FFTPL: An Analytic Placement Algorithm Using Fast Fourier Transform for Density Equalization

We propose a flat nonlinear placement algorithm FFTPL using fast Fourier transform for density equalization. The placement instance is modeled as an electrostatic system with the analogy of density cost to the potential energy. A well-defined Poisson's equation is proposed for gradient and cost computation. Our placer outperforms state-of-the-art placers with better solution quality and efficiency

PRKDC: new biomarker and drug target for checkpoint blockade immunotherapy

BackgroundImmunological checkpoint blockade is effective in treating various malignancies. Identifying predictive biomarkers to assist patient selection for immunotherapy has become a priority in both clinical and research settings.MethodsMutations in patients who responded to immunotherapy were identified through next-generation sequencing. Relationships among protein kinase, DNA-activated, catalytic polypeptide (PRKDC) mutations, mutation load and microsatellite instability (MSI) were analyzed using datasets from The Cancer Genome Atlas. These relationships were validated by conducting an in vitro study and by using tissue samples from 34 patients with gastric cancer. The CT26 animal model was used to evaluate the role of PRKDC as a predictive biomarker and the efficacy of the DNA-PK inhibitor.ResultsFrom the published literature, we found that among patients whose tumors harbored PRKDC mutations, 75%, 53.8%, and 50% of those with lung cancer, melanoma, and renal cell carcinoma, respectively, responded to immunotherapy. Most of these mutations were truncating and located in functional domains or in a destabilizing PRKDC protein structure. Additional analysis showed that a PRKDC mutation was significantly associated with a high mutation load in cervical cancer, colon adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma and endometrial cancer. Patients with gastric cancer or colon cancer harboring PRKDC mutations were also highly associated with MSI-high status. Finally, we found that knockout PRKDC or DNA-PK inhibitor (PRKDC encodes the catalytic subunit of DNA-dependent protein kinase) enhanced the efficacy of the anti-programmed cell death protein one pathway monoclonal antibody in the CT26 animal model.ConclusionsPRKDC is not only a predictive biomarker but also a drug target for immune checkpoint inhibitors

Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10 -11, odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10 -9, OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10 -12, OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings. The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.</p