Whole exome sequencing identifies frequent somatic mutations in cell-cell adhesion genes in chinese patients with lung squamous cell carcinoma

Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy

Scheduling for charging plug-in hybrid electric vehicles

We construct a dynamic stochastic model to study the scheduling problem for battery charging of multiple (possibly a large number of) PHEVs. Our model incorporates the stochasticity in future PHEV arrival process and future renewable generation. The objective of scheduling is to maximize the overall social welfare, which is derived from total customer utility, the electricity cost associated with PHEV charging, and the non-completion penalty for not satisfying PHEVs' charging requests. Through a dynamic programming formulation, we show the Less Laxity and Longer remaining Processing time (LLLP) principle: priority should be given to vehicles that have less laxity and longer remaining processing times, if the non-completion penalty (as a function of the additional time needed to fulfill the unsatisfied charging request) is convex. We introduce various forms of improved polices generated from a given heuristic policy according to the LLLP principle, and show that these improved polices can only improve social welfare, compared to the original heuristic

Two patterns of <i>ALK</i> gene alteration detected by FISH using Vysis LSI ALK Dual Color breakpoint probe.

<p>(A) Two distinct red and green signals. (B) Isolated red signal.</p

Comparison between FISH and IHC.

<p>Abbreviation: FISH: Fluorescence In Situ Hybridization; IHC: immunohistochemistry.</p

Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation

Abstract Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (Kras LSL-G12D/+ ;Lkb1 flox/flox , KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a “Yin-Yang” counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the “Yin-Yang” homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point