Follicular targeted drug delivery via nanocarriers in the treatment of (auto)inflammatory skin diseases

Today, it is widely known that nanoparticles (NPs) maximize follicular and minimize interfollicular drug delivery, thereby reducing systemic drug levels and severe side effects. Non-life-threatening skin diseases, like Alopecia Areata (AA), a reversible hair loss disorder associated with major negative effect on quality of life, lack of sufficient treatment, among other things caused by negative risk-benefit profiles of potent drugs such as Janus Kinase inhibitors, e.g., tofacitinib (TFB). Therefore, NPs are predestined to enable a targeted drug delivery into hair follicles (HFs) for a safer treatment against skin diseases like AA. As proof of concept, the NP deposition inside human scalp HFs was studied by adjustment of a quantification method for human forearm HFs. Investigations on healthy human, AAaffected hairless and hairy body donor scalp HFs showed that NP uptake into HFs depends on follicular density but is independent of hair shaft presence and hair type. Accordingly, TFB-loaded NPs were developed. Previously-synthesized squalenyl derivative NPs exceeded other approaches, demonstrating high drug loading capacity, biocompatibility, colloidal stability, and enhanced follicular delivery in an ex vivo pig ear model, which was supported by a biological effect in an in vivo dermatitis mouse model. Further investigations on follicular targeted delivery via NPs for a safe and potent treatment of skin diseases, leading to translation into the clinics, are highly desired.Nanopartikel (NP) maximieren den follikulären und minimieren den interfollikulären Arzneistofftransport. Sie reduzieren dabei systemische Wirkstoffspiegel und schwere Nebenwirkungen. Für nicht lebensbedrohliche Hauterkrankungen wie Alopecia Areata (AA) gibt es keine zufriedenstellende Behandlung, da unter anderem für potente Arzneistoffe wie Janus Kinase Inhibitor Tofacitinib (TFB) negative Nutzen-Risiko-Verhältnisse existieren. Daher ist ein gezielter Arzneistofftransport durch NP in Haarfollikeln (HF) prädestiniert, um eine sichere und effiziente Behandlung von AA zu ermöglichen. Die Machbarkeitsstudie untersuchte die NP-Deposition in menschlichen Kopfhaut-HF unter Zuhilfenahme einer Quantifizierungsmethode für menschliche Unterarm-HF. Sowohl Untersuchungen an gesunden, an AA-befallenen haarlosen als auch an Körperspenden Kopfhaut-HF zeigten, dass die NP-Aufnahme in HF abhängig ist von der Follikeldichte, jedoch nicht vom Haarschaft-Vorhandensein oder dem Haartyp. TFB beladene Squalen-Derivat-NP überzeugten durch hohe Arzneistoffbeladung, Biokompatibilität, kolloidale Stabilität und verbesserten follikulären Arzneistofftransport – gezeigt im Ex-vivo-Schweineohrmodell und unterstützt durch eine biologische Antwort im In-vivo-Dermatitis-Mausmodell. Weitere Untersuchungen des follikulären gezielten Arzneistofftransports mit NP zur Erreichung einer sicheren und effizienten Behandlung von Hauterkrankungen, welche zu einer Translation in die Klinik führen, sind sehnlichst erwünscht.Dr. Rolf M. Schwiete Stiftung, Mannheim, German

The interplay of incentives and mode-choice design in self-administered mixed-mode surveys

Self-administered mixed-mode surveys are increasingly used as an alternative to face-to-face surveys for collecting data from the general population. However, little is known about how decisions regarding the incentive scheme and the mode-choice design jointly affect key outcomes such as response rates, net sample composition, and survey costs. To study this, we drew a probability sample of the residential population of the city of Mannheim, Germany (N = 2,980) and randomly assigned target persons to one of four incentive schemes (€0, €1, or €2 prepaid incentive on first contact, and €2 delayed prepaid incentive) and one of two mode-choice designs (concurrent or sequential [web-push]). Our results indicate that small prepaid monetary incentives work better in concurrent than in sequential designs. Moreover, a €2 prepaid incentive in a concurrent design proved particularly successful for older target persons, probably reinforcing their sense of trust and reciprocity, while also fitting better with their survey-mode preferences. Finally, a €2 delayed prepaid incentive in a sequential design primarily motivated target persons aged under 50 years. This combination of incentive scheme and mode-choice design also proved to be most cost-effective in that age group. Based on our results, we recommend using sampling frame information on age to address different age groups with different combinations of incentive scheme and mode-choice design. This may help to maximize response rates, achieve a balanced net sample composition, and minimize survey costs

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

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 ex vivo 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 v/v). 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 in vivo efficacy and safety. These findings support the potential of TFB SqD NPs for developing a long-term topical therapy of AA

A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms

Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter-gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI-tobramycin (Tob) combination against PA biofilms using a tailor-made squalene-derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32-fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker-mediated therapy against PA infections opening up avenues for preclinical development

Kommunikation in Suizid-Foren. Eine inhaltsanalytische Untersuchung von Beiträgen der Online-Foren-Nutzer

Weltweit nehmen sich etwa 800.000 Menschen jährlich das Leben (vgl. World Health Organization 2014, 6). In Deutschland sterben 10.000 Menschen pro Jahr an Suizid (vgl. Statistisches Bundesamt 2016b). Die Gründe für die Selbsttötung sind vielfältig. Die vorliegende Arbeit untersucht das Phänomen, dass sich Menschen in Foren über ihre persönlichen Suizidgedanken austauschen, das Phänomen der Suizid-Foren. Dies tun sie sowohl auf präventive Art, als auch auf suizidfördernde Art. Die empirische Inhaltsanalyse zeigt, welche Kommunikationsinhalte zum Zeitpunkt 2015 in Deutschland zentral sind und wie sich die Online-Kommunikation in Suizid-Foren ausgestaltet. Insgesamt sind es drei Foren, die zum Zeitpunkt 2015 zentral für die Kommunikationsanalyse sind. Davon ist ein Forum pro-suizidal ausgestaltet, in diesem häufen sich Methodendiskussion, Suizidankündigungen, Verabredungen zum Suizid sowie der Austausch über suizidale Orte. Das Forenklima ist weitestgehend destruktiv. Die anderen beiden Foren sind Mischformen, bei denen der suizidpräventive Anteil sehr hoch ist. Ihnen liegt eine positive Forenstimmung zugrunde, die zentralen Themenkategorien sind die Berichterstattung über die eigene Geschichte, über Erfahrungen mit Ärzten und Therapeuten und die Bitte um Unterstützung. Die beiden Foren gelten jedoch nicht als reine Selbsthilfeforen, da auch suizidfördernde Inhalte Platz finden, die bei suizidalen Menschen triggernde1 Effekte haben könnten.The rate of suicide amounts to 800.000 people per year worldwide. Around 10.000 people yearly taking their own life in Germany. The causalities for suicide are various and differ from each other. This scientific paper examines the phenomenon of people who are talking about their suicidal thinkings in forums. It is the phenomenon of suicidal forums. People communicate either in a suicide preventive way or to strengthen their suicidal believings. The following empirical analysis shows the central content concerning communication in German suicidal forums in the year 2015. Moreover it shows how online communication is structured and arranged in suicidal forums. In this case three forums provide the basis of the empirical communication analysis. This analysis outlines that one of these forums is pro-suicidal oriented, where methods of execution, announcements of suicides, arrangements for group suicides and recommendations for execution places are discussed. The environment of this forum can be described as mostly destructive. The other two forums can be described as hybrid formats, whereas the preventive content is predominant to the pro-suicidal one. The atmosphere of these two forums can be described as positive, where personal stories and experiences with doctors and therapists are exchanged to support each other. Nonetheless, both forums can’t be described as pure preventive self-help forums, since pro-suicidal content is also located in these places, which can cause triggering effects on suicidal individuals

Adaptive upregulation of DNA repair genes following benzo(a)pyrene diol epoxide protects against cell death at the expense of mutations

A coordinated and faithful DNA damage response is of central importance for maintaining genomic integrity and survival. Here, we show that exposure of human cells to benzo(a)pyrene 9,10-diol-7,8-epoxide (BPDE), the active metabolite of benzo(a)pyrene (B(a)P), which represents a most important carcinogen formed during food preparation at high temperature, smoking and by incomplete combustion processes, causes a prompt and sustained upregulation of the DNA repair genes DDB2, XPC, XPF, XPG and POLH. Induction of these repair factors on RNA and protein level enhanced the removal of BPDE adducts from DNA and protected cells against subsequent BPDE exposure. However, through the induction of POLH the mutation frequency in the surviving cells was enhanced. Activation of these adaptive DNA repair genes was also observed upon B(a)P treatment of MCF7 cells and in buccal cells of human volunteers after cigarette smoking. Our data provide a rational basis for an adaptive response to polycyclic aromatic hydrocarbons, which occurs however at the expense of mutations that may drive cancer formation

The COP9 signalosome counteracts the accumulation of cullin SCF ubiquitin E3 RING ligases during fungal development

Defects in the COP9 signalosome (CSN) impair multicellular development, including embryonic plant or animal death or a block in sexual development of the fungus Aspergillus nidulans. CSN deneddylates cullin-RING ligases (CRLs), which are activated by covalent linkage to ubiquitin-like NEDD8. Deneddylation allows CRL disassembly for subsequent reassembly. An attractive hypothesis is a consecutive order of CRLs for development, which demands repeated cycles of neddylation and deneddylation for reassembling CRLs. Interruption of these cycles could explain developmental blocks caused by csn mutations. This predicts an accumulation of neddylated CRLs exhibiting developmental functions when CSN is dysfunctional. We tested this hypothesis in A. nidulans, which tolerates reduced levels of neddylation for growth. We show that only genes for CRL subunits or neddylation are essential, whereas CSN is primarily required for development. We used functional tagged NEDD8, recruiting all three fungal cullins. Cullins are associated with the CSN1/CsnA subunit when deneddylation is defective. Two CRLs were identified which are specifically involved in differentiation and accumulate during the developmental block. This suggests that an active CSN complex is required to counteract the accumulation of specific CRLs during development.Deutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft [SPP 1365, FOR 1334, SFB 860]Volkswagen-StiftungVolkswagenStiftungFonds der Chemischen IndustrieFonds der Chemischen IndustrieEraNet PathoGenoMicsEraNet PathoGenoMicsAlexander-von-Humboldt-StiftungAlexandervonHumboldtStiftun

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

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 ex vivo 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 v/v). 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 in vivo efficacy and safety. These findings support the potential of TFB SqD NPs for developing a long-term topical therapy of AA

The COP9 signalosome counteracts the accumulation of cullin SCF ubiquitin E3 RING ligases during fungal development

Defects in the COP9 signalosome (CSN) impair multicellular development, including embryonic plant or animal death or a block in sexual development of the fungus Aspergillus nidulans. CSN deneddylates cullin-RING ligases (CRLs), which are activated by covalent linkage to ubiquitin-like NEDD8. Deneddylation allows CRL disassembly for subsequent reassembly. An attractive hypothesis is a consecutive order of CRLs for development, which demands repeated cycles of neddylation and deneddylation for reassembling CRLs. Interruption of these cycles could explain developmental blocks caused by csn mutations. This predicts an accumulation of neddylated CRLs exhibiting developmental functions when CSN is dysfunctional. We tested this hypothesis in A. nidulans, which tolerates reduced levels of neddylation for growth. We show that only genes for CRL subunits or neddylation are essential, whereas CSN is primarily required for development. We used functional tagged NEDD8, recruiting all three fungal cullins. Cullins are associated with the CSN1/CsnA subunit when deneddylation is defective. Two CRLs were identified which are specifically involved in differentiation and accumulate during the developmental block. This suggests that an active CSN complex is required to counteract the accumulation of specific CRLs during development.Deutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft [SPP 1365, FOR 1334, SFB 860]Volkswagen-StiftungVolkswagenStiftungFonds der Chemischen IndustrieFonds der Chemischen IndustrieEraNet PathoGenoMicsEraNet PathoGenoMicsAlexander-von-Humboldt-StiftungAlexandervonHumboldtStiftun