Publications

Take a deeper look into all the publications produced by researchers at The Dartmouth Institute.

Jones HG, Battles MB, Lin CC, Bianchi S, Corti D, McLellan JS

2019 Jul 15;15(7):e1007944doi: 10.1371/journal.ppat.1007944

The respiratory syncytial virus (RSV) fusion (F) glycoprotein is a major target of neutralizing antibodies arising from natural infection, and antibodies that specifically bind to the prefusion conformation of RSV F generally demonstrate the greatest neutralization potency. Prefusion-stabilized RSV F variants have been engineered as vaccine antigens, but crystal structures of these variants have revealed conformational differences in a key antigenic site located at the apex of the trimer, referred to as antigenic site Ø. Currently, it is unclear if flexibility in this region is an inherent property of prefusion RSV F or if it is related to inadequate stabilization of site Ø in the engineered variants. Therefore, we set out to investigate the conformational flexibility of antigenic site Ø, as well as the ability of the human immune system to recognize alternative conformations of this site, by determining crystal structures of prefusion RSV F bound to neutralizing human-derived antibodies AM22 and RSD5. Both antibodies bound with high affinity and were specific for the prefusion conformation of RSV F. Crystal structures of the complexes revealed that the antibodies recognized distinct conformations of antigenic site Ø, each diverging at a conserved proline residue located in the middle of an α-helix. These data suggest that antigenic site Ø exists as an ensemble of conformations, with individual antibodies recognizing discrete states. Collectively, these results have implications for the refolding of pneumovirus and paramyxovirus fusion proteins and should inform development of prefusion-stabilized RSV F vaccine candidates.

PLoS Pathog|2019 Jul 15

Krans EE, Campopiano M, Cleveland LM, Goodman D, Kilday D, Kendig S, Leffert LR, Main EK, Mitchell KT, OʼGurek DT, DʼOria R, McDaniel D, Terplan M

2019 Jul 9;doi: 10.1097/AOG.0000000000003381

The opioid epidemic is a public health crisis, and pregnancy-associated morbidity and mortality due to substance use highlights the need to prioritize substance use as a major patient safety issue. To assist health care providers with this process and mitigate the effect of substance use on maternal and fetal safety, the National Partnership for Maternal Safety within the Council on Patient Safety in Women's Health Care has created a patient safety bundle to reduce adverse maternal and neonatal health outcomes associated with substance use. The Consensus Bundle on Obstetric Care for Women with Opioid Use Disorder provides a series of evidence-based recommendations to standardize and improve the quality of health care services for pregnant and postpartum women with opioid use disorder, which should be implemented in every maternity care setting. A series of implementation resources have been created to help providers, hospitals, and health systems translate guidelines into clinical practice, and multiple state-level Perinatal Quality Collaboratives are developing quality improvement initiatives to facilitate the bundle-adoption process. Structure, process, and outcome metrics have also been developed to monitor the adoption of evidence-based practices and ensure consistency in clinical care.

Obstet Gynecol|2019 Jul 9

LeBlanc RE, Yan S

2019 Jul 11;doi: 10.1097/PAS.0000000000001327

Am J Surg Pathol|2019 Jul 11

Lupien LE, Dunkley EM, Maloy MJ, Lehner IB, Foisey MG, Ouellette ME, Lewis LD, Bates Pooler D, Kinlaw WB, Baures PW

2019 Jul 12;pii: jpet.119.258947. doi: 10.1124/jpet.119.258947

It is well recognized that many cancers are "addicted" to a constant supply of fatty acids (FAs) and exhibit brisk FA synthesis. Upregulation of a key lipogenic enzyme, fatty acid synthase (FASN), is a near-universal feature of human cancers and their precursor lesions, and has been associated with chemoresistance, tumor metastasis, and diminished patient survival. FASN inhibition has been shown to be effective in killing cancer cells, but progress in the field has been hindered by off-target effects and poor pharmaceutical properties of candidate compounds. Our initial hit () was identified from a high-throughput screening effort by the Sanford-Burnham Center for Chemical Genomics using purified FASN thioesterase domain (FASN-TE). Despite being a potent inhibitor of purified FASN-TE, proved highly unstable in mouse plasma and only weakly cytotoxic to breast cancer (BC) cells in vitro. An iterative process of synthesis, cytotoxicity testing, and plasma stability assessment was used to identify a new lead (). This lead is more cytotoxic against multiple BC cell lines than (-)--C75, the literature standard for inhibiting FASN, is stable in mouse plasma, and shows negligible cytotoxic effects against non-tumorigenic mammary epithelial cells. Compound also has drug-like physical properties based on Lipinski's Rules and is therefore a valuable new lead for targeting fatty acid synthesis to exploit the requirement of tumor cells for fatty acids. SIGNIFICANCE STATEMENT: An iterative process of synthesis and biological testing was used to identify a novel thioesterase domain FASN inhibitor that has drug-like properties, is more cytotoxic to breast cancer cells than the widely used (-)--C75, and has negligible effects on the growth and proliferation of non-cancerous mammary epithelial cells. Our studies have both confirmed the value of using potent and selective FASN inhibitors in the treatment of BC cells and shown that the availability of exogenous lipoproteins may impact both cancer cell FA metabolism and survival.

J Pharmacol Exp Ther|2019 Jul 12

Lewis PJ, Catanzano TM, Davis LP, Jordan SG

2019 Jul 9;pii: S1076-6332(19)30307-1. doi: 10.1016/j.acra.2019.05.017

Advances in technology have resulted in the significant growth of web-based conferencing and teaching. While these remote sessions have many advantages, they may result in challenges and frustration for both host and attendees when there are technological issues, poor or distracting audio, or ineffective presentation styles. Knowing a few basic concepts behind web conferencing and preparing in advance can markedly improve the experience and facilitate effective distance learning and collaboration.

Acad Radiol|2019 Jul 9

Ouayogodé MH, Mainor AJ, Meara E, Bynum JPW, Colla CH

2019 Jul 3;2(7):e196939doi: 10.1001/jamanetworkopen.2019.6939

People with complex needs account for a disproportionate amount of Medicare spending, partially because of fragmented care delivered across multiple practitioners and settings. Accountable care organization (ACO) contracts give practitioners incentives to improve care coordination to the extent that coordination initiatives reduce total spending or improve quality.

JAMA Netw Open|2019 Jul 3

Divakar P, Moodie KL, Demidenko E, Jack Hoopes P, Wegst UGK

2019 Jul 11;doi: 10.1088/1748-605X/ab316a

Little used for the in vivo assessment of tissue scaffolds are quantitative methods for the evaluation of biocompatibility. To complement current histological techniques, we introduce a histomorphometric approach for the quantitative assessment of encapsulation thickness, cross-sectional area and shape of biomaterials and characteristics of their biomaterial-tissue interface in vivo as additional criteria for biocompatibility. Advantages of this new technique are that it enables a more complete and objective comparison of scaffold biocompatibility with differing compositions, architectures, and mechanical properties, on the one hand, and that it enables a more objective approach to their selection for a given application on the other. In this contribution, we focus on freeze-cast polymeric scaffolds for tissue regeneration and their subcutaneous implantation in mice for biocompatibility testing. Initially, seven different scaffold types are screened. Of these, three are selected for systematic biocompatibility studies based on histopathological criteria: EDC-NHS-crosslinked bovine collagen, EDC-NHS-crosslinked bovine collagen-nanocellulose, and chitin. Geometric models developed to quantify scaffold size, ovalization, and encapsulation thickness are evaluated as an objective metric to assess the in vivo performance of scaffolds and their biocompatibility.

Biomed Mater|2019 Jul 11

Lewis VA, Joynt Maddox K, Austin AM, Gottlieb DJ, Bynum JPW

2019 Aug;57(8):601-607doi: 10.1097/MLR.0000000000001154

To develop and validate a measure that estimates individual level poverty in Medicare administrative data that can be used in studies of Medicare claims.

Med Care|2019 Aug

Drake RE, Wallach MA

2019 Jul 10;doi: 10.1007/s10488-019-00954-x

Adm Policy Ment Health|2019 Jul 10

Barlow WE, Beaber EF, Geller BM, Kamineni A, Zheng Y, Haas JS, Chao CR, Rutter CM, Zauber AG, Sprague BL, Halm EA, Weaver DL, Chubak J, Doria-Rose VP, Kobrin S, Onega T, Quinn VP, Schapira MM, Tosteson ANA, Corley DA, Skinner CS, Schnall MD, Armstrong K, Wheeler CM, Silverberg MJ, Balasubramanian BA...

2019 Jul 11;pii: djz137. doi: 10.1093/jnci/djz137

Cancer screening is a complex process encompassing risk assessment, the initial screening examination, diagnostic evaluation, and treatment of cancer precursors or early cancers. Metrics that enable comparisons across different screening targets are needed. We present population-based screening metrics for breast, cervical, and colorectal cancers for nine sites participating in the PROSPR consortium.

J Natl Cancer Inst|2019 Jul 11

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