Abstract-We propose a self-contained, flat, forcedirected algorithm for global placement that is simpler than existing placers and easier to integrate into timingclosure flows. It maintains lower-bound and upper-bound placements that converge to a final solution. The upperbound placement is produced by a novel rough legalization algorithm. Our placer SimPL outperforms mPL6, NTUPlace3, FastPlace3, APlace2 and Capo simultaneously in runtime and solution quality, running 6.4 times faster than mPL6 and reducing wirelength by 2% on the ISPD 2005 benchmark suite. I. INTRODUCTIONGlobal placement currently remains at the core of physical design and is a gating factor for downstream optimizations during timing closure [2]. Despite impressive improvements reported by researchers [15] and industry software in the last five years, state-ofthe-art algorithms and tools for placement suffer several key shortcomings which are becoming more pronounced at recent technology nodes. These shortcomings fall into four categories: (i) speed, (ii) solution quality, (iii) simplicity and integration with other optimizations, (iv) support for multithreaded execution. We propose the SimPL algorithm that simultaneously improves results in the first three categories and lends itself naturally to parallelism on multicore CPUs. [6]. Forcedirected algorithms model total net length by a quadratic function of cell locations and minimize it by solving a large sparse system of linear equations. To discourage cell overlap, forces are added pulling cells away from high-density areas. These forces are modeled by pseudopins and pseudonets, which extend the original quadratic function [11]. They are updated after each linear-system solve until iterations converge. Non-linear optimization models net length by more sophisticated differentiable functions with linear asymptotic behavior which are then minimized by advanced numerical analysis techniques [12]. Cell density is modeled by functional terms, which are more accurate than forces, but also require updates after each change to placement [7], [12]. Algorithms in both categories are directly used in the industry or closely resemble those in industry placers.

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Background Few studies have compared the outcomes of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in patients with early gastric cancer. Methods We studied 780 lesions for which endoscopic treatment was indicated according to the Japanese Gastric Cancer Association (JGCA) criteria or the Results The median follow-up was 73 months in the EAM group and 65 months in the ESD group. Overall, the local recurrence rate was significantly lower in the ESD group (0.2 %, 1/421) than in the EAM group (4.2 %, 15/359) (p \ 0.05). For lesions meeting the JGCA criteria, the local recurrence rate was 2.9 % in the EAM group and 0 % in the ESD group (p \ 0.05). For lesions meeting the NCC criteria, the local recurrence rate was 12.5 % in the EAM group and 0.6 % in the ESD group (p \ 0.05). There was no significant difference between the groups in overall survival. Conclusions On long-term follow-up, ESD was associated with a lower rate of local recurrence than EAM for lesions that met the JGCA or the NCC criteria. From the point of view of radical curability, ESD can be recommended for the management of lesions that meet either set of criteria.

The well-studied gate-sizing optimization is a major contributor to IC power-performance tradeoffs. Viable optimizers must accurately model circuit timing, satisfy a variety of constraints, scale to large circuits, and effectively utilize a large (but finite) number of possible gate configurations, including V t and L g . Within the research-oriented infrastructure used in the ISPD 2012 Gate Sizing Contest, we develop a metaheuristic approach to gate sizing that integrates timing and power optimization, and handles several types of constraints. Our solutions are evaluated using a rigorous protocol that computes circuit delay with Synopsys PrimeTime. Our implementation Trident outperforms the best-reported results on all but one of the ISPD 2012 benchmarks. Compared to the 2012 contest winner, we further reduce leakage power by an average of 43%.

Reactive oxygen species (ROS) are known to promote mesothelial carcinogenesis that is closely associated with asbestos fibers and inflammation. Epithelial to mesenchymal cell transition (EMT) is an important process involved in the progression of tumors, providing cancer cells with aggressiveness. The present study was performed to determine if EMT is induced by H 2 O 2 in human malignant mesothelioma (HMM) cells. Cultured HMM cells were treated with H 2 O 2 , followed by measuring expression levels of EMT-related genes and proteins. Immunohistochemically, TWIST1 expression was confined to sarcomatous cells in HMM tissues, but not in epithelioid cells. Treatment of HMM cells with H 2 O 2 promoted EMT, as indicated by increased expression levels of vimentin, SLUG and TWIST1, and decreased E-cadherin expression. Expression of stemness genes such as OCT4, SOX2 and NANOG was also significantly increased by treatment of HMM cells with H 2 O 2 . Alteration of these genes was mediated via activation of hypoxia inducible factor 1 alpha (HIF-1α) and transforming growth factor beta 1 (TGF-β1). Considering that treatment with H 2 O 2 results in excess ROS, the present study suggests that oxidative stress may play a critical role in HMM carcinogenesis by promoting EMT processes and enhancing the expression of stemness genes.

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.

The role of microRNAs (miRNAs) as a post-transcriptional gene regulator has been elucidated in a broad range of organisms including domestic animals. Characterization of miRNAs in normal tissues is an important step to investigate the functions of miRNAs in various physiological and pathological conditions. Using Illumina Next Generation Sequencing (NGS) technology, we identified a total of 292 known and 329 novel miRNAs in normal horse tissues including skeletal muscle, colon and liver. Distinct sets of miRNAs were differentially expressed in a tissue-specific manner. The miRNA genes were distributed across all the chromosomes except chromosomes 29 and 31 in the horse reference genome. In some chromosomes, multiple miRNAs were clustered and considered to be polycistronic transcript. A base composition analysis showed that equine miRNAs had a higher frequency of A+U than G+C. Furthermore, U tended to be more frequent at the 5′ end of miRNA sequences. This is the first experimental study that identifies and characterizes the global miRNA expression profile in normal horse tissues. The present study enriches the horse miRNA database and provides useful information for further research dissecting biological functions of miRNAs in horse.

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