Cost-effectiveness of an Adjuvanted Recombinant Zoster Vaccine in older adults in the United States.

In the United States, herpes zoster (HZ) and related complications are estimated to result in approximately $1.3 billion in medical care costs and $1.7 billion in indirect costs annually. In this study, we compared the cost-effectiveness of a new Adjuvanted Recombinant Zoster Vaccine (RZV), containing recombinant varicella-zoster virus glycoprotein E and the AS01B Adjuvant System, versus No Vaccine, as well as versus the live attenuated HZ vaccine (Zoster Vaccine Live (ZVL)) in subjects aged 60+ years of age (YOA) and other age cohorts aged 50+ YOA. A multi-cohort Markov model was developed which follows 1 million individuals over their remaining lifetimes from the year of vaccination with annual cycle lengths. Second dose compliance for RZV was assumed to be 69%. Efficacy and waning parameters were derived from clinical trials for both vaccines. Epidemiological parameters, costs and utility model inputs were derived from US-specific population-based data. Costs and outcomes were discounted at 3% per year. Deterministic and probabilistic sensitivity analysis, along with scenario and threshold analysis were carried out to explore the overall uncertainty in the model. The model estimated that, compared to No Vaccine against HZ, RZV would prevent 103,603 HZ cases, 11,197 postherpetic neuralgia (PHN) cases, and 14,455 other complications, at an incremental cost of $11,863 per quality-adjusted life-year saved from a societal perspective. Compared to ZVL, the model estimated that, RZV would prevent 71,638 additional HZ cases, 6403 PHN cases, and over 10,582 other complications, resulting in net total societal cost savings of over $96 million. The results were robust to a wide range of sensitivity analyses. Vaccination against HZ with RZV is cost-effective compared to No Vaccine and cost-saving compared to ZVL, in the US population aged 60+ YOA. Clinicaltrial.gov. registered#: NA.

C-myc represses transiently transfected HLA class I promoter sequences not locus-specifically.

Overexpression of the c-myc oncogene is frequently accompanied by downregulation of Major Histocompatibility Complex (MHC, HLA in humans) class I antigens. In human melanoma c-myc overexpression downmodulates HLA-B expression, whereas HLA-A is hardly affected. Repression of HLA-B is mediated through the core promoter, containing a CAAT-box and a non-conventional TATA-box. We show evidence that in transient transfection assays the HLA-A2 and HLA-B7 promoters are repressed by c-myc to the same extent. Therefore, other sequences of the HLA-A and HLA-B genes, possibly intron/exon sequences, should contribute to the locus B-specificity of the downregulation. Furthermore, c-myc does not seem to alter binding of protein complexes to the CAAT- or TATA-box of HLA-B7 or HLA-A2 in gel retardation assays. Comparison of promoters repressed by c-myc reveals a weak consensus sequence of the initiator (Inr) element: TCA(+1)YYYNY. The presence of a TCA sequence in the initiator region of the MHC class I promoter makes downregulation by c-myc through the Inr likely. We speculate that the Inr contributes to MHC class I promoter activity by stimulating recruitment of TFIID to the weak, non-conventional TATA-box, thereby making it susceptible to repression by c-myc through the Inr.

Activation of the mas oncogene involves coupling to human alphoid sequences.

We have shown previously that mouse NIH3T3 cells transfected with DNA from a human ovarian carcinoma were rendered tumourigenic by an activated mas oncogene in four independent transfection experiments. In all cases the 5'-noncoding region was rearranged in comparison to the original ovarian tumour DNA. We now report that in all four transfectants the newly acquired sequences consist of human centromeric alpha satellite repeat DNA. In at least three transfectants the alphoid DNA originates from the centromere of chromosome three. Analysis of the sequences of the recombination site in one transfectant revealed that a homologous sequence of five base pairs (CAGCA) is present in both parental strands, and might thus have contributed to the recombinational event. To establish a conclusive role for alphoid DNA in the activation of mas, we performed a co-transfection experiment in NIH3T3 cells with cloned alphoid DNA and the mas coding sequence. We show that the transfectants expressing a transformed phenotype contain amplified mas linked to alphoid DNA. NIH3T3 cells transfected with plasmids that contained alphoid sequences cloned directly upstream of the mas coding sequence, and injected into nude mice, gave rise to tumours with amplified mas sequences (7/7). In six of these tumours the alphoid sequences were amplified as well. Our data suggest a novel mechanism of oncogene activation: recombination with normal alphoid repeat DNA resulting in amplification of the oncogene.

Isolation and characterization of the rat glutamine synthetase-encoding gene.

From a rat genomic library in phage lambda Charon4A, a complete glutamine synthetase-encoding gene was isolated. The gene is 9.5-10 kb long, consists of seven exons, and codes for two mRNA species of 1375 nucleotides (nt) and 2787 nt, respectively. For both mRNAs, full-length cDNAs containing a short poly(A) tract were identified. The sequences of the entire mRNA and of the exon-intron transitions were determined. The smaller mRNA is identical to the 5' 1375 nt of the long mRNA and contains the entire protein-coding region. The position of the transcription start point was mapped. Within the first 118 bp of promoter sequence, a (T)ATAA-box, a CCAAT-box and an SP1-binding site were identified.