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Tumor-specific alterations at the p53 gene locus were analyzed in 40 human brain tumor samples. Gliomas were more prevalent in young males and meningiomas in old females. Structural changes at the intron 1 region of the p53 gene were analyzed in these tumors by Southern blotting. Among the 40 tumors, 33 were informative and 21 of these (63.6%) informative cases showed loss of heterozygosity (LOH). This is the first report showing LOH at the intron 1 region of p53 gene in human brain tumors. The level of p53 mRNA, p53 protein and Ser 392 phosphorylated p53 protein were also analyzed in all tumor samples. Normal sized p53 mRNA and protein were present in all the tumor samples; however, their levels were 1.5- to 4-fold higher compared to the control suggesting deregulated p53 pathway in these tumors. No correlation was found between LOH status and the levels of p53 mRNA and protein. In all high-grade glioblastomas majority of the p53 protein existed as Ser 392 phosphorylated form as compared to low-grade gliomas. In addition, the percentage of Ser 392 phosphorylated form of p53 protein was lower in meningiomas and other brain tumor types irrespective of tumor grade. These results suggest involvement of Ser 392 phosphorylated form of p53 protein during the later stages of glioma development. These results also indicate that deregulation of p53 gene could occur at various steps in p53 pathway and suggest an overall deregulation of p53 gene in most brain tumor types.

Lens explant cultures were used to assess the mechanism of drug-induced cataractogenic potential of NVS001, a peroxisome proliferator-activated receptor delta (PPARδ) agonist, which resulted in cataract in all treated animals during a 13-week rat study. Ciglitazone, a PPARγ agonist and cataractogenic compound, was used as a positive control to validate this model. Rat lenses were extracted and cultured in medium supplemented with antibiotics for 24-h preincubation pretreatment. Lenses showing no signs of damage at the end of the preincubation pretreatment period were randomized into five experimental groups, (1) untreated control, (2) 0.1% dimethyl sulphoxide control, (3) 10μM NVS001, (4) 10μM ciglitazone, and (5) 10μM acetaminophen (negative control). Lenses were treated every 24 h after preincubation pretreatment for up to 48 h. Samples for viability, histology, and gene expression profiling were collected at 4, 24, and 48 h. There was a time-dependent increase in opacity, which correlated to a decrease in viability measured by adenosine triphosphate levels in NVS001 and ciglitazone-treated lenses compared with controls. NVS001 and ciglitazone had comparable cataractogenic effects after 48 h with histology showing rupture of the lens capsule, lens fiber degeneration, cortical lens vacuolation, and lens epithelial degeneration. Furthermore, no changes were seen when lenses were treated with acetaminophen. Gene expression analysis supported oxidative and osmotic stress, along with decreases in membrane and epithelial cell integrity as key factors in NVS001-induced cataracts. This study suggests that in vitro lens cultures can be used to assess cataractogenic potential of PPAR agonists and to study/understand the underlying molecular mechanism of cataractogenesis in rat.

Background: The addition of bevacizumab (bev) to atezolizumab (atezo) has demonstrated enhanced anti-tumor immune responses in pts with solid tumors (Wallin 2016). In IMmotion150 (NCT01984242), a phase II trial that compared atezo+/-bev vs sunitinib (sun) in untreated mRCC, encouraging antitumor activity of atezo+bev vs sun was observed in PD-L1 expressing tumors. We performed integrated tumor genomic analyses to correlate molecular signatures with clinical outcomes. Methods: PD-L1 status on tumor infiltrating immune cells (IC) was assessed with the SP142 IHC assay (IC0, IC1, IC2/3) (n=297). Exploratory analyses included mutation evaluation by WES (n=170) and gene expression analysis by RNA-Seq (n=263). Established gene signatures at < median (low) or > median (high) expression levels representing T effector and IFNγ response (Teff) and angiogenesis (Ang) were evaluated in relation to PFS (RECIST v1.1 by independent review). Results: PFS was longer in PD-L1 IC2/3 and in PD-L1 IC1/2/3 in atezo+bev pts vs sun pts and in PD-L1 IC2/3 in atezo pts vs sun pts. High Teff signature expression was associated with PD-L1 IHC and longer PFS in atezo+bev pts vs sun pts. High Ang expression was associated with improved clinical activity in the sun arm; but not the atezo+bev arm. Atezo+bev had improved PFS vs sun in the Ang low subset. Additional data exploring association of high prevalence mutations with clinical outcome will be presented. Conclusions: These data indicate that the addition of bev to atezo may improve clinical benefit in patients with pre-existing anti-tumor immunity (as determined by high Teff score or PD-L1 IHC) compared to sun. Molecular profiles identified in these analyses suggest that prediction of differential outcomes to VEGF TKI and immunotherapy may be possible in front line mRCC. These results will be further explored in the ongoing phase III study IMmotion151 (NCT02420821). Atezo + Bev vs SunAtezo vs SunPFS HR (95% CI)PD-L1 IHC IC1/2/30.66 (0.41-1.07)0.97 (0.61-1.55)PD-L1 IHC IC2/30.36 (0.14-0.88)0.54 (0.23-1.28)Teff high0.55 (0.32-0.95)0.85 (0.50-1.43)Teff low1.41 (0.84-2.03)1.33 (0.76-2.33)Ang high1.36 (0.78-2.36)1.46 (0.81-2.60)Ang low0.58 (0.35-0.98)0.75 (0.45-1.25)PD-L1 IHC: IC1/2/3, ≥ 1% of TILs are PD-L1+; IC2/3, ≥ 5% of TILs are PD-L1+.Teff signature: CD8A, IFNG, PRF1, EOMES, PD-L1.Ang signature: VEGFA, KDR, ESM1, PECAM1, ANGPTL4, CD34. Citation Format: David McDermott, Mahrukh Huseni, Brian Rini, Robert Motzer, Michael Atkins, Berard Escudier, Dorothee Nickles, Zach Boyd, Shruthi Sampath, Jennifer Doss, Ning Leng, Christina Schiff, Daniel S. Chen, Gregg Fine, Thomas Powles, Priti S. Hegde. Molecular correlates of differential response to Atezolizumab +/- Bevacizumab vs Sunitnib in a Phase II study in untreated metastatic renal cell carcinoma (RCC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT081. doi:10.1158/1538-7445.AM2017-CT081

: MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn’s disease and Ulcerative colitis which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies, by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.