22 research outputs found
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The molecularisation of security: medical countermeasure development and the Biomedical Advanced Research and Development Authority (BARDA), 2006-2015
How do advances in our varied understandings of biological life processes shape and influence contemporary security practices? Through an in-depth analysis of the Biomedical Advanced Research and Development Authority (BARDA), this thesis argues that security practices in the United States have undergone a process of molecularisation over the past two decades. Specifically, the thesis shows that: 1) a new molecular vision of life has emerged that operates beyond the parameters of biopolitics outlined by Foucault; 2) that this molecular conception of life is generating new notions of insecurity in the form of heightened concern with the threat of bioterrorism; and 3) that this shift in perceptions is also inciting the development of new molecular-based security technologies in the form of medical countermeasures. BARDA is the institution at the centre of government efforts in the United States to support companies in the development of medical countermeasures that aim to mitigate a bioterrorist attack. Such support is necessary as development is beset by the 'valley of death', the financial desert between preclinical research & development and procurement. Through financial and technical means BARDA facilitates the production of medical countermeasures through this valley. This support allows companies to take advantage of our ability to visualise and manipulate life at the molecular level made possible by the molecular vision of life. As this thesis demonstrates, our ability to map and manipulate DNA and visualise the bacterial structures that process DNA is essential to the development of these molecular-based security technologies. Through this exposition the way that this vision of life is driving understandings of security and insecurity in response to the threat of bioterrorism is demonstrated. In this case, our ability to visualise and manipulate life at the molecular level has characterised security in molecular terms
Additional file 4: Table S2. of Pitfalls of improperly procured adjacent non-neoplastic tissue for somatic mutation analysis using next-generation sequencing
Detailed information of all somatic mutations identified by WES, including coverage, variant allele fraction (VAF) and the predicted amino acid changes. (XLSX 19 kb
Additional file 3: Table S1. of Pitfalls of improperly procured adjacent non-neoplastic tissue for somatic mutation analysis using next-generation sequencing
Coverage summary of whole-exome sequencing (WES). (XLSX 12 kb
Treatment recommendations to cancer patients in the context of FDA guidance for next generation sequencing
Abstract Background Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations. Methods NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients’ medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated. Results Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively). Conclusions We found an appropriate “dose-response” relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance
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Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients.
BackgroundBiomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice.MethodsTumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome.ResultsFor 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant (p = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved (p = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%).ConclusionsCell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progression-free survival (PFS) along with sufficiently powered subgroups are required to further support these findings
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Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients.
BackgroundBiomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice.MethodsTumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome.ResultsFor 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant (p = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved (p = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%).ConclusionsCell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progression-free survival (PFS) along with sufficiently powered subgroups are required to further support these findings