo,V oxide bronze qualitatively match those observed in experimental HAADF-STEM data. Instrumental and sample-based noise adds to the variability but does not significantly distort the relative ratios of column intensity variation. We observed that we only required seven random configurations to represent the intensity variations along columns.
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http://dx.doi.org/10.1017/S1431927619015198DOI Listing
February 2020

A piperic acid CoA ligase produces a putative precursor of piperine, the pungent principle from black pepper fruits.

Plant J 2020 05 13;102(3):569-581. Epub 2020 Jan 13.

Department of Cell and Metabolic Biology, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle, Germany.

Black pepper (Piper nigrum L.) is known for its high content of piperine, a cinnamoyl amide derivative regarded as largely responsible for the pungent taste of this widely used spice. Despite its long history and worldwide use, the biosynthesis of piperine and related amides has been enigmatic up to now. In this report we describe a specific piperic acid CoA ligase from immature green fruits of P. nigrum. The corresponding enzyme was cloned and functionally expressed in E. coli. The recombinant enzyme displays a high specificity for piperic acid and does not accept the structurally related feruperic acid characterized by a similar C-2 extension of the general C6-C3 phenylpropanoid structure. The enzyme is also inactive with the standard set of hydroxycinnamic acids tested including caffeic acid, 4-coumaric acid, ferulic acid, and sinapic acid. Substrate specificity is corroborated by in silico modelling that suggests a perfect fit for the substrate piperic acid to the active site of the piperic acid CoA ligase. The CoA ligase gene shows its highest expression levels in immature green fruits, is also expressed in leaves and flowers, but not in roots. Virus-induced gene silencing provided some preliminary indications that the production of piperoyl-CoA is required for the biosynthesis of piperine in black pepper fruits.
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http://dx.doi.org/10.1111/tpj.14652DOI Listing
May 2020

A Critical Appraisal of Strategies to Optimize Vitamin D Status in Germany, a Population with a Western Diet.

Nutrients 2019 Nov 6;11(11). Epub 2019 Nov 6.

Center for Clinical and Experimental Photodermatology, Saarland University, Campus Homburg, 66421 Homburg, Germany.

During the last decade, our scientific knowledge of the pleiotropic biological effects of vitamin D metabolites and their relevance to human health has expanded widely. Beyond the well-known key role of vitamin D in calcium homeostasis and bone health, it has been shown that vitamin D deficiency is associated with a broad variety of independent diseases, including several types of cancer, and with increased overall mortality. Moreover, recent findings have demonstrated biological effects of the vitamin D endocrine system that are not mediated via activation of the classical nuclear vitamin D receptor (VDR) by binding with high affinity to its corresponding ligand, the biologically active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)D). In contrast, many of these new biological effects of vitamin D compounds, including regulation of the circadian clock and many metabolic functions, are mediated by other vitamin D metabolites, including 20-hydroxyvitamin D and 20,23-dihydroxyvitamin D, and involve their binding to the aryl hydrocarbon receptor (AhR) and retinoid-orphan receptor (ROR). In most populations, including the German population, UVB-induced cutaneous vitamin D production is the main source for fulfilling the human body's requirements of vitamin D. However, this causes a dilemma because solar or artificial UVR exposure is associated with skin cancer risk. In addition to UVB-induced vitamin D production in skin, in humans, there are two other possible sources of vitamin D: from diet and supplements. However, only a few natural foods contain substantial amounts of vitamin D, and in most populations, the dietary source of vitamin D cannot fulfill the body´s requirements. Because an increasing body of evidence has convincingly demonstrated that vitamin D deficiency is very common worldwide, it is the aim of this paper to (i) give an update of the vitamin D status in a population with a western diet, namely, the German population, and to (ii) develop strategies to optimize the vitamin D supply that consider both the advantages as well as the disadvantages/risks of different approaches, including increasing vitamin D status by dietary intake, by supplements, or by UVB-induced cutaneous synthesis of vitamin D.
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http://dx.doi.org/10.3390/nu11112682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893762PMC
November 2019

Ultrasensitive quantitative measurement of huntingtin phosphorylation at residue S13.

Biochem Biophys Res Commun 2020 01 31;521(3):549-554. Epub 2019 Oct 31.

Department of Neuroscience, IRBM S.p.A, Via Pontina Km 30.600, 00071, Pomezia, Rome, Italy.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of a CAG triplet repeat (encoding for a polyglutamine tract) within the first exon of the huntingtin gene. Expression of the mutant huntingtin (mHTT) protein can result in the production of N-terminal fragments with a robust propensity to form oligomers and aggregates, which may be causally associated with HD pathology. Several lines of evidence indicate that N17 phosphorylation or pseudophosphorylation at any of the residues T3, S13 or S16, alone or in combination, modulates mHTT aggregation, subcellular localization and toxicity. Consequently, increasing N17 phosphorylation has been proposed as a potential therapeutic approach. However, developing genetic/pharmacological tools to quantify these phosphorylation events is necessary in order to subsequently develop tool modulators, which is difficult given the transient and incompletely penetrant nature of such post-translational modifications. Here we describe the first ultrasensitive sandwich immunoassay that quantifies HTT phosphorylated at residue S13 and demonstrate its utility for specific analyte detection in preclinical models of HD.
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http://dx.doi.org/10.1016/j.bbrc.2019.09.097DOI Listing
January 2020

Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node.

J Clin Oncol 2019 11 26;37(32):3000-3008. Epub 2019 Sep 26.

Eberhard Karls University of Tübingen, Tübingen, Germany.

Purpose: We have previously reported on the 3-year results of the phase III German Dermatologic Cooperative Oncology Group trial (DeCOG; ClinicalTrials.gov identifier: NCT02434107) comparing distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS) in patients with positive sentinel lymph-node biopsy who were randomly assigned to complete lymph node dissection (CLND) or observation. Here, we report the final analysis with 72 months of median follow up.

Patients And Methods: The multicenter randomized phase III trial included patients with cutaneous melanoma of the trunk and extremities who were randomly assigned (1:1) to undergo CLND or observation. DMFS was analyzed as the primary end point, and RFS, OS, and recurrences in the regional lymph node basin were secondary end points. The analysis was by intention to treat. Disease and survival information were collected quarterly.

Results: From January 2006 to December 2014, 5,547 patients were screened to identify 1,256 with metastases in the sentinel lymph node (SLN). Of these, 483 (39%) were included: 241 in the observation arm and 242 in the CLND arm. In the final analysis, median follow up was 72 months (interquartile range, 67-77 months). No significant treatment-related difference was seen in the 5-year DMFS between the observation and CLND arms (67.6% 64.9%, respectively; hazard ratio [HR], 1.08; = .87). The 5-year RFS and OS also showed no difference (HR, 1.01 and 0.99, respectively). Grade 3 and 4 adverse effects occurred in 32 patients (13%) in the CLND arm; lymphedema (n = 20) and delayed wound healing (n = 5) were most common and no serious adverse events were reported.

Conclusion: The final results of the German Dermatologic Cooperative Oncology Group trial with a median follow up of 72 months showed higher event rates, but similar HRs compared with those at the 3-year analysis. These results confirm that immediate CLND in SLN-positive patients is not superior to observation in terms of DMFS, RFS, or OS and support not recommending CLND in patients with SLN metastasis.
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http://dx.doi.org/10.1200/JCO.18.02306DOI Listing
November 2019