Matter-wave Atomic Gradiometer Interferometric Sensor (MAGIS-100)

MAGIS-100 is a next-generation quantum sensor under construction at Fermilab that aims to explore fundamental physics with atom interferometry over a 100-meter baseline. This novel detector will search for ultralight dark matter, test quantum mechanics in new regimes, and serve as a technology pathfinder for future gravitational wave detectors in a previously unexplored frequency band. It combines techniques demonstrated in state-of-the-art 10-meter-scale atom interferometers with the latest technological advances of the world's best atomic clocks. MAGIS-100 will provide a development platform for a future kilometer-scale detector that would be sufficiently sensitive to detect gravitational waves from known sources. Here we present the science case for the MAGIS concept, review the operating principles of the detector, describe the instrument design, and study the detector systematics.Comment: 65 pages, 18 figure

The Bioinformatics Virtual Coordination Network: An open-source and interactive learning environment

Lockdowns and “stay-at-home” orders, starting in March 2020, shuttered bench and field dependent research across the world as a consequence of the global COVID-19 pandemic. The pandemic continues to have an impact on research progress and career development, especially for graduate students and early career researchers, as strict social distance limitations stifle ongoing research and impede in-person educational programs. The goal of the Bioinformatics Virtual Coordination Network (BVCN) was to reduce some of these impacts by helping research biologists learn new skills and initiate computational projects as alternative ways to carry out their research. The BVCN was founded in April 2020, at the peak of initial shutdowns, by an international group of early-career microbiology researchers with expertise in bioinformatics and computational biology. The BVCN instructors identified several foundational bioinformatic topics and organized hands-on tutorials through cloud-based platforms that had minimal hardware requirements (in order to maximize accessibility) such as RStudio Cloud and MyBinder. The major topics included the Unix terminal interface, R and Python programming languages, amplicon analysis, metagenomics, functional protein annotation, transcriptome analysis, network science, and population genetics and comparative genomics. The BVCN was structured as an open-access resource with a central hub providing access to all lesson content and hands-on tutorials (https://biovcnet.github.io/). As laboratories reopened and participants returned to previous commitments, the BVCN evolved: while the platform continues to enable “a la carte” lessons for learning computational skills, new and ongoing collaborative projects were initiated among instructors and participants, including a virtual, open-access bioinformatics conference in June 2021. In this manuscript we discuss the history, successes, and challenges of the BVCN initiative, highlighting how the lessons learned and strategies implemented may be applicable to the development and planning of future courses, workshops, and training programs

Toward a 21st-century health care system: Recommendations for health care reform

The coverage, cost, and quality problems of the U.S. health care system are evident. Sustainable health care reform must go beyond financing expanded access to care to substantially changing the organization and delivery of care. The FRESH-Thinking Project (www.fresh-thinking.org) held a series of workshops during which physicians, health policy experts, health insurance executives, business leaders, hospital administrators, economists, and others who represent diverse perspectives came together. This group agreed that the following 8 recommendations are fundamental to successful reform: 1. Replace the current fee-for-service payment system with a payment system that encourages and rewards innovation in the efficient delivery of quality care. The new payment system should invest in the development of outcome measures to guide payment. 2. Establish a securely funded, independent agency to sponsor and evaluate research on the comparative effectiveness of drugs, devices, and other medical interventions. 3. Simplify and rationalize federal and state laws and regulations to facilitate organizational innovation, support care coordination, and streamline financial and administrative functions. 4. Develop a health information technology infrastructure with national standards of interoperability to promote data exchange. 5. Create a national health database with the participation of all payers, delivery systems, and others who own health care data. Agree on methods to make de-identified information from this database on clinical interventions, patient outcomes, and costs available to researchers. 6. Identify revenue sources, including a cap on the tax exclusion of employer-based health insurance, to subsidize health care coverage with the goal of insuring all Americans. 7. Create state or regional insurance exchanges to pool risk, so that Americans without access to employer-based or other group insurance could obtain a standard benefits package through these exchanges. Employers should also be allowed to participate in these exchanges for their employees' coverage. 8. Create a health coverage board with broad stakeholder representation to determine and periodically update the affordable standard benefit package available through state or regional insurance exchanges

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response

Melanoma: A model for testing new agents in combination therapies

Treatment for both early and advanced melanoma has changed little since the introduction of interferon and IL-2 in the early 1990s. Recent data from trials testing targeted agents or immune modulators suggest the promise of new strategies to treat patients with advanced melanoma. These include a new generation of B-RAF inhibitors with greater selectivity for the mutant protein, c-Kit inhibitors, anti-angiogenesis agents, the immune modulators anti-CTLA4, anti-PD-1, and anti-CD40, and adoptive cellular therapies. The high success rate of mutant B-RAF and c-Kit inhibitors relies on the selection of patients with corresponding mutations. However, although response rates with small molecule inhibitors are high, most are not durable. Moreover, for a large subset of patients, reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress may also depend on identifying additional molecular targets, which in turn depends upon a better understanding of the mechanisms leading to response or resistance. More challenging but equally important will be understanding how to optimize the treatment of individual patients using these active agents sequentially or in combination with each other, with other experimental treatment, or with traditional anticancer modalities such as chemotherapy, radiation, or surgery. Compared to the standard approach of developing new single agents for licensing in advanced disease, the identification and validation of patient specific and multi-modality treatments will require increased involvement by several stakeholders in designing trials aimed at identifying, even in early stages of drug development, the most effective way to use molecularly guided approaches to treat tumors as they evolve over time

Cellular processes of v-Src transformation revealed by gene profiling of primary cells - Implications for human cancer

<p>Abstract</p> <p>Background</p> <p>Cell transformation by the Src tyrosine kinase is characterized by extensive changes in gene expression. In this study, we took advantage of several strains of the Rous sarcoma virus (RSV) to characterize the patterns of v-Src-dependent gene expression in two different primary cell types, namely chicken embryo fibroblasts (CEF) and chicken neuroretinal (CNR) cells. We identified a common set of v-Src regulated genes and assessed if their expression is associated with disease-free survival using several independent human tumor data sets.</p> <p>Methods</p> <p>CEF and CNR cells were infected with transforming, non-transforming, and temperature sensitive mutants of RSV to identify the patterns of gene expression in response to v-Src-transformation. Microarray analysis was used to measure changes in gene expression and to define a common set of v-Src regulated genes (CSR genes) in CEF and CNR cells. A clustering enrichment regime using the CSR genes and two independent breast tumor data-sets was used to identify a 42-gene aggressive tumor gene signature. The aggressive gene signature was tested for its prognostic value by conducting survival analyses on six additional tumor data sets.</p> <p>Results</p> <p>The analysis of CEF and CNR cells revealed that cell transformation by v-Src alters the expression of 6% of the protein coding genes of the genome. A common set of 175 v-Src regulated genes (CSR genes) was regulated in both CEF and CNR cells. Within the CSR gene set, a group of 42 v-Src inducible genes was associated with reduced disease- and metastasis-free survival in several independent patient cohorts with breast or lung cancer. Gene classes represented within this group include DNA replication, cell cycle, the DNA damage and stress responses, and blood vessel morphogenesis.</p> <p>Conclusion</p> <p>By studying the v-Src-dependent changes in gene expression in two types of primary cells, we identified a set of 42 inducible genes associated with poor prognosis in breast and lung cancer. The identification of these genes provides a set of biomarkers of aggressive tumor behavior and a framework for the study of cancer cells characterized by elevated Src kinase activity.</p