Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Davies, Helen,Morganella, Sandro,Purdie, Colin A.,Jang, Se Jin,Borgen, Elin,Russnes, Hege,Glodzik, Dominik,Zou, Xueqing,Viari, Alain,Richardson, Andrea L.,Børresen-Dale, Anne-Lise,Thompson, Alastair,E American Association for Cancer Research 2017 Cancer Research Vol.77 No.18

<P>The effectiveness of PD-1 blockade against DNA mismatch repair-deficient cancers makes it paramount to reliably identify the relatively rare cases beyond those with Lynch syndrome–associated colon cancers.</P><P>Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. <I>Cancer Res; 77(18); 4755–62. ©2017 AACR</I>.</P>

Is Screening for Type 2 diabetes Justified?

Davies, Melanie J Medical Publications Korea 1999 Medical Progress Vol.21 No.5

Regulatory Aspects of Passenger and Crew Safety: Crash Survivability and the Emergency Brace Position

Davies, Jan M. Korea Society of AirSpace Law and Policy 2018 한국항공우주정책·법학회지 Vol.33 No.2

Aviation's safety record continues to improve yearly, especially with respect to passenger and crew injuries and deaths. However, although the number of accidents has decreased over the decades, there are still many events, such as landings short of the runway and runway excursions, both of which pose threats to passenger and crew safety. Surviving any kind of aviation accident depends on the physiological threat and stress of the impact(s), the extent to which the physical structure surrounding the passengers and crew remains intact, and the ability of the passengers and crew to be able to escape the wreckage. The one action that both passengers and crew can carry out to help decrease the likelihood of crash-related injury or death is to assume an emergency brace position. Doing so has been demonstrated over several decades to improve survivability. While cabin crew are taught (and then might have to teach passengers in an emergency about the emergency brace position), passengers in many parts of the world never learn about the brace position unless they are involved in an emergency in which there is time to prepare for the landing. This lack of provision of information is related to the fact that most airlines do not provide information in the preflight safety briefing and some do not even provide the information in the passenger safety cards. Many countries do not require their airlines to do so, a fact, which in turn, is related to the lack of mention of the brace position in ICAO's Annex 6. Until standards and recommended practices are changed at the highest world level, passengers will continue to be deprived of this vital, life-saving information that they can use, potentially to help save their own lives.

Tuberculosis in the Elderly : Epidemiology and Optimal Management

Davies, Peter D.O. Medical Publications Korea 1996 Medical Progress Vol.18 No.9

Treatment of Anxiety Symptoms In General Practice

Davies, Brian Medical Publications Korea 1975 Medical Progress Vol.2 No.7

HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures

Davies, Helen,Glodzik, Dominik,Morganella, Sandro,Yates, Lucy R,Staaf, Johan,Zou, Xueqing,Ramakrishna, Manasa,Martin, Sancha,Boyault, Sandrine,Sieuwerts, Anieta M,Simpson, Peter T,King, Tari A,Raine, Nature Publishing Group, a division of Macmillan P 2017 Nature medicine Vol.23 No.4

<P>Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (similar to 1-5%) who could have selective therapeutic sensitivity to PARP inhibition.</P>

Nonlinear System Modeling and Identification

Davies,Patricia 대한기계학회 1993 Korea - U. S. Vibration Engineering Seminar Vol.1 No.1

Digital models have been used extensively to model the relationship between the sampled input and sampled output of vibrating linear systems. By using established mapping techniques, the parameters of these digital models can be translated into estimates of physical parameters, such as natural frequencies, damping ratios and modal amplitudes. The use of digital models to model the relationship between the sampled input and sampled output of nonlinear systems is not so widespread. Mapping between the digital model parameters and the physical parameters that describe the system behavior is not straightforward. The paper will contain an overview of system identification techniques for nonlinear systems. The use of some of the techniques to identify the behavior of thin plates with coincident natural frequencies will be discussed.

Jet Fuel Intoxication

Davies, Nocholas E.,金肯培 공군본부 의무감실 1964 항공의학 Vol.12 No.2

The Theology of Henry G. Appenzeller.

Davies, Daniel M. 성화대학교 1993 成和論叢 Vol.- No.1

Henry G. Appenzeller (1858-1902), raised by pious German Reformed parents and in the German Reformed Church of Pennsylvania, had a rebirth experience in 1876. He joined the Methodist Church in Lancaster, Pennsylvania in 1880 while attending the German Reformed Franklin and Marshall College. By 1882, when he entered Drew Theological Seminary in New Jersey to become a Methodist minister, Appenzeller had been immersed in the Heidelberg Catechism, Mercersburg Theology, and Methodist preaching. At Drew theological Seminary, Appenzeller received theological training from the "Great Five" (Strong, Miley, Buttz, Upham, and Crooks) and imbibed the pietistic spiritual atmosphere of the seminary. He continued his theological education in Korea through the study course required of all ordained Methodist ministers. Both as a student at Drew Theological Seminary and as a missionary in Korea, Appenzeller embraced a evangelical theology that reflected the Heidelberg Catechism, Mercersburg theology, and the teachings of the Great Five. He held conversion and sanctification as his paramount concerns, placing Jesus Christ and redemption through the Cross at the center of his theology. He concerned himself only with those theological categories, both at Drew Theological Seminary and in Korea, that he found pertinent to conversion and sanctification. In Korea, Appenzeller's theology developed through the influence of escapism and liberal theological ideas. Appenzeller's theology set the direction for theology in Korea that has continued until today. It is impossible to understand the evangelical, conservative character of present day Protestant theology in Korea without taking into account the impact of Appenzeller's theology.

Computer-aided design of metal chalcohalide semiconductors: from chemical composition to crystal structure

Davies, Daniel ,W.,Butler, Keith T.,Skelton, Jonathan M.,Xie, Congwei,Oganov, Artem R.,Walsh, Aron Royal Society of Chemistry 2018 Chemical Science Vol.9 No.4

<▼1><P>The standard paradigm in computational materials science is INPUT: <SMALL>STRUCTURE;</SMALL> OUTPUT: <SMALL>PROPERTIES</SMALL>, which has yielded many successes but is ill-suited for exploring large areas of chemical and configurational hyperspace.</P></▼1><▼2><P>The standard paradigm in computational materials science is INPUT: S<SMALL>TRUCTURE</SMALL>; OUTPUT: P<SMALL>ROPERTIES</SMALL>, which has yielded many successes but is ill-suited for exploring large areas of chemical and configurational hyperspace. We report a high-throughput screening procedure that uses compositional descriptors to search for new photoactive semiconducting compounds. We show how feeding high-ranking element combinations to structure prediction algorithms can constitute a pragmatic computer-aided materials design approach. Techniques based on structural analogy (data mining of known lattice types) and global searches (direct optimisation using evolutionary algorithms) are combined for translating between chemical composition and crystal structure. The properties of four novel chalcohalides (Sn<SUB>5</SUB>S<SUB>4</SUB>Cl<SUB>2</SUB>, Sn<SUB>4</SUB>SF<SUB>6</SUB>, Cd<SUB>5</SUB>S<SUB>4</SUB>Cl<SUB>2</SUB> and Cd<SUB>4</SUB>SF<SUB>6</SUB>) are predicted, of which two are calculated to have bandgaps in the visible range of the electromagnetic spectrum.</P></▼2>