The spectrum-averaged cross section investigation of 117Sn(n,n')117mSn and 67Zn(n,p)67Cu reactions.

The spectrum averaged cross sections (SACS) in standard neutron field, e.g. 252Cf(s.f.), is a preferable tool for cross section evaluation and validation. A set of reaction measurements with high energy thresholds was previously performed. The presented work focuses on lower energy threshold reactions, namely on the inelastic scattering of the tin foil, more specifically the reaction 117Sn(n,n')117mSn, and the zinc foil reaction, namely 67Zn(n,p)67Cu. These reactions are of special interest due to their intermediate energy range, which is essential in classical reactor dosimetry and fast reactor dosimetry. The experiments were carried out in a standard neutron field formed by 252Cf(s.f.) source in Rez. The experimental results were compared with calculations using MCNP6.2, ENDF/B-VII.1 transport library, and ENDF/B-VIII.0 and IRDFF-II cross section data library. Additionally, the calculations using CEA code DARWIN/PEPIN2 using JEFF-3.0/A were executed. The obtained experimental SACS of previously measured reactions were in good agreement with the SACS calculated using the IRDFF-II library. Additionally, the calculational reaction rate of 67Zn(n,p)67Cu was in accordance with the experimental data in case of ENDF/B-VIII.0 nuclear data library. Moreover, the calculational results of 117Sn(n,n')117mSn obtained by DARWIN/PEPIN2 code (using JEFF-3.0/A nuclear data library) are closest to the experimental results.

Experimental validation of 23Na( γ, n)22Na cross section.

Photonuclear reactions are gaining importance due to their influence on the shielding and activation of components of widely spread accelerators. Therefore, there is a need for accurate data describing photonuclear reactions. The MT25 microtron operated at NPI was used for validation of cross section in the bremsstrahlung. The gold and copper activation foils with known cross sections were used as flux monitors. The bremsstrahlung spectra was simulated with Geant4 code and the spectral averaged cross section above 10MeV for reaction 23Na(γ, x)22Na was calculated. The experimental result was compared with data from the evaluated data libraries and EXFOR database. It was proved that the facility can be used for validation of cross sections and it was showed that all libraries overestimate the photon cross section on 23Na with the best results with data from JENDL-5 library.

[Conventional and molecular diagnostics in onychomycosis-part 2 : Molecular identification of causative dermatophytes by polymerase chain reaction and sequence analysis of the internal transcribed spacer region of ribosomal DNA]. / Konventionelle und molekulare Diagnostik bei Onychomykose ­ Teil 2 : Molekulare Identifizierung der ursächlichen Dermatophyten mit Polymerasekettenreaktion und Sequenzanalyse der ITS("internal transcribed spacer")-Region der ribosomalen Desoxyribonukleinsäure.

Dermatophyte identification using traditional methods such as optics-based direct fluorescence microscopy and culture is nowadays supplemented by molecular biological methods. The validity of dermatophyte DNA detection with direct uniplex-polymerase chain reaction-enzyme immunoassay (PCR-EIA) in nail samples was proven by sequence analysis of the ribosomal internal transcribed spacer (ITS) region. A total of 108 dermatophytes, isolated from patients with onychomycosis, were positive for Trichophyton rubrum (TR) and Trichophyton interdigitale (TI) in culture and/or uniplex-PCR-EIA. Conventional methods for dermatophyte identification were complemented by direct uniplex-PCR-EIA and sequence analysis of the ribosomal ITS region (18S rRNA, ITS1, 5.8S rRNA, ITS2, 28S rRNA). Of 108 patients (average age 62, median age 73), 56 showed cultural growth with 31 of them being identified as TR and 23 as TI. There was high agreement with the sequence analysis. Surprisingly, the pathogen of a single nail sample was identified as T. quinckeanum (formerly T. mentagrophytes sensu stricto), a rare zoophilic dermatophyte in Germany. A single TI strain turned out to be a misidentified T. tonsurans based on the sequence analysis. In all, 34 of the 52 specimens lacking cultural growth were detected by PCR as TR, and 18 specimens could be identified as TI. The results of dermatophyte identification of culture-negative nail samples were also in agreement with the results of sequence analysis. Molecular biological methods are well applicable, and they show high reliability for direct dermatophyte identification in nail samples without prior cultivation. Especially for nail samples without cultural growth, PCR-based dermatophyte identification was highly specific and sensitive.

[Conventional and molecular diagnostics in onychomycosis-part 1 : Conventional differentiation of dermatophytes-Trichophyton rubrum, Trichophyton interdigitale]. / Konventionelle und molekulare Diagnostik bei Onychomykose ­ Teil 1 : Konventionelle Differenzierung von Dermatophyten ­ Trichophyton rubrum, Trichophyton interdigitale.

Onychomycosis is a common infectious nail disease occurring worldwide. The mycological diagnosis of onychomycosis is primarily used for differential diagnostic differentiation from other, mostly inflammatory nail diseases, such as nail psoriasis or onychodystrophies of other causes. Conventional laboratory diagnostics when onychomycosis is suspected is based on microscopic detection of fungi in the nail material using fluorescence-optical potassium hydroxide preparations and culture of the pathogen. Molecular amplification methods allow a more sensitive and specific identification of the causative dermatophyte. Here, in 108 patients with onychomycosis, the dermatophytes were identified by culture and/or molecular biology using polymerase chain reaction (PCR) and the species identification was confirmed with subsequent sequencing. The dermatophytes were analyzed based on macromorphological and microscopic features. A dermatophyte was cultured in 56 of the 108 patients. Among them were 31 isolates of Trichophyton (T.) rubrum and 25 of T. interdigitale. All species identifications were subsequently confirmed by rDNA sequencing with concordant results in 54 of 56 patients. Two primarily as T. interdigitale identified specimens were revealed to be T. quinckeanum and T. tonsurans by molecular methods. T. quinckeanum, which is a zoophilic dermatophyte and a so-called emerging pathogen in dermatomycology, was isolated here for the first time as the causative agent of onychomycosis. The other dermatophyte, initially thought to be T. interdigitale, turned out to be T. tonsurans on molecular biology. This anthropophilic dermatophyte is also a rarity in onychomycosis. In addition, T. rubrum was identified by PCR in 34 of the 52 nail specimens that did not grow culture, and T. interdigitale in 18 nail specimens. However, the morphological identification of the four different dermatophytes species proved problematic. Neither the colony morphology nor the microscopic features of the dermatophytes allow clear differentiation of the pathogens. Microconidia, macroconidia, chlamydospores, and arthrospores are inconsistent in occurrence, number, microscopic distribution, and shape. The urease activity also did not allow an assignment of the dermatophyte species. These results indicate that the most sensitive detection and reliable identification of causative dermatophytes in onychomycosis is only possible by molecular methods.

Genome architecture and genetic diversity of allopolyploid okra (Abelmoschus esculentus).

The allopolyploid okra (Abelmoschus esculentus) unveiled telomeric repeats flanking distal gene-rich regions and short interstitial TTTAGGG telomeric repeats, possibly representing hallmarks of chromosomal speciation. Ribosomal RNA (rRNA) genes organize into 5S clusters, distinct from the 18S-5.8S-28S units, indicating an S-type rRNA gene arrangement. The assembly, in line with cytogenetic and cytometry observations, identifies 65 chromosomes and a 1.45 Gb genome size estimate in a haploid sibling. The lack of aberrant meiotic configurations implies limited to no recombination among sub-genomes. k-mer distribution analysis reveals 75% has a diploid nature and 15% heterozygosity. The configurations of Benchmarking Universal Single-Copy Ortholog (BUSCO), k-mer, and repeat clustering point to the presence of at least two sub-genomes one with 30 and the other with 35 chromosomes, indicating the allopolyploid nature of the okra genome. Over 130 000 putative genes, derived from mapped IsoSeq data and transcriptome data from public okra accessions, exhibit a low genetic diversity of one single nucleotide polymorphisms per 2.1 kbp. The genes are predominantly located at the distal chromosome ends, declining toward central scaffold domains. Long terminal repeat retrotransposons prevail in central domains, consistent with the observed pericentromeric heterochromatin and distal euchromatin. Disparities in paralogous gene counts suggest potential sub-genome differentiation implying possible sub-genome dominance. Amino acid query sequences of putative genes facilitated phenol biosynthesis pathway annotation. Comparison with manually curated reference KEGG pathways from related Malvaceae species reveals the genetic basis for putative enzyme coding genes that likely enable metabolic reactions involved in the biosynthesis of dietary and therapeutic compounds in okra.

Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG.

BACKGROUND: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy. METHODS: For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments. RESULTS: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004). CONCLUSIONS: BRAFmut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.

Food allergy - New risks through vegan diet? Overview of new allergen sources and current data on the potential risk of anaphylaxis.

A vegan diet is increasingly en vogue, i.e., a diet based on plants, in which animal products are completely avoided, often for health and environmental reasons. The menu is supplemented with pulses (e.g., soy, lentils, peas), nuts (e.g., cashew, macadamia, almond, pecan, para, walnut) and seeds (e.g., chia, flaxseed) or pseudo-grains (quinoa, buckwheat). Indeed, the product range is expanding to include vegan foods such as milk alternatives (e.g., oat, almond, soy drinks) and cheese or meat substitutes (e.g., soy-based). Food allergies are also on the rise, with an increasing prevalence worldwide. It is worthy of note that the main allergens of anaphylactic reactions to food in adults are predominantly of plant origin, mainly pulses and nuts - the very foods that form the main source of protein in the vegan diet. In this context, allergies to storage proteins (e.g., Gly m 5 and Gly m 6 from soya beans) can lead to severe anaphylactic reactions, while highly processed substitute products containing plant protein isolates (e.g., pea flour) in concentrated form continue to be of particular concern and may therefore be allergologically problematic. In this article, we aim to provide an overview of allergens and emerging allergen sources in vegan foods and highlight the anaphylaxis risk of the vegan diet.

Single-cell transcriptomics reveals prominent expression of IL-14, IL-18, and IL-32 in psoriasis.

RATIONALE: Psoriasis is a chronic inflammatory skin disease involving different cytokines and chemokines. OBJECTIVES: Here we use single-cell transcriptomic analyses to identify relevant immune cell and nonimmune cell populations for an in-depth characterization of cell types and inflammatory mediators in this disease. METHODS: Psoriasis skin lesions of eight patients are analyzed using single-cell technology. Data are further validated by in situ hybridization (ISH) of human tissues, serum analyses of human samples and tissues of a murine model of psoriasis, and by in vitro cell culture experiments. RESULTS: Several different immune-activated cell types with particular cytokine patterns are identified such as keratinocytes, T-helper cells, dendritic cells, macrophages, and fibroblasts. Apart from well-known factors, IL-14 (TXLNA), IL-18, and IL-32 are identified with prominent expression in individual cell types in psoriasis. The percentage of inflammatory cellular subtypes expressing IL-14, IL-18, and IL-32 was significantly higher in psoriatic skin compared with healthy control skin. These findings were confirmed by ISH of human skin samples, in a murine model of psoriasis, in human serum samples, and in in vitro experiments. CONCLUSIONS: Taken together, we provide a differentiated view of psoriasis immune-cell phenotypes that support the role of IL-14, IL-18, and IL-32 in psoriasis pathogenesis.

Characterization of the secondary neutron field inside a cyclotron for production of radiopharmaceuticals.

During production of radiopharmaceuticals, the radiation situation in cyclotron pit is an important parameter, which is being monitored to ensure fulfilment of the limits and conditions of safe operation. The neutron flux in the structural components of the accelerator is also an important parameter, because the secondary neutrons are responsible for activation of cyclotron structural components and may even affect structural changes in it. This paper aims to characterize the neutron field in inner positions of medical accelerator IBA 18/9 by activation detectors and by means of scintillation spectrometry. The backward angle measurement was realized also in special liquid water target (H218O) at U120M cyclotron to confirm the data obtained in IBA 18/9 cyclotron.

Repurposing DPP4 Inhibition to Improve Hair Follicle Activation and Regeneration.

Skin injury and several diseases elicit fibrosis and induce hair follicle (HF) growth arrest and loss. The resulting alopecia and disfiguration represent a severe burden for patients, both physically and psychologically. Reduction of profibrotic factors such as dipeptidyl peptidase 4 (DPP4) might be a strategy to tackle this issue. We show DPP4 overrepresentation in settings with HF growth arrest (telogen), HF loss, and nonregenerative wound areas in mouse skin and human scalp. Topical DPP4 inhibition with Food and Drug Administration/European Medicines Agency-approved sitagliptin on preclinical models of murine HF activation/regeneration results in accelerated anagen progress, whereas treatment of wounds with sitagliptin results in reduced expression of fibrosis markers, increased induction of anagen around wounds, and HF regeneration in the wound center. These effects are associated with higher expression of Wnt target Lef1, known to be required for HF anagen/HF-activation and regeneration. Sitagliptin treatment decreases profibrotic signaling in the skin, induces a differentiation trajectory of HF cells, and activates Wnt targets related to HF activation/growth but not those supporting fibrosis. Taken together, our study shows a role for DPP4 in HF biology and shows how DPP4 inhibition, currently used as oral medication to treat diabetes, could be repurposed into a topical treatment agent to potentially reverse HF loss in alopecia and after injury.

Developments and perspectives in allergology.

Allergology is a key part of dermatological care. This paper reviews current pathophysiological, diagnostic and therapeutic developments in immediate-type allergies. Type-2 inflammation is involved in several allergological diseases such as allergic rhinitis and asthma. Allergen immunotherapy as an important therapeutic procedure is regulated in Germany by an official legal directive (Therapieallergene-Verordnung). Therapeutically, several biologics are already available that target interleukin (IL)-4, -5, -13, -33, or TSLP (thymic stromal lymphopoietin). Collateral efficacy may result in simultaneous treatment of allergological comorbidities. In mast cell mediated diseases (urticaria, anaphylaxis), there is increasing understanding of mast cell activation pathways. Several mast cell receptors such as MRGPRX2 (mas-related G protein coupled receptor X2) and Siglec-8 (sialinic acid binding Ig like lectin-8) as well as intracellular signaling pathways have recently been identified. Clinical trials are underway with drugs acting on mast cell receptors and intracellular signaling, i.e., Bruton's tyrosine kinase inhibitors. Further perspectives on biomarkers, novel therapeutics and unmet needs for future research activities are presented.

Modulation of Dietary Fatty Acids in an Open-Label Study Improves Psoriasis and Dampens the Inflammatory Activation Status.

Obesity and high abdominal fat mass are risk factors for developing the chronic inflammatory skin disease psoriasis. They are associated with increased incidence, prevalence and severity of the disease. A positive effect of weight loss on psoriasis activity has been shown in several studies. Obesity-related factors such as the dysregulation of glucose and lipid metabolism, the activation of adipose tissue and resultant persistent low-grade inflammation have been discussed as links of obesity and inflammatory diseases. Recently, we demonstrated a critical role of free fatty acids (FFAs) in obesity-mediated exacerbation of psoriatic skin inflammation in both mice and humans. In the present study, we translated these findings into a therapeutic intervention. An open-label study focusing on the dietary reduction of FFAs was conducted in patients with mild-to-moderate plaque psoriasis, and disease severity and serum markers of inflammation were analyzed. Here, we show that such a dietary intervention improves psoriatic disease activity independently of weight loss. Diet-related metabolic changes, such as a reduction in saturated free fatty acids (SFAs), may thus be more important than weight loss itself. Moreover, dietary intervention inhibited the overall pro-inflammatory activation status in patients, as shown by analysis of serum inflammatory parameters using the Olink platform. From our pilot study, we conclude that dietary intervention focusing on SFA reduction has the capacity to reduce disease activity and general inflammatory status in psoriasis patients.

Atypical fibroxanthoma and pleomorphic dermal sarcoma - gene expression analysis compared with undifferentiated cutaneous squamous cell carcinoma.

BACKGROUND: The histogenetic origin of atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) has not been definitively elucidated. In addition to a fibroblastic origin, a keratinocytic differentiation is discussed due to strong clinical, histomorphological and molecular genetic similarities with undifferentiated cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS: 56 cases (36 AFXs, 8 PDSs, 12 undifferentiated cSCCs) were evaluated for their clinical, histomorphological, and immunohistochemical characteristics. RNA transcriptome analysis was performed on 18 cases (6 AFXs/PDSs, 6 undifferentiated cSCCs, 6 differentiated cSCCs). RESULTS: Clinically, the strong similarities in age, gender and tumor location were confirmed. Without further immunohistochemical staining, histomorphological differentiation between AFX/PDS and undifferentiated cSCC is often impossible. Principal component analysis of the RNA transcriptome analysis showed that AFX/PDS and differentiated cSCC each formed their own cluster, while the undifferentiated cSCCs fall in between these two groups, but without forming a cluster of their own. When examining differentially expressed genes (DEGs), the heat maps showed that there were cases within the undifferentiated cSCC that were more likely to be AFX/PDS than differentiated cSCC based on their expression profile. CONCLUSIONS: The results provide evidence of molecular similarities between AFX/PDS and undifferentiated cSCC and suggest a common histogenetic origin.