We investigated polymorphic Alu insertion (POALIN) frequencies at five loci in the major histocompatibility complex (MHC) class I genomic region to determine their allele and haplotype frequencies and associations with the human leukocyte antigen (HLA)-B and -Cw genes in seven different Chinese ethnic populations, the Han, Bulang, Wa, Dai, Maonan, Hani and Jinuo. The POALINs varied in frequency between 0% and 42.3% with significant differences between populations at all of the loci. Each POALIN was in significant linkage disequilibrium with a variety of HLA-B or -Cw four-digit alleles. The percentage association between Alu insertions and the HLA-B or -Cw alleles was calculated in pairwise analyses of haplotypes to show possible crossing over events between loci. The POALIN insertions also helped to further stratify the HLA-B:-Cw haplotypes into different POALIN:HLA-B:HLA-Cw haplotype frequencies. Of the two-locus, five-locus and seven-locus haplotype analyses, the seven-locus haplotypes showed the largest number of differences between the populations. The most common multilocus haplotype in Han was MICB*1:B*4601:Cw*0102:TF*1:HJ*1:HG*2:HF*1 (15.6%) associated with the AluHG insertion, whereas the second most common multilocus haplotype in Han was MICB*1:B*1502:Cw*0801:TF*1:HJ*2:HG*1:HF*1 (11.8%) associated with the AluHJ insertion. This comparative study of multilocus POALINs in the HLA class I region of seven Chinese ethnic populations shows that POALINs alone or together with the HLA class I alleles are informative genetic markers for the identification of HLA class I allele and haplotype lineages and variations such as crossing over events within the same and/or different populations.

The study of the association between polymorphic Alu insertions [human leukocyte antigen (HLA)-Alu] at five loci and HLA class I alleles at two loci allows for better identification of the origins and evolution of HLA class I region haplotypes in different populations. In the present study, we determined the frequencies of five HLA-Alus and their associations with HLA-A and -B alleles in Han, Wa, Maonan, and Jinuo populations. Our results showed a strong association between AluHG insertion and HLA-A*02 in all populations studied; however, the associations between AluHJ insertion and HLA-A*1101 and HLA-A*2402 and AluHF insertion and HLA-A*2601 were only observed in Han. The AluMICB insertion showed a strong association with HLA-B*5502 in Han, Maonan, and Jinuo. HLA-A*0101, HLA-A*0201, HLA-A*0203, HLA-A*1101, HLA-A*2402, HLA-A*2601, and HLA-A*3101 alleles were associated with one or more of the three different Alu elements within the alpha block as independent haplotypes, and HLA-A*0101, HLA-A*0201, HLA-A*0203, HLA-A*1101, and HLA-A*2402 alleles were associated with at least two different Alu insertions as a haplotype within the alpha block. We conclude that the HLA class I region haplotypes of the four populations were derived from different progenitor haplotypes, and relatively high rates of recombination between individuals with HLA-A alleles and different HLA-Alus occurred in this region.

Background: The blockade of entering the cell cycle represents a hallmark of chemoresistant cancer cells, especially in chemoresistant cancer stem cells. Cell cycle blockade in quiescent cancer (stem) cells is largely attributed to the natural dormant behaviour of stem cells, and in a natural state the quiescent stem cells respond to stimuli rapidly for activation. Thus, eliminating quiescent chemoresistant cancer (stem) cells by extrinsic stimuli that promote entry into cell cycle provides a potential strategy for overcoming chemoresistance.Methods: Lung cancer cells were treated with or without IL6 before cDDP chemotherapy and a lung cancer patient derived single cell ex-vivo system and mice xenograft in-vivo model were developed.Results: Here we report that in lung adenocarcinoma the interleukin 6 (IL6) treatment resulted in the expansion of cancer stem cells (EpCAM + /CD133 + /CD44 + /CD24 -) and reduction of quiescent cancer (stem) cells (Hoechst 33342 and Pyronin g double negative population, G0 cells) in several primary lung adenocarcinoma patientderived primary lung cancer cells. IL6 pre-treatment increased cDDP chemosensitivity in lung adenocarcinoma by promoting quiescent lung cancer (stem) cells to enter the cell cycle. In parallel, we showed a mechanism for regulating the sensitivity of the IL6-STAT3 pathway to IL6 treatment, by ChIP-PCR and duo-luciferase reporter assay we identified an AP2 transcription factor TFAP2A activates the expression of IL6 receptor transcriptionally in lung cancer cell lines. Moreover, using a mice tail vein xenograft in vivo chemotherapy model with lung cancer cell lines, we report that IL6 pre-treatment significantly induced more cell death in platinum-based chemotherapy.Conclusions: Our data indicate that IL6 contributes to quiescent lung cancer (stem) cells entering the cell cycle, which significantly undermines chemoresistance and introduces a considerable clinical approach for platinum-based chemotherapy in lung adenocarcinoma.Legal entity responsible for the study: The authors.

distribution of patients with different PD-L1 TPS values, followed by analysis of response rate (RR), survival rate, and incidence of secondary T790M mutation according to the PD-L1 TPS group. Results: Among the 131 patients analyzed, the proportion of patients with PD-L1 TPS 50%, 1%-49%, and < 1%, was 17.6%, 32.8%, and 49.6%, respectively. The RR was significantly lower in the group with PD-L1 TPS 50% than in the other groups (43.5% vs. 72.1% vs. 78.5%, all p ¼ 0.001). In multivariate analysis, PD-L1 TPS 50% was independently associated with a significantly shorter PFS in the overall population (hazard ratio [HR] ¼ 2.64, p ¼ 0.004), and associated with shorter OS in patients with exon 19 deletion (HR ¼ 2.55, p ¼ 0.041) compared with PD-L1 TPS < 50%. In addition, the frequency of secondary T790M mutation after TKI failure was significantly lower in the group with PD-L1 TPS 50% than in the other groups (13.3% vs. 40.0% vs. 53.3%, all p ¼ 0.001). PD-L1 TPS 50% was an independent predictor of a lower frequency of this mutation (HR ¼ 0.63, p ¼ 0.043). Conclusion: High PD-L1 expression was associated with unfavorable clinical outcome, and less development of secondary T790M mutation, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach.

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