Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prime position of the insulin-like growth factor 1 receptor (IGF-1R), at the head of the principle mitogenic and anti-apoptotic signalling cascades, along with the resilience to transformation of IGF-1R deficient cells fuelled great excitement for its anti-cancer targeting. Yet its potential has not been fulfilled, as clinical trial results fell far short of expectations. Advancements in understanding of other receptors' function have now begun to shed light on this incongruity, with the now apparent parallels highlighting the immaturity of our understanding of IGF-1R biology, with the model used for drug development now recognised as having been too simplistic. Gathering together the many advancements of the field of IGF-1R research over the past decade, alongside those in the GPCR field, advocates for a major paradigm shift in our appreciation of the subtle workings of this receptor. This review will emphasise the updating of the IGF-1R's classification from an RTK, to an RTK/GPCR functional hybrid, which integrates both canonical kinase signalling with many functions characteristic of a GPCR. Recognition of the shortcomings of IGF-1R inhibitor drug development programs and the models used not only allows us to reignite the initial interest in the IGF-1R as an anti-cancer therapeutic target, but also points to the possibility of biased ligand therapeutics, which together may hold a very powerful key to unlocking the true potential of IGF-1R modulation.
...
PMID:The dichotomy of the Insulin-like growth factor 1 receptor: RTK and GPCR: friend or foe for cancer treatment? 2546 6

Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV) is the most common cause of congenital infection. By using unbiased systems analyses of transcriptomic resources for HCMV neonatal infection, we find the systemic response of a preterm congenital HCMV infection, involves a focused IFN regulatory response associated with dendritic cells. Further analysis of transcriptional-programming of neonatal dendritic cells in response to HCMV infection in culture revealed an early dominant IFN-chemokine regulatory subnetworks, and at later times the plasticity of pathways implicated in cell-cycle control and lipid metabolism. Further, we identify previously unknown suppressed networks associated with infection, including a select group of GPCRs. Functional siRNA viral growth screen targeting 516-GPCRs and subsequent validation identified novel GPCR-dependent antiviral (ADORA1) and proviral (GPR146, RGS16, PTAFR, SCTR, GPR84, GPR85, NMUR2, FZ10, RDS, CCL17, and SORT1) roles. By contrast a gene family cluster of protocadherins is significantly differentially induced in neonatal cells, suggestive of possible immunomodulatory roles. Unexpectedly, programming responses of adult and neonatal dendritic cells, upon HCMV infection, demonstrated comparable quantitative and qualitative responses showing that functionally, neonatal dendritic cell are not overly compromised. However, a delay in responses of neonatal cells for IFN subnetworks in comparison with adult-derived cells are notable, suggestive of subtle plasticity differences. These findings support a set-point control mechanism rather than immaturity for explaining not only neonatal susceptibility but also resilience to infection. In summary, our findings show that neonatal HCMV infection leads to a highly plastic and functional robust programming of dendritic cells in vivo and in vitro. In comparison with adults, a minimal number of subtle quantitative and temporal differences may contribute to variability in host susceptibility and resilience, in a context dependent manner.
 ...
PMID:Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and In Vitro Cytomegalovirus Infection Reveal Plastic and Robust Immune Pathway Biology Responses. 2899 67