No abstract

No abstract

Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti-PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8 þ T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNgproducing E7-specifc CD8 þ T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti-PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic.

Fragile x syndrome (FXS) is the most common form of inherited mental retardation disease. This is caused due to expansion of CGG triplet in 5'-untranslated region of fragile x mental retardation 1 (FMR-1) gene. In most of the cases, abnormally large size of the CGG repeat (>200) undergoes hypermethylation, which in turn silences the FMR-1 gene causing thereby complete lack of its protein product called fragile x mental retardation protein (FMRP). Lack of FMRP due to gene silencing or production of faulty protein due to point mutation in KH2 domain of FMRP alters the translational process in neurons and leads to expression of mental retardation phenotype on the patients. The FMRP is expressed ubiquitously in all tissues; however, it is predominantly expressed in neurons and testis. It possesses heterogeneity and is found in many isoforms due to alternative splicing of the FMR-1 transcript. Based on our data from the Western-, slot-, Northern blotting and immunohistochemical studies, we report here the down regulation of Fmr-1 gene and FMRP in mice brain in age-dependent manner. The present finding is important in respect to FMRP-dependent various brain functions i.e., learning, memory, cognition etc. that decrease with advancing age.