1,470 research outputs found
Methylation patterns in serum DNA for early identification of disseminated breast cancer
Get PDFBACKGROUND: Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need.
Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We
hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of
substantial quantities of background DNA.
METHODS: We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays
based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical
use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy
samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as
Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative
Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer
(which will or will not lead to death), respectively, as primary endpoints.
RESULTS: A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in
serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in
pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs)
(HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in
their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy
samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25%
of women who were diagnosed with a fatal BC within 3–6 and 6–12 months of sample donation, respectively, with a
specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC.
CONCLUSIONS: Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of
disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of
radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become
clinically apparent
DNA methylation markers for early detection of women's cancer: promise and challenges
Get PDFBreast, ovarian and endometrial cancers cause significant morbidity and mortality. Despite the presence of existing screening, diagnostic and treatment modalities, they continue to pose considerable unsolved challenges. Overdiagnosis is a growing problem in breast cancer screening and neither screening nor early diagnosis of ovarian or endometrial cancer is currently possible. Moreover, treatment of the diversity of these cancers presenting in the clinic is not sufficiently personalized at present. Recent technological advances, including reduced representation bisulfite sequencing, methylation arrays, digital PCR, next-generation sequencing and advanced statistical data analysis, enable the analysis of methylation patterns in cell-free tumor DNA in serum/plasma. Ongoing work is bringing these methods together for the analysis of samples from large clinical trials, which have been collected well in advance of cancer diagnosis. These efforts pave the way for the development of a noninvasive method that would enable us to overcome existing challenges to personalized medicine
CRPV Genomes with Synonymous Codon Optimizations in the CRPV E7 Gene Show Phenotypic Differences in Growth and Altered Immunity upon E7 Vaccination
Get PDFPapillomaviruses use rare codons relative to their hosts. Recent studies have demonstrated that synonymous codon changes in viral genes can lead to increased protein production when the codons are matched to those of cells in which the protein is being expressed. We theorized that the immunogenicity of the virus would be enhanced by matching codons of selected viral genes to those of the host. We report here that synonymous codon changes in the E7 oncogene are tolerated in the context of the cottontail rabbit papillomavirus (CRPV) genome. Papilloma growth rates differ depending upon the changes made indicating that synonymous codons are not necessarily neutral. Immunization with wild type E7 DNA yielded significant protection from subsequent challenge by both wild type and codon-modified genomes. The reduction in growth was most dramatic with the genome containing the greatest number of synonymous codon changes
Protection of Sinorhizobium against Host Cysteine-Rich Antimicrobial Peptides Is Critical for Symbiosis
Get PDFA bacterial membrane protein, BacA, protects Sinorhizobium meliloti against the antimicrobial activity of host peptides, enabling the peptides to induce bacterial persistence rather than bacterial death
Archaeology of insular sectors in the Beagle Channel (Argentina). The case of the archipelago of the Bridges Islands and adjacent islands
Get PDFEn este trabajo se exponen los resultados de las recientes investigaciones arqueológicas realizadas en el sector del archipiélago de las islas Bridges e islas adyacentes (canal Beagle, Tierra del Fuego, Argentina). El uso del ambiente que llevaron a cabo los cazadores-recolectores marítimos de esta región es conocido a partir de los estudios efectuados principalmente en sitios arqueológicos de la costa sur de la Isla Grande de Tierra del Fuego y de la costa norte de la isla Navarino. Hasta el momento no se había desarrollado de manera sistemática el estudio de islas pequeñas o islotes en el canal Beagle. Aquí se analiza el uso del archipiélago de las islas Bridges en relación con la distribución espacial y temporal de los sitios, así como el estudio de las estrategias humanas de su ocupación en función de la composición de los conjuntos arqueológicos. Los resultados obtenidos evidencian que el archipiélago de las islas Bridges fue integrado en los circuitos de movilidad regional desde el Holoceno medio, aunque los hallazgos indican una baja intensidad de ocupación para estos momentos. La elevada frecuencia de estructuras de concheros, así como el tamaño de sitios arqueológicos registrados en sectores circundantes a la línea de costa actual señalan una mayor intensidad de ocupación para momentos más tardíos del Holoceno. En conclusión, esta evidencia y la composición de los conjuntos arqueológicos conducen a sostener un uso programado de estos espacios a partir de la obtención de recursos que resultan críticos para la habitabilidad humana de estos sectores.This paper presents the results of recent archaeological investigations carried out in the Bridges Islands archipelago and adjacent islands (Beagle Channel, Tierra del Fuego, Argentina). The use of this environment by maritime hunter-gatherers is known from research carried out mainly in archaeological sites along the southern coast of the Isla Grande de Tierra del Fuego and the northern coast of Navarino Island. Until now, the study of small islands or islets in the Beagle Channel had not been systematically developed. Here, we analyze the use of the Bridges Islands archipelago in relation to the spatial and temporal distribution of the archaeological sites, as well as the study of human subsistence and settlement patterns, based on the composition of the archaeological assemblages. The results obtained show that the archipelago of the Bridges Islands was integrated into the regional mobility circuits since the Middle Holocene, although the findings indicate a low occupation intensity by that time. The high frequency of shell middens, as well as the size of archaeological sites recorded in sectors near the current coastline, points to a greater intensity of occupation for later moments of the Holocene. In conclusion, this evidence and the composition of archaeological assemblages lead to sustain a planned use of these spaces from the procurement of critical resources for the human habitability of these sectors
Search for narrow resonances in dilepton mass spectra in proton-proton collisions at root s=13 TeV and combination with 8 TeV data
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