Translational Application of Circulating DNA in Oncology: Review of the Last Decades Achievements.
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ABSTRACT:
SUBMITTER: Tuaeva NO
PROVIDER: S-EPMC6829588 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
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Project description:Circulating tumor DNA (ctDNA) has emerged as a potential new biomarker with diagnostic, predictive, and prognostic applications for various solid tumor types. Before beginning large prospective clinical trials to prove the added value of utilizing ctDNA in clinical practice, it is essential to investigate the effects of various preanalytical conditions on the quality of cell-free DNA (cfDNA) in general and of ctDNA in particular in order to optimize and standardize these conditions. Whole blood samples were collected from patients with metastatic cancer bearing a known somatic variant. The following preanalytical conditions were investigated: (a) different time intervals to plasma isolation (1, 24, and 96 h) and (b) different preservatives in blood collection tubes (EDTA, CellSave, and BCT). The quality of cfDNA/ctDNA was assessed by DNA quantification, digital polymerase chain reaction (dPCR) for somatic variant detection and a ?-actin fragmentation assay for DNA contamination from lysed leukocytes. In 11 (69%) of our 16 patients, we were able to detect the known somatic variant in ctDNA. We observed a time-dependent increase in cfDNA concentrations in EDTA tubes, which was positively correlated with an increase in wild-type copy numbers and large DNA fragments (> 420 bp). Using different preservatives did not affect somatic variant detection ability, but did stabilize cfDNA concentrations over time. Variant allele frequency was affected by fluctuations in cfDNA concentration only in EDTA tubes at 96 h. Both CellSave and BCT tubes ensured optimal ctDNA quality in plasma processed within 96 h after blood collection for downstream somatic variant detection by dPCR.
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Project description:Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and the availability of "safer" antibiotics approved at that time. Therefore, knowledge on polymyxins had been scarce until recently, when enormous efforts have been made by several research teams around the world to elucidate the chemical, microbiological, pharmacokinetic/pharmacodynamic, and toxicological properties of polymyxins. One of the major achievements is the development of the first scientifically based dosage regimens for colistin that are crucial to ensure its safe and effective use in patients. Although the guideline has not been developed for polymyxin B, a large clinical trial is currently being conducted to optimize its clinical use. Importantly, several novel, safer polymyxin-like lipopeptides are developed to overcome the nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin. This review discusses the latest achievements on polymyxins and highlights the major challenges ahead in optimizing their clinical use and discovering new-generation polymyxins. To save lives from the deadly infections caused by Gram negative "superbugs," every effort must be made to improve the clinical utility of the last-line polymyxins. SIGNIFICANCE STATEMENT: Antimicrobial resistance poses a significant threat to global health. The increasing prevalence of multidrug-resistant (MDR) bacterial infections has been highlighted by leading global health organizations and authorities. Polymyxins are a last-line defense against difficult-to-treat MDR Gram negative pathogens. Unfortunately, the pharmacological information on polymyxins was very limited until recently. This review provides a comprehensive overview on the major achievements and challenges in polymyxin pharmacology and clinical use and how the recent findings have been employed to improve clinical practice worldwide.
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Project description:It is thought that the science of ecology has experienced conceptual shifts in recent decades, chiefly from viewing nature as static and balanced to a conception of constantly changing, unpredictable, complex ecosystems. Here, we ask if these changes are reflected in actual ecological research over the last 30 years. We surveyed 750 articles from the entire pool of ecological literature and 750 articles from eight leading journals. Each article was characterized according to its type, ecological domain, and applicability, and major topics. We found that, in contrast to its common image, ecology is still mostly a study of single species (70% of the studies); while ecosystem and community studies together comprise only a quarter of ecological research. Ecological science is somewhat conservative in its topics of research (about a third of all topics changed significantly through time), as well as in its basic methodologies and approaches. However, the growing proportion of problem-solving studies (from 9% in the 1980s to 20% in the 2000 s) may represent a major transition in ecological science in the long run.
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Project description:Changing trends of caesarean section during last twenty years have been studied. There seems to be a gradual increase in the incidence of caesarean section over the years with a simultaneous decline in the perinatal mortality rate. The incidence of caesarean section has slowly been increasing for post-caesarean pregnancy, breech presentation and foetal distress. This opens up a debate as to what extent this increase is justifiable. The trend needs a close observation.
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Project description:Background This retrospective single center study aimed to describe circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) utilization in a community practice for patients with advanced solid tumors. Methods All patients were included who were seen at the Scripps Hillcrest Oncology Clinic (San Diego, CA, USA) between September 2016 to March 2018 who had ctDNA assay testing performed. In this cohort, all ctDNA testing was performed to aid therapeutic decision making with wide variety in both the type of advanced solid tumor, as well as the line of therapy. Results Of the assays performed in the 41 patients included in this review, 42% of therapeutic actions following ctDNA assay results were influenced by the ctDNA result, including initiation of the corresponding Federal Drug Administration (FDA) approved therapy, placement on clinical trial, and initiation of off label-targeted options. In addition, CGP results guided clinicians away from futile or harmful treatments, such as EGFR inhibition in colorectal cancer patients with discovered KRAS mutations. No additional prognostic or therapeutic information was gathered in one quarter of patients for which ctDNA was drawn. Furthermore, discovered genomic alterations by ctDNA testing did not influence therapeutic action in 58% of cases. Conclusions These results highlight the conundrum that having additional information regarding an individual’s tumor biology does not yet translate into meaningful targeted therapy in the majority of cases. Further studies are needed regarding ctDNA utilization to help guide community oncologists who will continue to face the choice between targeted therapy, immunotherapy, and cytotoxic chemotherapy as science advances.
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Project description:ObjectiveAs the number of female medical students and surgical residents increases, the increasing number of female academic surgeons has been disproportionate. The purpose of this brief report is to evaluate the AAMC data from 1969 to 2018 to compare the level of female academic faculty representation for surgical specialties over the past four decades.DesignThe number of women as a percentage of the total surgeons per year were recorded for each year from 1969-2018, the most recent year available. Descriptive statistics were performed. Poisson regression examined the percentage of women in each field as the outcome of interest with the year and specialty (using general surgery as a reference) as two predictor variables.SettingData from the American Association of Medical Colleges (AAMC).ParticipantsAll full-time academic faculty physicians in the specialties of obstetrics and gynecology (OB/GYN), general surgery, ophthalmology, otolaryngology (ENT), plastic surgery, plastic surgery, urology, neurosurgery, orthopaedic surgery and cardiothoracic surgery as per AAMC records.ResultsThe percentage of women in surgery for all specialties evaluated increased from 1969 to 2018 (OR 1.04, p<0.001). Compared with general surgery, the rate of yearly percentage change increased more slowly in neurosurgery (OR 0.84; P = .004), orthopaedic surgery (OR 0.82; P = .002), urology (OR 0.59; P < .001), and cardiothoracic surgery (OR 0.38; P < .001). There was no significant difference in the rate of yearly percentage change for plastic surgery (OR 1.01; P = .840). The rate of yearly percentage change increased more rapidly in OB/GYN (OR 2.86; P < .001), ophthalmology (OR 1.79; P < .001) and ENT (OR 1.70; P < .001).ConclusionsRepresentation of women in academic surgery is increasing overall but is increasing more slowly in orthopaedic surgery, neurosurgery, cardiothoracic surgery and urology compared with that in general surgery. These data may be used to inform and further the discussion of how mentorship and sponsorship of female students and trainees interested in surgical careers may improve gender equity in the future.
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Project description:Dyslexia, a specific reading disability, is a common (up to 10% of children) and highly heritable (~70%) neurodevelopmental disorder. Behavioral and molecular genetic approaches are aimed towards dissecting its significant genetic component. In the proposed review, we will summarize advances in twin and molecular genetic research from the past 20 years. First, we will briefly outline the clinical and educational presentation and epidemiology of dyslexia. Next, we will summarize results from twin studies, followed by molecular genetic research (e.g., genome-wide association studies (GWASs)). In particular, we will highlight converging key insights from genetic research. (1) Dyslexia is a highly polygenic neurodevelopmental disorder with a complex genetic architecture. (2) Dyslexia categories share a large proportion of genetics with continuously distributed measures of reading skills, with shared genetic risks also seen across development. (3) Dyslexia genetic risks are shared with those implicated in many other neurodevelopmental disorders (e.g., developmental language disorder and dyscalculia). Finally, we will discuss the implications and future directions. As the diversity of genetic studies continues to increase through international collaborate efforts, we will highlight the challenges in advances of genetics discoveries in this field.
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Project description:BACKGROUND: DNA barcoding has been successfully established in animals as a tool for organismal identification and taxonomic clarification. Slower nucleotide substitution rates in plant genomes have made the selection of a DNA barcode for land plants a much more difficult task. The Plant Working Group of the Consortium for the Barcode of Life (CBOL) recommended the two-marker combination rbcL/matK as a pragmatic solution to a complex trade-off between universality, sequence quality, discrimination, and cost. METHODOLOGY/PRINCIPAL FINDINGS: It is expected that a system based on any one, or a small number of plastid genes will fail within certain taxonomic groups with low amounts of plastid variation, while performing well in others. We tested the effectiveness of the proposed CBOL Plant Working Group barcoding markers for land plants in identifying 46 bromeliad species, a group rich in endemic species from the endangered Brazilian Atlantic Rainforest. Although we obtained high quality sequences with the suggested primers, species discrimination in our data set was only 43.48%. Addition of a third marker, trnH-psbA, did not show significant improvement. This species identification failure in Bromeliaceaecould also be seen in the analysis of the GenBank's matK data set. Bromeliaceae's sequence divergence was almost three times lower than the observed for Asteraceae and Orchidaceae. This low variation rate also resulted in poorly resolved tree topologies. Among the three Bromeliaceae subfamilies sampled, Tillandsioideae was the only one recovered as a monophyletic group with high bootstrap value (98.6%). Species paraphyly was a common feature in our sampling. CONCLUSIONS/SIGNIFICANCE: Our results show that although DNA barcoding is an important tool for biodiversity assessment, it tends to fail in taxonomy complicated and recently diverged plant groups, such as Bromeliaceae. Additional research might be needed to develop markers capable to discriminate species in these complex botanical groups.
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