Publications by authors named "H D Giles"

253 Publications

Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia.

Nat Cancer 2021 Aug 1;2(8):853-864. Epub 2021 Jul 1.

European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.

Chronic Lymphocytic Leukemia (CLL) has a complex pattern of driver mutations and much of its clinical diversity remains unexplained. We devised a method for simultaneous subgroup discovery across multiple data types and applied it to genomic, transcriptomic, DNA methylation and ex-vivo drug response data from 217 Chronic Lymphocytic Leukemia (CLL) cases. We uncovered a biological axis of heterogeneity strongly associated with clinical behavior and orthogonal to the known biomarkers. We validated its presence and clinical relevance in four independent cohorts (=547 patients). We find that this axis captures the proliferative drive (PD) of CLL cells, as it associates with lymphocyte doubling rate, global hypomethylation, accumulation of driver aberrations and response to pro-proliferative stimuli. CLL-PD was linked to the activation of mTOR-MYC-oxidative phosphorylation (OXPHOS) through transcriptomic, proteomic and single cell resolution analysis. CLL-PD is a key determinant of disease outcome in CLL. Our multi-table integration approach may be applicable to other tumors whose inter-individual differences are currently unexplained.
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http://dx.doi.org/10.1038/s43018-021-00216-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611543PMC
August 2021

The Science and Art of Clinical Genetic Variant Classification and Its Impact on Test Accuracy.

Annu Rev Genomics Hum Genet 2021 08 26;22:285-307. Epub 2021 Apr 26.

Center for Genomic Interpretation, Sandy, Utah 84092, USA; email:

Clinical genetic variant classification science is a growing subspecialty of clinical genetics and genomics. The field's continued improvement is essential for the success of precision medicine in both germline (hereditary) and somatic (oncology) contexts. This review focuses on variant classification for DNA next-generation sequencing tests. We first summarize current limitations in variant discovery and definition, and then describe the current five- and four-tier classification systems outlined in dominant standards and guideline publications for germline and somatic tests, respectively. We then discuss measures of variant classification discordance and the field's bias for positive results, as well as considerations for panel size and population screening in the context of estimates of positive predictive value thatincorporate estimated variant classification imperfections. Finally, we share opinions on the current state of variant classification from some of the authors of the most widely used standards and guideline publications and from other domain experts.
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http://dx.doi.org/10.1146/annurev-genom-121620-082709DOI Listing
August 2021

Genome Sequence of Lactiplantibacillus plantarum DmPark25_157, a Bacterial Strain Isolated from Drosophila melanogaster.

Microbiol Resour Announc 2021 Apr 22;10(16). Epub 2021 Apr 22.

Department of Plant and Wildlife Sciences, Brigham Young University, Provo, Utah, USA

We present the genome sequence of a bacterial strain isolated from mutants of as part of efforts to better understand the microbial communities in We isolated and sequenced a strain. We present a preliminary comparative analysis with a closely related strain.
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http://dx.doi.org/10.1128/MRA.01372-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063652PMC
April 2021

A novel excisional wound pain model for evaluation of analgesics in rats.

Korean J Pain 2021 Apr;34(2):165-175

Vapogenix Inc., Houston, TX, USA.

Background: Management of pain from open wounds is a growing unmet healthcare need. However, the models available to study pain from wounds or to develop analgesics for the patients suffering from them have primarily relied on incisional models. Here, we present the first characterized and validated model of open wound pain.

Methods: Unilateral full-skin excisional punch biopsy wounds on rat hind paws were evaluated for evoked pain using withdrawal responses to mechanical and thermal stimulation, and spontaneous pain was measured using hind paw weight distribution and guarding behavior. Evaluations were done before wounding (baseline) and 2-96 hours post-wounding. The model was validated by testing the effects of buprenorphine and carprofen.

Results: Pain responses to all tests increased within 2 hours post-wounding and were sustained for at least 4 days. Buprenorphine caused a reversal of all four pain responses at 1 and 4 hours post-treatment compared to 0.9% saline ( < 0.001). Carprofen decreased the pain response to thermal stimulation at 1 ( ≤ 0.049) and 4 hours ( < 0.011) post-treatment compared to 0.9% saline, but not to mechanical stimulation.

Conclusions: This is the first well-characterized and validated model of pain from open wounds and will allow study of the pathophysiology of pain in open wounds and the development of wound-specific analgesics. Key Words.
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http://dx.doi.org/10.3344/kjp.2021.34.2.165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019955PMC
April 2021

Spindle cell morphology in myeloma.

Br J Haematol 2021 06 2;193(5):861. Epub 2021 Mar 2.

Histopathology, Heart of England NHS Foundation Trust, Birmingham, UK.

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http://dx.doi.org/10.1111/bjh.17349DOI Listing
June 2021
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