Schistosomiasis in the People’s Republic of China (PRC) can be traced back to antiquity. In the past 60 years, the Chinese government has made great efforts to control this persistent disease with elimination slated by 2020 through the implementation of a comprehensive control strategy. This strategy aims to reduce the role of bovines and humans as sources of infection as a pre-requisite for elimination through transmission interruption. The goal of elimination will be achievable only by the implementation of a sustainable surveillance and control system, with sensitive diagnosis a key feature so that the true disease burden is not underestimated. Currently used diagnostics lack the necessary sensitivity to accurately determine the prevalence of Schistosoma japonicum infection in areas with low infection intensities. It is of critical importance to find and treat people and to identify animals with low-level infections if the National Control Programme for China is to achieve schistosomiasis elimination. We evaluated a real-time polymerase chain reaction (qPCR) assay using 633 human stool samples collected from five villages in Hunan, Anhui, Hubei, and Jiangxi provinces, and 182 bovine (70 cattle and 112 buffalo) stool samples obtained from four villages in Hunan, Anhui, and Jiangxi provinces in the PRC. All stool samples were subjected to the miracidium hatching test (MHT, a diagnostic procedure used in the National Schistosomiasis Control Programme) and the qPCR assay. Samples positive by MHT were subjected to either the Kato-Katz technique for humans, or the formalin-ethyl acetate sedimentation-digestion (FEA-SD) procedure for bovines, to determine infection intensities. The qPCR assay exhibited a high level of sensitivity in the detection of S. japonicum infections. With both the human and bovine samples, a significantly higher prevalence was determined using the qPCR assay (11.06% humans, 24.73% bovines) than with the MHT (0.93% humans, 7.69% bovines). The animal contamination index (calculated using data obtained with the qPCR technique) for all positive bovines was 27 618 000 eggs per day, indicating a considerable amount of environmental egg contamination that would be underestimated using less sensitive diagnostic procedures. The qPCR assay we have evaluated will be applicable as a future field diagnostic and surveillance tool in low-transmission zones where schistosomiasis elimination is targeted and for monitoring post-intervention areas to verify that elimination has been maintained.

Schizophrenia is a common neuropsychiatric disorder with a lifetime risk of 1%. Accumulation of common polygenic variations has been found to be an important risk factor. Recent studies showed a role for the enrichment of minor alleles (MAs) of SNPs in complex diseases such as Parkinson’s disease. Here we similarly studied the role of genome wide MAs in schizophrenia using public datasets. Relative to matched controls, schizophrenia cases showed higher average values in minor allele content (MAC) or the average amount of MAs per subject. By risk prediction analysis based on weighted genetic risk score (wGRS) of MAs, we identified an optimal MA set consisting of 23 238 variants that could be used to predict 3.14% of schizophrenia cases, which is comparable to using 22q11 deletion to detect schizophrenia cases. Pathway enrichment analysis of these SNPs identified 30 pathways with false discovery rate (FDR) <0.02 and of significant P-value, most of which are known to be linked with schizophrenia and other neurological disorders. These results suggest that MAs accumulation may be a risk factor to schizophrenia and provide a method to genetically screen for this disease.

Schistosomiasis is among the major neglected tropical diseases and effective prevention by boosting the immune system is still not available. T cells are key cellular components governing adaptive immune response to various infections. While common laboratory mice, such as C57BL/6, are highly susceptible to schistosomiasis, the SD rats are extremely resistant. However, whether adaptive immunity is necessary for such natural resistance to schistosomiasis in rats remains to be determined. Therefore, it is necessary to establish genetic model deficient in T cells and adaptive immunity on the resistant SD background, and to characterize liver pathology during schistosomiasis. In this study we compared experimental schistosomiasis in highly susceptible C57BL/6 (B6) mice and in resistant SD rats, using cercariae of Schistosoma japonicum. We observed a marked T cell expansion in the spleen of infected B6 mice, but not resistant SD rats. Interestingly, CD3e^−/− B6 mice in which T cells are completely absent, the infectious burden of adult worms was significantly higher than that in WT mice, suggesting an anti-parasitic role for T cells in B6 mice during schistosome infection. In further experiments, we established Lck deficient SD rats by using CRISPR/Cas9 in which T cell development was completely abolished. Strikingly, we found that such Lck deficiency in SD rats severely impaired their natural resistance to schistosome infection, and fostered parasite growth. Together with an additional genetic model deficient in T cells, the CD3e^−/− SD rats, we confirmed the absence of T cell resulted in loss of natural resistance to schistosome infection, but also mitigated liver immunopathology. Our further experiments showed that regulatory T cell differentiation in infected SD rats was significantly decreased during schistosomiasis, in contrast to significant increase of regulatory T cells in infected B6 mice. These data suggest that T cell mediated immune tolerance facilitates persistent infection in mice but not in SD rats. The demonstration of an important role for T cells in natural resistance of SD rats to schistosomiasis provides experimental evidences supporting the rationale to boost T cell responses in humans to prevent and treat schistosomiasis.

E14517 Background: Standard early endpoints (ORR, PFS) are often poor predictors of overall survival (OS) for immunotherapies. Model-based tumor kinetic (TUK) metrics may offer an alternative (Claret, JCO 2009 and 2013). We investigated the predictive performance of TUK metrics using early data from atezolizumab clinical trials in patients (pts) with non-small cell lung cancer (NSCLC). Methods: OS benefit with atezolizumab (atezo) vs. docetaxel (doc) was observed in both Phase II POPLAR (hazard ratio 0.73, p = 0.040, n = 297, Fehrenbacher Lancet 2016) and Phase III OAK (HR = 0.73, p = 0.0003, n = 850, Rittmeyer Lancet 2016) studies although PFS was similar between arms. A multivariate model linking baseline patient characteristics and tumor growth rate (TGR, estimated using time profile of sum of longest diameters of target lesions, RECIST 1.1) to OS was developed using POPLAR data and qualified to predict outcome by PD-L1 status in both POPLAR and OAK. This model was used to predict OAK OS outcome based on patient characteristics and estimated TGR from TUK data at several OAK data cut-offs ranging from 10 to 122 weeks. Results: In POPLAR, TUK profile in atezo and doc arms crossed at about 25 weeks with more initial shrinkage in doc-treated patients and slower TGR in atezo-treated patients. A lognormal OS model with albumin and number of metastatic sites as independent baseline prognostic factors and estimated TGR predicted OS HR in sub-populations of pts based on baseline PD-L1 expression both in POPLAR as well as in OAK e.g model-predicted OAK HR: 0.73 [0.63-0.85]. Based a retrospective analysis on TUK data cuts, the POPLAR OS model predicted significant OS HR in OAK as soon as 40 week cut-off: HR: 0.67 [0.56-0.80] with success in 99% of the replicates with only 50% of the total number of tumor assessments. At this 40 week data cut, immature observed OS HR was 0.84 [0.59-1.21, p = 0.347] and HR only reached significance at 70 weeks. Conclusions: Model predictions based on TUK can be used to predict success early before maturation of OS data as shown with OAK. The model-based biomarker TUK metric TGR has strong potential as an alternative early endpoint to evaluate efficacy in cancer immunotherapy studies.

Background: We identified a novel ABCD1 variant (c.773T>G, p.Leu258Arg, NM_000033.4) in a Chinese pedigree affected by X‐linked adrenoleukodystrophy (X‐ALD). This missense variant in exon 1 is predicted to be pathogenic and likely constitutes the genetic basis of the disease phenotype in this family. Methods: ABCD1 gene sequencing was performed in the Chinese pedigree. The pathogenicity of identified variants was assessed using computational prediction tools. Subcellular localization studies were conducted, and very‐long‐chain fatty acid (VLCFA) levels were quantified in patient‐derived samples. Results: Sequencing analysis identified a hemizygous missense variant in the ABCD1 gene (c.773T>G; p.Leu258Arg). In silico pathogenicity prediction using SIFT and PolyPhen‐2 algorithms classified the p.Leu258Arg substitution as deleterious. Functional characterization revealed that the p.Leu258Arg variant impairs the peroxisomal membrane localization of the ABCD1 protein. Consistent with the established role of ABCD1 in peroxisomal β‐oxidation, individuals harboring this variant exhibited significantly elevated serum levels of VLCFA. Specifically, the C26:0/C22:0 ratio was elevated 2.8‐fold compared to control values, confirming impaired VLCFA metabolism. Conclusion: In accordance with the “Standards and Guidelines for the Interpretation of Sequence Variants” established by the American College of Medical Genetics and Genomics (ACMG), we assessed the pathogenicity of the novel ABCD1 gene variant c.773T>G. This variant meets the following ACMG evidence criteria: PM1 (located within a critical functional domain or mutational hotspot known to lack benign variation); PM2 (absent or observed at very low frequency in population databases e.g., gnomAD, EXAC, 1000 Genomes); PP3 (multiple in silico prediction tools consistently suggest a deleterious effect on the gene or gene product). Integrating this evidence (PM1 + PM2 + PP3), the variant is classified as likely pathogenic based on ACMG guidelines. Experimental data from this study further substantiate the pathogenicity of the c.773T>G variant located in exon 1 of the ABCD1 gene. This finding broadens the spectrum of known pathogenic mutations in ABCD1 associated with X‐ALD and provides crucial information for the molecular diagnosis of affected patients.