RANTES (regulated on activation normal T cell expressed and secreted) is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showed that peripheral blood mononuclear cells or CD4 ؉ lymphocytes obtained from different individuals had wide variations in their ability to secrete RANTES. These findings prompted us to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. Our results showed that there were two polymorphic positions, one of which was associated with reduced CD4 ؉ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This mutation, RANTES؊28G, occurred at an allele frequency of Ϸ17% in the non-HIV-1-infected Japanese population and exerted no inf luence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the RANTES؊28G mutation increases transcription of the RAN-TES gene. Taken together, these data suggest that the RANTES؊28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease.The chemokine receptor CCR5 is an essential coreceptor for the cellular entry of R5 strains (macrophage tropic͞non-syncytium-inducing strains) of HIV-1 (1-6), which predominate in the early stages of infection (7). During the course of infection, variants called X4 strains (T cell-line tropic͞ syncytium-inducing strains) emerge (1, 8-11), which use CXCR4 as a coreceptor (12). In vitro replication of R5 strains can be blocked by the ligands for CCR5, macrophage inflammatory peptide-1␣ and -1, and RANTES (regulated on activation normal T cell expressed and secreted; refs. 13 and 14), whereas that of X4 strains can be blocked by the CXCR4 ligands stromal cell derived factor-1␣ and -1 (15, 16).Mutations in HIV-1 coreceptors and their natural ligand genes have been shown to modify HIV-1 transmission and disease progression. Individuals homozygous for a 32-nt deletion in the CCR5 coding region were resistant to HIV-1 infection (17, 18), whereas heterozygosity delays disease progression (19,20). A single V-to-I substitution in the first transmembrane segment of CCR2, a minor coreceptor for dual tropic R5X4 strains (3, 5), has a significant impact on disease progression but not on HIV-1 transmission in cohorts of seroconverters (21,22). Finally, homozygosity of a single G-to-A mutation in the 3Ј noncoding region of the stromal cell derived factor-1 gene also showed a disease-retarding effect (23), although later studies could not confirm this effect (24,25).Among three natural CCR5 ligands, RANTES showed the highest potency to suppress in vitro replication of R5 strains of HIV-1 (13). Phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) or CD4 ϩ enriched lymphocytes obtained from different...
SummaryBackground30-day mortality might be a useful indicator of avoidable harm to patients from systemic anticancer treatments, but data for this indicator are limited. The Systemic Anti-Cancer Therapy (SACT) dataset collated by Public Health England allows the assessment of factors affecting 30-day mortality in a national patient population. The aim of this first study based on the SACT dataset was to establish national 30-day mortality benchmarks for breast and lung cancer patients receiving SACT in England, and to start to identify where patient care could be improved.MethodsIn this population-based study, we included all women with breast cancer and all men and women with lung cancer residing in England, who were 24 years or older and who started a cycle of SACT in 2014 irrespective of the number of previous treatment cycles or programmes, and irrespective of their position within the disease trajectory. We calculated 30-day mortality after the most recent cycle of SACT for those patients. We did logistic regression analyses, adjusting for relevant factors, to examine whether patient, tumour, or treatment-related factors were associated with the risk of 30-day mortality. For each cancer type and intent, we calculated 30-day mortality rates and patient volume at the hospital trust level, and contrasted these in a funnel plot.FindingsBetween Jan 1, and Dec, 31, 2014, we included 23 228 patients with breast cancer and 9634 patients with non-small cell lung cancer (NSCLC) in our regression and trust-level analyses. 30-day mortality increased with age for both patients with breast cancer and patients with NSCLC treated with curative intent, and decreased with age for patients receiving palliative SACT (breast curative: odds ratio [OR] 1·085, 99% CI 1·040–1·132; p<0·0001; NSCLC curative: 1·045, 1·013–1·079; p=0·00033; breast palliative: 0·987, 0·977–0·996; p=0·00034; NSCLC palliative: 0·987, 0·976–0·998; p=0·0015). 30-day mortality was also significantly higher for patients receiving their first reported curative or palliative SACT versus those who received SACT previously (breast palliative: OR 2·326 99% CI 1·634–3·312; p<0·0001; NSCLC curative: 3·371, 1·554–7·316; p<0·0001; NSCLC palliative: 2·667, 2·109–3·373; p<0·0001), and for patients with worse general wellbeing (performance status 2–4) versus those who were generally well (breast curative: 6·057, 1·333–27·513; p=0·0021; breast palliative: 6·241, 4·180–9·319; p<0·0001; NSCLC palliative: 3·384, 2·276–5·032; p<0·0001). We identified trusts with mortality rates in excess of the 95% control limits; this included seven for curative breast cancer, four for palliative breast cancer, five for curative NSCLC, and seven for palliative NSCLC.InterpretationOur findings show that several factors affect the risk of early mortality of breast and lung cancer patients in England and that some groups are at a substantially increased risk of 30-day mortality. The identification of hospitals with significantly higher 30-day mortality rates should promote review of clinical dec...
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