18 research outputs found
Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression.
BACKGROUND
DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown.
METHODS
We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24âh and 6âweeks) surgery. In a separate cohort (nâ=â189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival.
RESULTS
Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5âyears (HR 2.4; 95% CIs 1.2-4.8, pâ=â0.014).
CONCLUSIONS
CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease
Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma.
The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barrett's esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett's epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture
The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes
The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.The METABRIC project was funded by Cancer Research UK, the British Columbia Cancer Foundation and Canadian Breast Cancer Foundation BC/Yukon. This sequencing project was funded by CRUK grant C507/A16278 and Illumina UK performed all the sequencing. The authors also acknowledge the support of the University of Cambridge, Hutchinson Whampoa, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, the Centre for Translational Genomics (CTAG) Vancouver and the BCCA Breast Cancer Outcomes Unit. We thank the Genomics, Histopathology, and Biorepository Core Facilities at the Cancer Research UK Cambridge Institute, and the Addenbrookeâs Human Research Tissue Bank (supported by the National Institute for Health Research Cambridge Biomedical Research Centre).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1147
STOPPIT Baby Follow-Up Study:The Effect of Prophylactic Progesterone in Twin Pregnancy on Childhood Outcome
Funding: This study was funded by the Chief Scientist Office, Scotland (grant number CZH/2/575) and the charity, Tommyâs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: The STOPPIT Baby Follow-up Study uses two linked datasets, the STOPPIT clinical trial data and routine NHS data collected by Information Services Division (ISD), NHS Scotland. The governance and ethics approvals for this project around anonymity for the participants do not permit us to deposit the linked dataset on a publicly available website. Individuals wishing to access the STOPPIT clinical trial data should contact Professor Jane E Norman [email protected] or Professor John Norrie [email protected] for access. General information on how to access data held by ISD for research purposes is available from ISDâs research coordination team â see http://www.isdscotland.org/Products-and-âServices/eDRIS. Please contact Rachael Wood [email protected] for queries about the specific ISD data used in this study.Peer reviewedPublisher PD
Helen Northen interview, 1987
Northen, Helen - Oral History Interview - CSWA ⧠Interviewed by John Milner on June 10, 1987. An interview with Helen Northen as she discusses her entrance into social work; education: group work and case work at U. of Pittsburgh; field instructor at U. of Pittsburgh; Ph.D. at Bryn Mawr; position at University of Hawaii School of Social Work; position at USC in School of Social Work; teaching generic practice at USC; Metropolitan State Hospital Project, Los Angeles NIMH project; leadership in local and national programs, eg, Campfire girls; major changes in social work practice; agency vs. private practice; publications; chair of national conference held in LA in 1967; personal philosophy of social work; future plans. ⧠Helen Northen. Professor, USC School of Social Work. Interviewed by John Milner. Date of interview: 6-10-87. 1 cassette tape (no duplicate tape, although notation on envelope states one exists). Length of interview: 33 minutes. Transcript of interview: 13 pp. CD containing interview and transcript. ⧠INTERVIEW TOPICS: Entrance into social work; education: group work and case work at U. of Pittsburgh; field instructor at U. of Pittsburgh; Ph.D. at Bryn Mawr; position at University of Hawaii School of Social Work; position at USC in School of Social Work; teaching generic practice at USC; Metropolitan State Hospital Project, Los Angeles NIMH project; leadership in local and national programs, eg, Campfire girls; major changes in social work practice; agency vs. private practice; publications; chair of national conference held in LA in 1967; personal philosophy of social work; future plans. ⧠ADDITIONAL MATERIALS: 1. California Social Work Hall of Distinction Biography ( http://socialworkhallofdistinction.usc.edu/honorees/ ). 2. 1 videotape: "Helen Northen, Oral History." 3. Curriculum Vitae. 4. 2 3.5 x 4 in. photographs of two unidentified women (Helen Northen?). 5. 2 programs for "Phi Kappa Phi Annual Faculty Recognition Awards and Exhibition" (3-26-82). 6. Handwritten outline of interview topics, by John Milner
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Zn deficiency disrupts Cu and S homeostasis in Chlamydomonas resulting in over accumulation of Cu and Cysteine.
Growth of Chlamydomonas reinhardtii in zinc (Zn) limited medium leads to disruption of copper (Cu) homeostasis, resulting in up to 40-fold Cu over-accumulation relative to its typical Cu quota. We show that Chlamydomonas controls its Cu quota by balancing Cu import and export, which is disrupted in a Zn deficient cell, thus establishing a mechanistic connection between Cu and Zn homeostasis. Transcriptomics, proteomics and elemental profiling revealed that Zn-limited Chlamydomonas cells up-regulate a subset of genes encoding "first responder" proteins involved in sulfur (S) assimilation and consequently accumulate more intracellular S, which is incorporated into L-cysteine, Îł-glutamylcysteine, and homocysteine. Most prominently, in the absence of Zn, free L-cysteine is increased âŒ80-fold, corresponding to âŒ2.8 Ă 109 molecules/cell. Interestingly, classic S-containing metal binding ligands like glutathione and phytochelatins do not increase. X-ray fluorescence microscopy showed foci of S accumulation in Zn-limited cells that co-localize with Cu, phosphorus and calcium, consistent with Cu-thiol complexes in the acidocalcisome, the site of Cu(I) accumulation. Notably, cells that have been previously starved for Cu do not accumulate S or Cys, causally connecting cysteine synthesis with Cu accumulation. We suggest that cysteine is an in vivo Cu(I) ligand, perhaps ancestral, that buffers cytosolic Cu