Research conducted over the past two decades has shown the importance of the type 1insulin-like growth factor receptor (IGF1R) in tumorigenesis, metastasis, and resistance to existing forms of cancer therapy. The IGF1R itself has only recently been accepted as a credible treatment target, however, perhaps reflecting the potential problems for drug design posed by normal tissue IGF1R expression, and close homology with the insulin receptor. Currently f12 anti-IGF1R therapeutics are undergoing clinical evaluation, including blocking antibodies and tyrosine kinase inhibitors. This review will summarize the principal signaling pathways activated by IGF1R and the preclinical data that validated this receptor as a treatment target.We will review clinical progress in the testing of IGF1R inhibitory drug candidates, the relative benefits and potential toxicities of coinhibition of the insulin receptor, and the rationale for combining IGF1R blockade with other cancer treatments. An understanding of IGF1R signaling is important because it will guide the incorporation of appropriate molecular markers into clinical trial design. This will be key to the identification of patients most likely to benefit, and so will influence the ability of IGF1R inhibition to make the transition from experimental intervention to clinical therapy.

Policy makers across the tropics propose that carbon finance could provide incentives for forest frontier communities to transition away from swidden agriculture (slash-and-burn or shifting cultivation) to other systems that potentially reduce emissions and/or increase carbon sequestration. However, there is little certainty regarding the carbon outcomes of many key land-use transitions at the center of current policy debates. Our meta-analysis of over 250 studies reporting above- and below-ground carbon estimates for different land-use types indicates great uncertainty in the net total ecosystem carbon changes that can be expected from many transitions, including the replacement of various types of swidden agriculture with oil palm, rubber, or some other types of agroforestry systems. These transitions are underway throughout Southeast Asia, and are at the heart of REDD+ debates. Exceptions of unambiguous carbon outcomes are the abandonment of any type of agriculture to allow forest regeneration (a certain positive carbon outcome) and expansion of agriculture into mature forest (a certain negative carbon outcome). With respect to swiddening, our meta-analysis supports a reassessment of policies that encourage land-cover conversion away from these [especially long-fallow] systems to other more cash-crop-oriented systems producing ambiguous carbon stock changes - including oil palm and rubber. In some instances, lengthening fallow periods of an existing swidden system may produce substantial carbon benefits, as would conversion from intensely cultivated lands to high-biomass plantations and some other types of agroforestry. More field studies are needed to provide better data of above- and below-ground carbon stocks before informed recommendations or policy decisions can be made regarding which land-use regimes optimize or increase carbon sequestration. As some transitions may negatively impact other ecosystem services, food security, and local livelihoods, the entire carbon and noncarbon benefit stream should also be taken into account before prescribing transitions with ambiguous carbon benefits.

Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in -mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in-null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that -null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in-null cell lines. EZH2 inhibition delayed tumor onset in -null cells and caused regression of-null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of , which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2.

No abstract