Specification of endothelial cell (EC) fate

The C/C++11 memory model defines the semantics of concurrent memory accesses in C/C++, and in particular supports racy "atomic" accesses at a range of different consistency levels, from very weak consistency ("relaxed") to strong, sequential consistency ("SC"). Unfortunately, as we observe in this paper, the semantics of SC atomic accesses in C/C++11, as well as in all proposed strengthenings of the semantics, is flawed, in that (contrary to previously published results) both suggested compilation schemes to the Power architecture are unsound. We propose a model, called RC11 (for Repaired C11), with a better semantics for SC accesses that restores the soundness of the compilation schemes to Power, maintains the DRF-SC guarantee, and provides stronger, more useful, guarantees to SC fences. In addition, we formally prove, for the first time, the correctness of the proposed stronger compilation schemes to Power that preserve load-to-store ordering and avoid "out-of-thin-air" reads.

Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may coreside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a crosscontrol mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators. (Blood. 2010;116(1):140-150)

Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients’ tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.

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