The Kaplan–Meier (KM) plot of RFS by the dichotomized multi-marker score in Arm B (patients treated with one month of interferon-α).

<p>One month pro-inflammatory cytokines (IL2Rα, IL-12p40 and IFN-α) predict one year RFS.</p

Pro-Inflammatory Cytokines Predict Relapse-Free Survival after One Month of Interferon-α but Not Observation in Intermediate Risk Melanoma Patients

<div><p>Background</p><p>E1697 was a phase III trial of adjuvant interferon (IFN)-α2b for one month (Arm B) versus observation (Arm A) in patients with resected melanoma at intermediate risk. We evaluated the levels of candidate serum cytokines, the HLA genotype, polymorphisms of CTLA4 and FOXP3 genes and the development of autoantibodies for their association with relapse free survival (RFS) in Arm A and Arm B among 268 patients with banked biospecimens.</p><p>Methods</p><p>ELISA was used to test 5 autoantibodies. Luminex/One Lambda LABTypeRSSO was used for HLA Genotyping. Selected <i>CTLA4</i> and <i>FOXP3</i> Single nucleotide polymorphisms (SNPs) and microsatellites were tested for by polymerase chain reaction (PCR). Sixteen serum cytokines were tested at baseline and one month by Luminex xMAP multiplex technology. Cox Proportional Hazards model was applied and the Wald test was used to test the marginal association of each individual marker and RFS. We used the Lasso approach to select the markers to be included in a multi-marker Cox Proportional Hazards model. The ability of the resulting models to predict one year RFS was evaluated by the time-dependent ROC curve. The leave-one-out method of cross validation (LOOCV) was used to avoid over-fitting of the data.</p><p>Results</p><p>In the multi-marker modeling analysis conducted in Arm B, one month serum IL2Rα, IL-12p40 and IFNα levels predicted one year RFS with LOOCV AUC = 82%. Among the three markers selected, IL2Rα and IFNα were the most stable (selected in all the cross validation cycles). The risk score (linear combination of the 3 markers) separated the RFS curves of low and high risk groups well (p = 0.05). This model did not hold for Arm A, indicating a differential marker profile in Arm B linked to the intervention (adjuvant therapy).</p><p>Conclusions</p><p>Early on-treatment proinflammatory serum markers (IL2Rα, IL-12p40, IFNα) significantly predict RFS in our cohort of patients treated with adjuvant IFN-α2b and warrant further study.</p></div

The association of clinical factors with relapse free survival (RFS).

<p>The association of clinical factors with relapse free survival (RFS).</p

Table_1_The prognostic impact of PD-L1 and CD8 expression in anal cancer patients treated with chemoradiotherapy.docx

BackgroundProgrammed death-ligand 1 (PD-L1) expression has been shown to be prognostic in many cancer types and used in consideration of checkpoint inhibitor immunotherapy. However, there are very limited and conflicting data on the prognostic impact of PD-L1 in patients with anal squamous cell carcinoma (ASCC). The objectives of this study were to measure the expression of PD-L1 and CD8 in patients with ASCC treated with radical chemoradiotherapy (CRT) and to correlate tumor expression with progression-free survival (PFS) and overall survival (OS).MethodsNinety-nine patients with ASCC treated with primary CRT at two tertiary care cancer centers between 2000 and 2013, with available pre-treatment tumors, were included. Tissue microarrays (TMAs) from pre-treatment tumor specimens were stained for PD-L1 and CD8. PD-L1 expression in the tumor and stroma was quantified using HALO image analysis software, and results were interpreted using quantitative methods. The density of CD8 cells within the tumor was interpreted by a trained pathologist semi-quantitatively, using a 0-4 scoring system. Kaplan-Meier analysis with log-rank was used to determine the significance in the association of tumor markers with PFS and OS. Cox multivariate analysis was used to explore independent predictors of PFS and OS.ResultsOf the 99 patients, 63 (64%) had sufficient tumor samples available for full analysis. CD8 high status was documented in 32 of 63 (50.8%) % of cases. PD-L1 expression was positive in 88.9% of cases. Approximately half the patients had tumor PD-L1 ≥ 5%. Patients with tumor PD-L1 ≥ 5% had better OS vs those with lower expression, HR=0.32 (95% CI 0.11-0.87), p=0.027; 10 years OS: 84% for tumor PD-L1 ≥ 5% vs 49% for PD-L1 ConclusionsTumor PD-L1≥5% is associated with OS in patients with ASCC treated with CRT. PD-L1 expression status using this unique cut-point warrants further validation for prognostication in patients with this disease. Future studies are required to determine the benefit of alternative treatment strategies based on PD-L1 status.</p

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Additional file 3: of Comparative genomics of the miniature wasp and pest control agent Trichogramma pretiosum

Table S14. Trichogramma singleton genes identified by OrthoMCL, and the GO terms overrepresented in that set. (XLSX 97 kb

Additional file 4: of Comparative genomics of the miniature wasp and pest control agent Trichogramma pretiosum

Table S15. Trichogramma proteins identified to be rapidly evolving as compared to Nasonia, using Tajima’s relative rate test, along with overrepresented GO terms. (XLSX 119 kb

Additional file 1: of Comparative genomics of the miniature wasp and pest control agent Trichogramma pretiosum

Supplemental methods and data, Tables S1–S12., and Figures S1–S5. (DOCX 1157 kb

Additional file 7: of Comparative genomics of the miniature wasp and pest control agent Trichogramma pretiosum

Table S18. Comparisons to a sexual genome. Proteins and overrepresented GO terms for proteins most diverged between sexual and asexual lines of Trichogramma, frameshifted, and dN/dS greater than 1. (XLSX 69 kb

Overcoming Mutagenicity and Ion Channel Activity: Optimization of Selective Spleen Tyrosine Kinase Inhibitors

Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log <i>D</i>, PSA, and p<i>K</i>_a. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a <i>Salmonella</i> strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles