The described technology offers all discovery chemists access to real synthesis automation without any of the barriers that have previously restricted its utility.In highly competitive research environments, the ability to access more complex structural spaces efficiently is a predictor of a company’s ability to generate novel IP-protected small molecule candidates with adequate properties, hence filling their development pipelines. SpiroChem is consistently developing new synthetic methodologies and strategies to access complex molecular structure, thereby facilitating and accelerating small molecule drug discovery. Pushing the limits of what are perceived as complex molecular structures allows SpiroChem and its clients to unleash creativity and explore meaningful chemical spaces, which are under-exploited sources of novel active molecules. In this article, we explain how we differentiated ourselves in a globalized R&D environment and we provide several snapshots of how efficient methodologies can generate complex structures, rapidly.Systemic lupus erythematosus (SLE) is an autoimmune disease that often leads to functional disorder in multiple organs, most often with symptoms related to skin lesions, cardiovascular disease and kidney damage. Although significant efforts have been made to find efficient therapies, it still remains uncured. Furthermore, the current therapy is often associated with adverse side effects and leads to a high economic burden for society. At Saverna Therapeutics, in collaboration with our partners, we initiated a lead discovery program that aims to modulate the biogenesis of miR-155. This non-coding RNA is upregulated in SLE patients and SLE mouse models. We used our drug discovery platform based on iterative fragment-based screening by nuclear magnetic resonance (NMR) and machine learning to identify ligands of pre-miR-155. After several iterations and chemical modifications, we have identified compounds that show structure-activity relationships in cellular assays. These inhibitors reduced the level of miR-155 as well as its associated inflammatory protein TNF α whereas the cells remained viable during exposure of the compounds.

Obesity in children and adolescents is associated with increased morbidity and mortality due to multisystemic impairment, including deleterious changes in lung function, which are poorly understood.

To perform a systematic review to assess lung function in children and adolescents affected by obesity and to verify the presence of pulmonary changes due to obesity in individuals without previous or current respiratory diseases.

A systematic search was performed in the MEDLINE-PubMed (Medical Literature Analysis and Retrieval System Online), Embase (Excerpta Medica Database) and VHL (Virtual Health Library/Brazil) databases using the terms “Lung Function” and “Pediatric Obesity” and their corresponding synonyms in each database. A period of 10 years was considered, starting in February/2008. After the application of the filters, 33 articles were selected. Using the PICOS strategy, the following information was achieved (Patient) children and adolescents; (Intervention/exposure) obesity; (Control) healthy c reach a consensus on lung function changes in children and adolescents with obesity, highlighting the need for more publications on this topic with a standardized methodology.

Understanding the drivers of recurrence in aggressive prostate cancer requires detailed molecular and genomic understanding in order to aid therapeutic interventions. We provide here a case report of histological, transcriptional, proteomic, immunological, and genomic features in a longitudinal study of multiple biopsies from diagnosis, through treatment, and subsequent recurrence.

Here we present a case study of a male in 70s with high-grade clinically-localised acinar adenocarcinoma treated with definitive hormone therapy and radiotherapy. Ro 61-8048 clinical trial The patient progressed rapidly with rising PSA and succumbed without metastasis 52months after diagnosis. We identified the expression of canonical histological markers of neuroendocrine PC (NEPC) including synaptophysin, neuron-specific enolase and thyroid transcription factor 1, as well as intact AR expression, in the recurrent disease only. The resistant disease was also marked by an extremely low immune infiltrate, extensive genomic chromosomal aberrations, and overactivity in molecular hallmarks of NEPC disease including Aurora kinase and E2F, as well as novel alterations in the cMYB pathway. We also observed that responses to both primary treatments (high dose-rate brachytherapy and androgen deprivation therapies) were consistent with known optimal responses-ruling out treatment inefficacy as a factor in relapse.

These data provide novel insights into a case of locally recurrent aggressive prostate cancer harbouring NEPC pathology, in the absence of detected metastasis.

These data provide novel insights into a case of locally recurrent aggressive prostate cancer harbouring NEPC pathology, in the absence of detected metastasis.

DNA polymerase D (PolD) is the representative member of the D family of DNA polymerases. It is an archaea-specific DNA polymerase required for replication and unrelated to other known DNA polymerases. PolD consists of a heterodimer of two subunits, DP1 and DP2, which contain catalytic sites for 3′-5′ editing exonuclease and DNA polymerase activities, respectively, with both proteins being mutually required for the full activities of each enzyme. However, the processivity of the replicase holoenzyme has additionally been shown to be enhanced by the clamp molecule proliferating cell nuclear antigen (PCNA), making it crucial to elucidate the interaction between PolD and PCNA on a structural level for a full understanding of its functional relevance. We present here the 3D structure of a PolD-PCNA-DNA complex from Thermococcus kodakarensis using single-particle cryo-electron microscopy (EM).

Two distinct forms of the PolD-PCNA-DNA complex were identified by 3D classification analysis. Fitting the reported cryf its activity. This hook function of the clamp molecule may be conserved in the three domains of life.