Head and neck cancer is the 6th most common malignancy worldwide and urgently requires novel therapy methods to change the situation of low 5-years survival rate and poor prognosis. Targeted therapy provides more precision, higher efficiency while lower adverse effects than traditional treatments like surgery, radiotherapy, and chemotherapy. Blockade of PD-1 pathway with antibodies against PD-1 or PD-L1 is such a typical targeted therapy which reconstitutes anti-tumor activity of T cell in treatments of cancers, especially those highly expressing PD-L1, including head and neck cancers. There are many clinical trials all over the world and FDA has approved anti-PD-1/PD-L1 drugs for head and neck cancers. However, with the time going, the dark side of this therapy has emerged, including some serious side effects and drug resistance. Novel materials like nanoparticles and combination therapy have been developed to improve the efficacy. At the same time, standards for evaluation of activity and safety are to be established for this new therapy. Here we provide a systematic review with comprehensive depth on the application of anti-PD1/PD-L1 antibodies in head and neck cancer treatment: mechanism, drugs, clinical studies, influencing factors, adverse effects and managements, and the potential future developments.

The purpose of this research was to investigate and identify PAX9 gene variants in four Chinese families with non-syndromic tooth agenesis. We identified pathogenic gene variants by whole-exome sequencing (WES) and Sanger sequencing and then studied the effects of these variants on function by bioinformatics analysis and in vitro experiments. Four novel PAX9 heterozygous variants were identified: two missense variants (c.191G > T (p.G64V) and c.350T > G (p.V117G)) and two frameshift variants (c.352delC (p.S119Pfs*2) and c.648_649insC(p.Y217Lfs*100)). The bioinformatics analysis showed that these variants might be pathogenic. The tertiary structure analysis showed that these four variants could cause structural damage to PAX9 proteins. In vitro functional studies demonstrated that (1) the p.Y217Lfs*100 variant greatly affects mRNA stability, thereby affecting endogenous expression; (2) the p. S119Pfs* 2 variant impairs the subcellular localization of the nuclear expression of the wild-type PAX9 protein; and (3) the four variants (p.G64V, p.V117G, p.S119Pfs*2, and p.Y217Lfs*100) all significantly affect the downstream transcriptional activity of the BMP4 gene. In addition, we summarized and analyzed tooth missing positions caused by PAX9 variants and found that the maxillary second molar (84.11%) and mandibular second molar (84.11%) were the most affected tooth positions by summarizing and analyzing the PAX9-related non-syndromic tooth agenesis positions. Our results broaden the variant spectrum of the PAX9 gene related to non-syndromic tooth agenesis and provide useful information for future genetic counseling.

No abstract