The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS

The expression of p53-induced protein with death domain (Pidd) and apoptosis in oral squamous cell carcinoma

The Pidd (p53-induced protein with death domain) gene was shown to be induced by the tumour suppressor p53 and to mediate p53-dependent apoptosis in mouse and human cells, through interactions with components of both the mitochondrial and the death receptor signalling pathways. To study the role of Pidd in clinical tumours, we measured its expression by quantitative reverse transcription-PCR in microdissected oral squamous cell carcinomas (OSCC) with and without p53 mutation. Tumour cell apoptosis was assessed by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Tumour proliferation was assessed by immunohistochemical staining for the Ki-67 antigen. We found a wide range of Pidd expression among OSCC. Statistical analysis revealed an association between Pidd expression and apoptotic index (Mann–Whitney test, P<0.001), consistent with a role of Pidd in apoptosis in this tumour type. Furthermore, we showed a positive correlation between apoptotic index and proliferative index that has not been previously described for OSCC. There was no correlation between Pidd expression and the p53 mutation status of these tumours, suggesting that Pidd expression may be regulated by p53-independent mechanisms. Further characterisation of these molecular defects in the control of proliferation and apoptosis should help in developing treatments that target OSCC according to their biological properties

Serum, AP-1 and Ets-1 stimulate the human ets-1 promoter.

The ets-1 proto-oncogene codes for a transcription factor. In order to understand how ets-1 is regulated, we have cloned its promoter. We show that the promoter is inducible by serum and expression of c-Fos and c-Jun, and it is positively auto-regulated by its gene product. A 50 base-pair sequence is sufficient to confer c-Fos + c-Jun and c-Ets-1 responsiveness to a heterologous promoter. This element contains two AP1 and one Ets-1 like motifs. Striking, AP-1 and Ets-1 motifs are found in oncogene responsive units (ORU's) of other promoters, suggesting that combining these motifs is a common mechanism for generating mitogen responsive transcription elements

Low frequency noise characterization and modeling of microwave bipolar devices: Application to the design of low phase noise oscillator

This paper addresses advanced low frequency noise measurements and modeling of SiGe HBTs. Results have been implemented into a non linear Gummel Poon model which has been validated through the design of a DRO made of an integrated SiGe negative resistance in the 10 GHz range. We have obtained phase noise of -105 dBc/Hz at 10 kHz offset, which is close to the state of the art, and we have demonstrated a design technique that provides an accurate phase noise prediction

Low frequency noise characterization and modeling of microwave bipolar devices : application to the design of low phase noise oscillator

This paper addresses advanced low frequency noise measurements and modeling of SiGe HBTs. Results have been implemented into a nonlinear Gummel Poon model which has been validated through the design of a DRO made of an integrated SiGe negative resistance in the 10 GHz range. We have obtained phase noise of -105 dBc/Hz at 10 kHz offset, which is close to the state of the art, and we have demonstrated a design technique that provides an accurate phase noise prediction

Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1)

Previous results have suggested that the Ras signaling pathway is involved in learning and memory. Ras is activated by nucleotide exchange factors, such as the calmodulin-activated guanine-nucleotide releasing factor 1 (Ras-GRF1). To test whether Ras-GRF1 is required for learning and memory, we inactivated the Ras-GRF1 gene in mice. These mutants performed normally in a rota-rod motor coordination task, and in two amygdala-dependent tasks (inhibitory avoidance and contextual conditioning). In contrast the mutants were impaired in three hippocampus-dependent learning tasks: contextual discrimination, the social transmission of food preferences, and the hidden-platform version of the Morris water maze. These studies indicate that Ras-GRF1 plays a role in hippocampal-dependent learning and memory. (C) 2001 Elsevier Science Ltd. All rights reserved