Gene and protein expression of O-GlcNAc-cycling enzymes in human laryngeal cancer

Aberrant protein O-GlcNAcylation may contribute to the development and malignant behavior of many cancers. This modification is controlled by O-linked β-N-acetylglucosamine transferase (OGT) and O-GlcNAcase (OGA). The aim of this study was to determine the expression of O-GlcNAc cycling enzymes mRNA/protein and to investigate their relationship with clinicopathological parameters in laryngeal cancer. The mRNA levels of OGT and MGEA5 genes were determined in 106 squamous cell laryngeal cancer (SCLC) cases and 73 non-cancerous adjacent laryngeal mucosa (NCLM) controls using quantitative real-time PCR. The level of OGT and OGA proteins was analyzed by Western blot. A positive expression of OGT and MGEA5 transcripts and OGT and OGA proteins was confirmed in 75.5 and 68.9 % and in 43.7 and 59.4 % samples of SCLC, respectively. Higher levels of mRNA/protein for both OGT and OGA as well as significant increases of 60 % in total protein O-GlcNAcylation levels were noted in SCLC compared with NCLM (p < 0.05). As a result, an increased level of OGT and MGEA5 mRNA was related to larger tumor size, nodal metastases, higher grade and tumor behavior according to TFG scale, as well as incidence of disease recurrence (p < 0.05). An inverse association between OGT and MGEA5 transcripts was determined with regard to prognosis (p < 0.05). In addition, the highest OGT and OGA protein levels were observed in poorly differentiated tumors (p < 0.05). No correlations with other parameters were noted, but the results showed a trend of more advanced tumors to be more frequently OGT and OGA positive. The results suggest that increased O-GlcNAcylation may have an effect on tumor aggressiveness and prognosis in laryngeal cancer.This work was supported, in part, by a grant from the National Science Council, Poland (N403 043 32/2326), by the statutory fund of the Department of Cytobiochemistry, University of Łódź, Poland (506/811

Cancer vaccines: Enhanced immunogenic modulation through therapeutic combinations

Therapeutic cancer vaccines have gained significant popularity in recent years as new approaches for specific oncologic indications emerge. Three therapeutic cancer vaccines are FDA approved and one is currently approved by the EMA as monotherapy with modest treatment effects. Combining therapeutic cancer vaccines with other treatment modalities like radiotherapy (RT), hormone therapy, immunotherapy, and/or chemotherapy have been investigated as a means to enhance immune response and treatment efficacy. There is growing preclinical and clinical data that combination of checkpoint inhibitors and vaccines can induce immunogenic intensification with favorable outcomes. Additionally, novel methods for identifying targetable neoantigens hold promise for personalized vaccine development. In this article, we review the rationale for various therapeutic combinations, clinical trial experiences, and future directions. We also highlight the most promising developments that could lead to approval of novel therapeutic cancer vaccines

Gene Therapy in the Nervous System: Failures and Successes

Genetic disorders, caused by deleterious changes in the DNA sequence away from the normal genomic sequence, affect millions of people worldwide. Gene therapy as a treatment option for patients is an attractive proposition due to its conceptual simplicity. In principle, gene therapy involves correcting the genetic disorder by either restoring a normal functioning copy of a gene or reducing the toxicity arising from a mutated gene. In this way specific genetic function can be restored without altering the expression of other genes and the proteins they encode. The reality however is much more complex, and as a result the vector systems used to deliver gene therapies have by necessity continued to evolve and improve over time with respect to safety profile, efficiency, and long-term expression. In this chapter we examine the current approaches to gene therapy, assess the different gene delivery systems utilized, and highlight the failures and successes of relevant clinical trials. We do not intend for this chapter to be a comprehensive and exhaustive assessment of all clinical trials that have been conducted in the CNS, but instead will focus on specific diseases that have seen successes and failures with different gene therapy vehicles to gauge how preclinical models have informed the design of clinical trials