Zytokinbestimmung im Verlauf der Schwangerschaft und deren Bedeutung bei intrauterinen Infektionen

Infektionen werden als Hauptursache für die Entwicklung vorzeitiger Wehentätigkeit mit nachfolgender Frühgeburtlichkeit angesehen. Durch eine aszendierende Infektion kann sich eine intrauterine Infektion ausbilden, welche einen akuten Gefahrenzustand für Mutter und Kind darstellt. Eine frühzeitige Diagnose ist anhand klinischer Zeichen und laborchemischer Parameter wie CRP nicht immer sicher möglich. Die Parameter sind zu unspezifisch und bei subklinischen Infektionen nicht vorhanden. Durch die vorzeitige Schwangerschaftsbeendigung lassen sich zwar mögliche infektionsbedingte Gefahren für Mutter und Kind reduzieren, doch sind die Patienten häufig mit den Folgen einer Frühgeburt konfrontiert. Eine möglichst spezifische und sensitive Diagnostik hätte also den Vorteil, die Rate an durch den Geburtshelfer verursachten Frühgeburtlichkeit und die Morbidität für Mutter und Kind zu senken. In dieser Arbeit wurden die Zytokine IL-6, IL-15, Pro-IL1β und CXCL10/IP-10 auf ihre Konzentration im Fruchtwasser bei Patientinnen mit Anhalt auf eine intrauterine Infektion und bei Patientinnen ohne Infektionsanhalt untersucht. Hierfür schlossen wir insgesamt 215 Patientinnen ein und unterteilten diese in folgende Gruppen: Fruchtwasser, das im Rahmen einer Amniozentese gewonnen wurde, teilten wir der Gruppe „Amniozentesen“ (n=81) zu. Während der Geburt entnommene Fruchtwasserproben teilten wir je nach Geburtsmodus den Gruppen „Spontangeburten“ (n=20) – im Rahmen einer Spontangeburt durch Amniotomie - oder „Sectiones“ (n=101) – im Rahmen einer operativen Entbindung - zu. Die vierte Gruppe wurde gebildet aus Fruchtwasserproben, die wir im Rahmen einer Amniozentese bei Verdacht auf Amnioninfektionssyndrom erhielten (n=13). Bezüglich der Konzentrationen im Fruchtwasser konnte kein signifikanter Unterschied zwischen Patientinnen mit Infektionsverdacht und den Kontrollgruppen für die Zytokine IL-6, IL- 15 und CXCL10/IP-10 nachgewiesen werden. Ein signifikanter Unterschied ergab sich lediglich für das Zytokin Pro-IL-1β. Auch konnten unsere Untersuchungen zeigen, dass die Zytokinexpression von den Faktoren „maternales Alter“, „Gestationsalter“ und „fetales Geschlecht“ unabhängig ist. Zusammenfassend könnte sich Pro-IL-1β als Infektionsmarker eignen. Hierzu sollten in Zukunft aber noch weitere Studien mit größerem Patientenkollektiv durchgeführt werden

Design of chemical space networks incorporating compound distance relationships

Networks, in which nodes represent compounds and edges pairwise similarity relationships, are used as coordinate-free representations of chemical space. So-called chemical space networks (CSNs) provide intuitive access to structural relationships within compound data sets and can be annotated with activity information. However, in such similarity-based networks, distances between compounds are typically determined for layout purposes and clarity and have no chemical meaning. By contrast, inter-compound distances as a measure of dissimilarity can be directly obtained from coordinate-based representations of chemical space. Herein, we introduce a CSN variant that incorporates compound distance relationships and thus further increases the information content of compound networks. The design was facilitated by adapting the Kamada-Kawai algorithm. Kamada-Kawai networks are the first CSNs that are based on numerical similarity measures, but do not depend on chosen similarity threshold values

Pan‑cancer analysis of transmembrane protease serine 2 and cathepsin L that mediate cellular SARS‑CoV‑2 infection leading to COVID-19

Severe acute respiratory syndrome (SARS) coronavirus‑2 (SARS‑CoV2) is the cause of a new disease (COVID‑19) which has evolved into a pandemic during the first half of 2020. Older age, male sex and certain underlying diseases, including cancer, appear to significantly increase the risk for severe COVID‑19. SARS‑CoV‑2 infection of host cells is facilitated by the angiotensin‑converting enzyme 2 (ACE‑2), and by transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL). With the exception of ACE‑2, a systematic analysis of these two other SARS‑CoV2 infection mediators in malignancies is lacking. Here, we analysed genetic alteration, RNA expression, and DNA methylation of TMPRSS2 and CTSL across a wide spectrum of tumors and controls. TMPRSS2 was overexpressed in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), uterine corpus endometrial carcinoma and uterine carcinosarcoma, with PRAD and READ exhibiting the highest expression of all cancers. CTSL was upregulated in lymphoid neoplasm diffuse large B‑cell lymphoma, oesophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, lower grade glioma, pancreatic adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, and thymoma. Hypo‑methylation of both genes was evident in most cases where they have been highly upregulated. We have expanded on our observations by including data relating to mutations and copy number alterations at pan‑cancer level. The novel hypotheses that are stemming out of these data need to be further investigated and validated in large clinical studies

Simultaneous prediction of four ATP-binding cassette transporters' substrates using multi-label QSAR

Efflux by the ATP-binding cassette (ABC) transporters affects the pharmacokinetic profile of drugs and it has been implicated in drug-drug interactions as well as its major role in multi-drug resistance in cancer. It is therefore important for the pharmaceutical industry to be able to understand what phenomena rule ABC substrate recognition. Considering a high degree of substrate overlap between various members of ABC transporter family, it is advantageous to employ a multi-label classification approach where predictions made for one transporter can be used for modeling of the other ABC transporters. Here, we present decision tree-based QSAR classification models able to simultaneously predict substrates and non-substrates for BCRP1, P-gp/MDR1 and MRP1 and MRP2, using a dataset of 1493 compounds. To this end, two multi-label classification QSAR modelling approaches were adopted: Binary Relevance (BR) and Classifier Chain (CC). Even though both multi-label models yielded similar predictive performances in terms of overall accuracies (close to 70), the CC model overcame the problem of skewed performance towards identifying substrates compared with non-substrates, which is a common problem in the literature. The models were thoroughly validated by using external testing, applicability domain and activity cliffs characterization. In conclusion, a multi-label classification approach is an appropriate alternative for the prediction of ABC efflux. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation.

In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought

Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking

Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway

Plate-based diversity subset screening generation 2: An improved paradigm for high throughput screening of large compound files

High throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time-consuming and costly and the use of subsets as an efficient alternative to screening these large collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity, or biological target focus. Previously we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer