PubMed Health⌕ Search

Biomedical subjects

Nicholas Williams

Publications and source records attributed to Nicholas Williams.

4 recordsLinked to original sources
PubMed2026

Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis.

UNLABELLED: Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts, but disease can progress to myelofibrosis or acute myeloid leukemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of hematopoietic colonies revealed age-appropriate polyclonal hematopoiesis in triple-negative essential thrombocythemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C > G mutations following azacitidine and characteristic T > A/T > G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate that progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis. SIGNIFICANCE: Longitudinal whole-genome sequencing shows MPN progression is genomically encoded years before clinical transformation, with distinct evolutionary routes to leukemia and MF. It identifies DNA mutagenesis associated with HC and 5-azacitidine, suggests some triple-negative cases are nonclonal, and supports serial clinical genomic monitoring for improved risk stratification and long-term management. See related commentary by Agarwal and Sankaran, p. 1724.

Humans↗
PubMed2006

Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer.

PURPOSE: The initial goal of this study was to test the immunologic and clinical effects of a new cancer vaccine consisting of dendritic cells (DC) transduced with the full-length wild-type p53 gene delivered via an adenoviral vector in patients with extensive stage small cell lung cancer. EXPERIMENTAL DESIGN: Twenty-nine patients with extensive stage small cell lung cancer were vaccinated repeatedly at 2-week intervals. Most of the patients received three immunizations. p53-specific responses were evaluated, and phenotype and function of T cells, DCs, and immature myeloid cells were analyzed and correlated with antigen-specific immune responses. Objective clinical response to vaccination as well as subsequent chemotherapy was evaluated. RESULTS: p53-specific T cell responses to vaccination were observed in 57.1% of patients. Immunologic responses to vaccination were positively associated with a moderate increase in the titer of antiadenovirus antibodies, and negatively with an accumulation of immature myeloid cells. One patient showed a clinical response to vaccination whereas most of the patients had disease progression. However, we observed a high rate of objective clinical responses to chemotherapy (61.9%) that immediately followed vaccination. Clinical response to subsequent chemotherapy was closely associated with induction of immunologic response to vaccination. CONCLUSIONS: This study provides clinical support for an emerging paradigm in cancer immunotherapy, wherein optimal use of vaccination might be more effective, not as a separate modality, but in direct combination with chemotherapy.

Adult↗
PubMed2006

Providing opioid substitution treatment to Indigenous heroin users within a community health service setting in Adelaide.

In the late 1990s there was major concern regarding heroin use among the Nunga community in Adelaide. [Nunga is a generic term used for Aboriginal people from South Australia, similar to Koori's from Victoria and Nyungars from south-western Australia.] Heroin use was so common that community members reported that most families were affected by it in some way. There were few Nunga specific services provided, and those mainstream services available were not seen as culturally appropriate or for other reasons were difficult to access. In response to this, the Parks Community Health Centre, together with the Drug and Alcohol Services Council (DASC) [in 2005 the Drug and Alcohol Services Council (DASC) changed its name to Drug and Alcohol Services South Australia (DASSA)], and with the assistance of Nunkuwarrin Yunti Aboriginal Health Service [Adelaide's Aboriginal Community Controlled Health Service, based in the City Centre], commenced a programme offering treatment interventions for Nunga heroin users. The 'Way Out' Program commenced in March 1999. It is multi-faceted and includes an opioid substitution programme which is attracting and maintaining Nunga clients in greater numbers than ever before in South Australia. The programme locates the drug problem within a holistic view of the individual's health. It utilises networks throughout the Nunga community and in recent years has formed a strong working partnership with the Aboriginal Kinship Program [the Aboriginal Kinship Program (Department of Human Services, Metropolitan Health Division) works with Aboriginal families and individuals seeking support for family members in relation to illicit drug issues by providing support, referral, follow-up and advocacy services]. The 'Way Out' Program is succeeding in making essential treatment services available to Aboriginal people using heroin within Adelaide. This article provides an overview of the programme.

Buprenorphine↗