Minimum Technical Data Elements for Liquid Biopsy Data Submitted to Public Databases

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154656/1/cpt1747.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154656/2/cpt1747-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154656/3/cpt1747_am.pd

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

Emerging oncology drug targets in the 21st century: An FDA analysis

Abstract only e14067 Background: Traditional chemotherapy agents are cytotoxic and typically act on all rapidly dividing cells. In contrast, targeted cancer therapies take advantage of unique genetic or proteomic susceptibility in cancer cells, their microenvironment, or the immune system to selectively target tumor tissue or stimulate immune activity. We catalogued oncology drug approvals in the U.S. in the 21 st century to study the evolution of molecular targets over the last twenty years. Methods: We used internal FDA databases and data repositories to generate a dataset of all oncology approvals granted 1/1/2000-12/31/2019. This dataset was curated through a comprehensive survey of drug labels, drug reviews, and published literature to include target gene(s), mechanism of action, drug class, and approved indications for each drug. Approvals were grouped into five-year periods for trend analyses. Results: There has been an increase in the number of oncology approvals over the last twenty years, the vast majority of which are targeted therapies. There have been considerable recent advances in some disease sites. Three disease sites (ovary, bladder, and liver) had many approvals in the last five years after few to none 2000-2014; lung cancer and melanoma have seen substantial advances in the last ten years. Additionally, the first site-agnostic approvals occurred in the last five years. Kinase inhibitors are the most common drug class by both number of drugs and indications. Immune checkpoint inhibitors (ICI) are the second most common class by number of indications, despite having only entered the market in 2011 and being the sixth most common class by number of drugs. The target gene PD-1 has the highest number of approved indications, followed by EGFR and the BCR-ABL fusion gene. The number of novel genes targeted by drugs approved in 2010-2019 is nearly double that of 2000-2009, with the most novel gene targets in 2019 (n = 7). Conclusions: This analysis captures the landscape of targeted drug approvals in the 21 st century, including the continued dominance of kinase inhibitors despite the dramatic impact of ICIs on cancer care since their introduction in 2011. The promise of targeted therapy in oncology is especially evident from the introduction of site-agnostic indications, new approvals in cancer types with limited therapy options, and ICIs with many indications due to targeting tumors indirectly via the immune system. The continual introduction of novel gene targets provides a snapshot of ongoing novel drug development, and it will be interesting to see whether this trend continues over the next twenty years

Biogeography and co-occurrence of 16 planktonic species of Keratella Bory de St. Vincent, 1822 (Rotifera, Ploima, Brachionidae) in lakes and reservoirs of the United States

Tausz, Claudia E., Beaver, John R., Renicker, Thomas R., Klepach, Julia A., Pollard, Amina I., Mitchell, Richard M. (2019): Biogeography and co-occurrence of 16 planktonic species of Keratella Bory de St. Vincent, 1822 (Rotifera, Ploima, Brachionidae) in lakes and reservoirs of the United States. Zootaxa 4624 (3): 337-350, DOI: https://doi.org/10.11646/zootaxa.4624.3.