Publications by authors named "Robert Bell"

478 Publications

A meta-analysis of the impact of point of view on narrative processing and persuasion in health messaging.

Psychol Health 2021 Mar 6:1-18. Epub 2021 Mar 6.

Department of Communication, University of California, Davis, CA, USA.

Objective: To synthesize experimental research on the impact of narrative point of view (POV) on message processing and persuasion outcomes in health promotion. Moderators examined included characteristics of study design, participants, and experimental stimuli.

Design And Main Outcome Measures: Random effects model meta-analysis of 16 health promotion experiments, using the package in R. Studies included compared the effects of first- and third-person POV on risk perceptions, attitudes, behavioral intention, identification and transportation.

Results: There was no evidence of publication bias. Narratives told in the first-person POV led to higher levels of perceived susceptibility ( = 0.10, 95% CI [0.01, 0.20]) and identification feelings ( = 0.10, 95% CI [0.10, 0.21]) than third-person narratives. The effects of first-person POV narratives were significantly stronger for stories that were written in the past-tense and that depicted the protagonist as being similar to message recipients.

Conclusion: Findings support a theoretical model of POV impact in which a first-person perspective increases identification with the character, thereby leading to higher levels of perceived susceptibility to the health threat. The practical implication is that the effectiveness of narrative persuasion is enhanced by using the first-person point of view, emphasizing target audience-protagonist similarities, and telling stories in the past tense.
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http://dx.doi.org/10.1080/08870446.2021.1894331DOI Listing
March 2021

Strategies for delivering therapeutics across the blood-brain barrier.

Nat Rev Drug Discov 2021 Mar 1. Epub 2021 Mar 1.

Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, ON, Canada.

Achieving sufficient delivery across the blood-brain barrier is a key challenge in the development of drugs to treat central nervous system (CNS) disorders. This is particularly the case for biopharmaceuticals such as monoclonal antibodies and enzyme replacement therapies, which are largely excluded from the brain following systemic administration. In recent years, increasing research efforts by pharmaceutical and biotechnology companies, academic institutions and public-private consortia have resulted in the evaluation of various technologies developed to deliver therapeutics to the CNS, some of which have entered clinical testing. Here we review recent developments and challenges related to selected blood-brain barrier-crossing strategies - with a focus on non-invasive approaches such as receptor-mediated transcytosis and the use of neurotropic viruses, nanoparticles and exosomes - and analyse their potential in the treatment of CNS disorders.
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http://dx.doi.org/10.1038/s41573-021-00139-yDOI Listing
March 2021

Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling.

Transl Psychiatry 2021 Feb 19;11(1):136. Epub 2021 Feb 19.

Takeda Pharmaceuticals, Cambridge, MA, 02139, USA.

Schizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8 mutation resulted in reduced zinc transport into the cell, suggesting a loss in the tight control of zinc in the synaptic cleft. Electrophysiological recordings from perturbed neurons revealed a significant reduction in NMDA- and AMPA-mediated spontaneous EPSCs (sEPSCs) and a reduction in GluN2A and GluA1/2/3 receptor surface expression. All phenotypes were rescued by re-expression of wild-type ZIP8 (ZIP8) or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also resulted in decreased BBB integrity, increased IL-6/IL-1β protein expression, and increased NFκB following TNFα stimulation, indicating that ZIP8 loss-of-function may exacerbate immune and inflammatory signals. Together, our findings demonstrate that the A391T missense mutation results in alterations in glutamate and immune function and provide novel therapeutic targets relevant to schizophrenia.
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http://dx.doi.org/10.1038/s41398-021-01262-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895948PMC
February 2021

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

Eur Heart J 2021 Feb 18. Epub 2021 Feb 18.

Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, UK.

Background: Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients.

Methods And Results: One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).

Conclusions: During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.
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http://dx.doi.org/10.1093/eurheartj/ehab075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928984PMC
February 2021

Predictors of intention to vaccinate against COVID-19: Results of a nationwide survey.

Vaccine 2021 02 9;39(7):1080-1086. Epub 2021 Jan 9.

Department of Communication, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States. Electronic address:

Background: Public polling indicates that vaccine uptake will be suboptimal when COVID-19 vaccines become available. Formative research seeking an understanding of weak vaccination intentions is urgently needed.

Methods: Nationwide online survey of 804 U.S. English-speaking adults. Compensated participants were recruited from the U.S. through an internet survey panel of 2.5 million residents developed by a commercial survey firm. Recruitment was based on quota sampling to produce a U.S. Census-matched sample representative of the nation with regard to region of residence, sex, and age.

Results: COVID-19 vaccination intentions were weak, with 14.8% of respondents being unlikely to get vaccinated and another 23.0% unsure. Intent to vaccinate was highest for men, older people, individuals who identified as white and non-Hispanic, the affluent and college-educated, Democrats, those who were married or partnered, people with pre-existing medical conditions, and those vaccinated against influenza during the 2019-2020 flu season. In a multiple linear regression, significant predictors of vaccination intent were general vaccine knowledge (β = 0.311, p < .001), rejection of vaccine conspiracies (β = -0.117, p = .003), perceived severity of COVID-19 (β = 0.273, p < .001), influenza vaccine uptake (β = 0.178, p < .001), having ≥ 5 pre-existing conditions (β = 0.098, p = .003), being male (β = 0.119, p < .001), household income of ≥ $120,000 (β = 0.110, p = .004), identifying as a Democrat (β = 0.075, p < .029), and not relying upon social media for virus information (β = -0.090, p 〈002). Intent to vaccinate was lower for Fox News (57.3%) than CNN/MSNBC viewers (76.4%) (χ2(1) = 12.68, p < .001). Political party differences in threat appraisals and vaccine conspiracy beliefs are described.

Conclusions: Demographic characteristics, vaccine knowledge, perceived vulnerability to COVID-19, risk factors for COVID-19, and politics likely contribute to vaccination hesitancy.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794597PMC
February 2021

Multiomics characterization of low-grade serous ovarian carcinoma identifies potential biomarkers of MEK inhibitor sensitivity and therapeutic vulnerability.

Cancer Res 2021 Jan 13. Epub 2021 Jan 13.

Gynecologic Oncology, University of British Columbia

Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates in patients with metastatic disease. There is a pressing need to develop effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here we use multiomics integration of whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics on fourteen LGSOC cell lines to elucidate novel biomarkers and therapeutic vulnerabilities. Comparison of LGSOC cell line data to LGSOC tumor data enabled predictive biomarker identification of MEK inhibitor (MEKi) efficacy, with KRAS mutations found exclusively in MEKi-sensitive cell lines and NRAS mutations found mostly in MEKi-resistant cell lines. Distinct patterns of COSMIC mutational signatures were identified in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes were more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. These LGSOC cell lines were representative models of the molecular aberrations found in LGSOC tumors. For prediction of in vitro MEKi efficacy, proteomic data provided better discrimination than gene expression data. Condensin, MCM, and RFC protein complexes were identified as potential treatment targets in MEKi-resistant cell lines. This study suggests that CDKN2A/B or MTAP deficiency may be exploited using synthetically lethal treatment strategies, highlighting the importance of using proteomic data as a tool for molecular drug prediction. Multiomics approaches are crucial to improving our understanding of the molecular underpinnings of LGSOC and applying this information to develop new therapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2222DOI Listing
January 2021

The hematology laboratory's response to the COVID-19 pandemic: A scoping review.

Int J Lab Hematol 2021 Apr 12;43(2):148-159. Epub 2020 Nov 12.

Department of Pathology and Immunology, Washington University, St. Louis, MO, USA.

The ongoing COVID-19 pandemic has had a profound worldwide impact on the laboratory hematology community. Nevertheless, the pace of COVID-19 hematology-related research has continued to accelerate and has established the role of laboratory hematology data for many purposes including disease prognosis and outcome. The purpose of this scoping review was to assess the current state of COVID-19 laboratory hematology research. A comprehensive search of the literature published between December 1, 2019, and July 3, 2020, was performed, and we analyzed the sources, publication dates, study types, and topics of the retrieved studies. Overall, 402 studies were included in this scoping review. Approximately half of these studies (n = 202, 50.37%) originated in China. Retrospective cohort studies comprised the largest study type (n = 176, 43.89%). Prognosis/ risk factors, epidemiology, and coagulation were the most common topics. The number of studies published per day has increased through the end of May. The studies were heavily biased in favor of papers originating in China and on retrospective clinical studies with limited use of and reporting of laboratory data. Despite the major improvements in our understanding of the role of coagulation, automated hematology, and cell morphology in COVID-19, there are gaps in the literature, including biosafety and the laboratory role in screening and prevention of COVID-19. There is a gap in the publication of papers focused on guidelines for the laboratory. Our findings suggest that, despite the large number of publications related to laboratory data and their use in COVID-19 disease, many areas remain unexplored or under-reported.
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http://dx.doi.org/10.1111/ijlh.13381DOI Listing
April 2021

Integrated Expression of Circulating miR375 and miR371 to Identify Teratoma and Active Germ Cell Malignancy Components in Malignant Germ Cell Tumors.

Eur Urol 2021 Jan 4;79(1):16-19. Epub 2020 Nov 4.

Department of Medicine, Medical Oncology Division, BC Cancer, Vancouver Centre, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease.
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http://dx.doi.org/10.1016/j.eururo.2020.10.024DOI Listing
January 2021

Investigation of confocal microscopy for differentiation of renal cell carcinoma versus benign tissue. Can an optical biopsy be performed?

Asian J Urol 2020 Oct 24;7(4):363-368. Epub 2019 Dec 24.

Department of Urology, University of Arizona College of Medicine, Arizona, USA.

Objective: Novel optical imaging modalities are under development with the goal of obtaining an "optical biopsy" to efficiently provide pathologic details. One such modality is confocal microscopy which allows visualization of cells within a layer of tissue and imaging of cellular-level structures. The goal of this study is to validate the ability of confocal microscopy to quickly and accurately differentiate between normal renal tissue and cancer.

Methods: Specimens were obtained from patients who underwent robotic partial nephrectomy for renal mass. Samples of suspected normal and tumor tissue were extracted from the excised portion of the kidney and stained with acridine orange. The stained samples were imaged on a Nikon E600 C1 Confocal Microscope. The samples were then submitted for hematoxylin and eosin processing and read by an expert pathologist to provide a gold-standard diagnosis that can later be compared to the confocal images.

Results: This study included 11 patients, 17 tissue samples, and 118 confocal images. Of the 17 tissue samples, 10 had a gold-standard diagnosis of cancer and seven were benign. Of 118 confocal images, 66 had a gold-standard diagnosis of cancer and 52 were benign. Six confocal images were used as a training set to train eight observers. The observers were asked to rate the test images on a six point scale and the results were analyzed using a web based receiver operating characteristic curve calculator. The average accuracy, sensitivity, specificity, and area under the empirical receiver operating characteristic curve for this study were 91%, 98%, 81%, and 0.94 respectively.

Conclusion: This preliminary study suggest that confocal microscopy can be used to distinguish cancer from normal tissue with high sensitivity and specificity. The observers in this study were trained quickly and on only six images. We expect even higher performance as observers become more familiar with the confocal images.
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http://dx.doi.org/10.1016/j.ajur.2019.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498942PMC
October 2020

3D-3D topotactic transformation in aluminophosphate molecular sieves and its implication in new zeolite structure generation.

Nat Commun 2020 Jul 28;11(1):3762. Epub 2020 Jul 28.

Bezerlii Center EXSELENT on Porous Materials, Department of Materials and Environmental Chemistry, Stockholm University, SE-106 91, Stockholm, Sweden.

Zeolites have unique pore structures of molecular dimensions and tunable compositions, making them ideal for shape selective catalysis and separation. However, targeted synthesis of zeolites with new pore structures and compositions remains a key challenge. Here, we propose an approach based on a unique 3D-3D topotactic transformation, which takes advantage of weak bonding in zeolites. This is inspired by the structure transformation of PST-5, a new aluminophosphate molecular sieve, to PST-6 by calcination. The structure of nano-sized PST-5 crystals is determined by 3D electron diffraction. We find that the 3D-3D topotactic transformation involves two types of building units where penta- or hexa-coordinated Al is present. We apply this approach to several other zeolite systems and predict a series of new zeolite structures that would be synthetically feasible. This method provides a concept for the synthesis of targeted zeolites, especially those which may not be feasible by conventional methods.
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http://dx.doi.org/10.1038/s41467-020-17586-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387333PMC
July 2020

A Physiologically-Based Pharmacokinetic Model for the Prediction of "Half-Life Extension" and "Catch and Release" Monoclonal Antibody Pharmacokinetics.

CPT Pharmacometrics Syst Pharmacol 2020 Sep 17;9(9):534-541. Epub 2020 Aug 17.

BioMedicine Design, Pfizer Worldwide R&D, Cambridge, Massachusetts, USA.

Monoclonal antibodies (mAbs) can be engineered to have "extended half-life" and "catch and release" properties to improve target coverage. We have developed a mAb physiologically-based pharmacokinetic model that describes intracellular trafficking, neonatal Fc receptor (FcRn) recycling, and nonspecific clearance of mAbs. We extended this model to capture target binding as a function of target affinity, expression, and turnover. For mAbs engineered to have an extended half-life, the model was able to accurately predict the terminal half-life (82% within 2-fold error of the observed value) in the human FcRn transgenic (Tg32) homozygous mouse and human. The model also accurately captures the trend in pharmacokinetic and target coverage data for a set of mAbs with differing catch and release properties in the Tg32 mouse. The mechanistic nature of this model allows us to explore different engineering techniques early in drug discovery, potentially expanding the number of "druggable" targets.
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http://dx.doi.org/10.1002/psp4.12547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499188PMC
September 2020

Epstein Virus Barr-Positive Diffuse Large B-Cell Lymphoma Associated with Hemophagocytic Lymphohistiocytosis.

J Neuropathol Exp Neurol 2020 08;79(8):915-920

From the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal disease if not diagnosed and treated promptly. HLH can be due to genetic factors or infections, malignancies and collagen-associated vascular diseases. Malignancy-associated HLH is not only more common in the setting of T/NK-cell lymphomas, but may also rarely be seen in the setting of B-cell lymphoma. Here, we describe a unique case of a patient who initially was diagnosed with HLH secondary to Epstein Barr virus (EBV) infection and subsequently developed EBV-positive diffuse large B-cell lymphoma affecting the brain. This case highlights the spectrum of findings associated with EBV infections and the challenges in diagnosing underlying diseases associated with HLH.
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http://dx.doi.org/10.1093/jnen/nlaa061DOI Listing
August 2020

Well-Differentiated Papillary Mesothelioma of the Peritoneum Is Genetically Distinct from Malignant Mesothelioma.

Cancers (Basel) 2020 Jun 13;12(6). Epub 2020 Jun 13.

Department of Pathology, Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process and, if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPMs of the peritoneum, we have identified distinct mutations in , , , , , , and shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C > A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked the alterations involving , , , , , , and that are frequently found in malignant mesotheliomas. We conclude that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas and, based on observed mutations, do not appear to be precursors of malignant mesotheliomas.
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http://dx.doi.org/10.3390/cancers12061568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352777PMC
June 2020

G3BP1-linked mRNA partitioning supports selective protein synthesis in response to oxidative stress.

Nucleic Acids Res 2020 07;48(12):6855-6873

Vancouver Prostate Centre, Vancouver, BC, Canada.

Cells limit energy-consuming mRNA translation during stress to maintain metabolic homeostasis. Sequestration of mRNAs by RNA binding proteins (RBPs) into RNA granules reduces their translation, but it remains unclear whether RBPs also function in partitioning of specific transcripts to polysomes (PSs) to guide selective translation and stress adaptation in cancer. To study transcript partitioning under cell stress, we catalogued mRNAs enriched in prostate carcinoma PC-3 cell PSs, as defined by polysome fractionation and RNA sequencing (RNAseq), and compared them to mRNAs complexed with the known SG-nucleator protein, G3BP1, as defined by spatially-restricted enzymatic tagging and RNAseq. By comparing these compartments before and after short-term arsenite-induced oxidative stress, we identified three major categories of transcripts, namely those that were G3BP1-associated and PS-depleted, G3BP1-dissociated and PS-enriched, and G3BP1-associated but also PS-enriched. Oxidative stress profoundly altered the partitioning of transcripts between these compartments. Under arsenite stress, G3BP1-associated and PS-depleted transcripts correlated with reduced expression of encoded mitochondrial proteins, PS-enriched transcripts that disassociated from G3BP1 encoded cell cycle and cytoprotective proteins whose expression increased, while transcripts that were both G3BP1-associated and PS-enriched encoded proteins involved in diverse stress response pathways. Therefore, G3BP1 guides transcript partitioning to reprogram mRNA translation and support stress adaptation.
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http://dx.doi.org/10.1093/nar/gkaa376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337521PMC
July 2020

The ONETEP linear-scaling density functional theory program.

J Chem Phys 2020 May;152(17):174111

School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom.

We present an overview of the onetep program for linear-scaling density functional theory (DFT) calculations with large basis set (plane-wave) accuracy on parallel computers. The DFT energy is computed from the density matrix, which is constructed from spatially localized orbitals we call Non-orthogonal Generalized Wannier Functions (NGWFs), expressed in terms of periodic sinc (psinc) functions. During the calculation, both the density matrix and the NGWFs are optimized with localization constraints. By taking advantage of localization, onetep is able to perform calculations including thousands of atoms with computational effort, which scales linearly with the number or atoms. The code has a large and diverse range of capabilities, explored in this paper, including different boundary conditions, various exchange-correlation functionals (with and without exact exchange), finite electronic temperature methods for metallic systems, methods for strongly correlated systems, molecular dynamics, vibrational calculations, time-dependent DFT, electronic transport, core loss spectroscopy, implicit solvation, quantum mechanical (QM)/molecular mechanical and QM-in-QM embedding, density of states calculations, distributed multipole analysis, and methods for partitioning charges and interactions between fragments. Calculations with onetep provide unique insights into large and complex systems that require an accurate atomic-level description, ranging from biomolecular to chemical, to materials, and to physical problems, as we show with a small selection of illustrative examples. onetep has always aimed to be at the cutting edge of method and software developments, and it serves as a platform for developing new methods of electronic structure simulation. We therefore conclude by describing some of the challenges and directions for its future developments and applications.
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http://dx.doi.org/10.1063/5.0004445DOI Listing
May 2020

Acute cardiotoxicity associated with alemtuzumab infusion for multiple sclerosis.

Mult Scler 2020 05 16;26(6):735-737. Epub 2020 Apr 16.

National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust, London, UK.

Alemtuzumab infusion is rarely associated with serious cardiac toxicity. We report a case of acute troponin-negative chest pain with dynamic T-wave changes, immediately following first infusion of alemtuzumab in a patient with multiple sclerosis. The chest pain and ECG (electrocardiogram) changes improved with cessation of alemtuzumab and conservative management. The presumed cause was infusion-associated cytokine release, but the precise mechanism is unknown.
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http://dx.doi.org/10.1177/1352458519855725DOI Listing
May 2020

Lipoblast-Like Morphology in a Uveal Melanoma with Delayed Metastasis to the Liver.

Ocul Oncol Pathol 2020 Mar 4;6(2):87-92. Epub 2019 Sep 4.

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.

Uveal melanomas are typically described as having epithelial or spindled cell morphology; however, as is the nature of melanomas, the morphology of the malignant melanocytes can be varied. We describe a unique case of metastatic uveal melanoma with lipoblast-like morphology, identified in the liver during an autopsy of a 75-year-old woman. Apart from a remote history of uveal melanoma in the right eye, there was no other history of cancer, and there were no concerning skin lesions present. The liver exhibited hepatomegaly with diffuse and extensive involvement of malignant tumor cells. Histopathological evaluation of liver sections showed malignant epithelioid and spindle cell proliferation. A distinct, spiculated, tan-white area revealed sheets of malignant cells with small and large vacuoles within the cytoplasm and scalloped nuclei, mimicking lipoblasts and adipocytes. Immunohistochemical stains confirmed these cells to be malignant melanoma cells. Being aware of this morphology in uveal melanomas is important especially when there is metastasis to the liver, so that it is not mistaken for more benign processes such as steatosis.
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http://dx.doi.org/10.1159/000501619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109438PMC
March 2020

SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models.

Biochim Biophys Acta Mol Basis Dis 2020 07 17;1866(7):165770. Epub 2020 Mar 17.

Amsterdam UMC, University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam Infection & Immunity, Meibergdreef 9, AZ, 1105 Amsterdam, the Netherlands. Electronic address:

The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of effective drugs managing patients, who suffer from type 2 diabetes (T2D): Landmark clinical trials including EMPA-REG, CANVAS and Declare-TIMI have demonstrated that SGLT2 inhibitors reduce cardiovascular mortality and re-hospitalization for heart failure (HF) in patients with T2D. It is well established that there is a strong independent relationship among infarct size measured within 1 month after reperfusion and all-cause death and hospitalization for HF: The fact that cardiovascular mortality was significantly reduced with the SGLT2 inhibitors, fuels the assumption that this class of therapies may attenuate myocardial infarct size. Experimental evidence demonstrates that SGLT2 inhibitors exert cardioprotective effects in animal models of acute myocardial infarction through improved function during the ischemic episode, reduction of infarct size and a subsequent attenuation of heart failure development. The aim of the present review is to outline the current state of preclinical research in terms of myocardial ischemia/reperfusion injury (I/R) and infarct size for clinically available SGLT2 inhibitors and summarize some of the proposed mechanisms of action (lowering intracellular Na and Ca, NHE inhibition, STAT3 and AMPK activation, CamKII inhibition, reduced inflammation and oxidative stress) that may contribute to the unexpected beneficial cardiovascular effects of this class of compounds.
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http://dx.doi.org/10.1016/j.bbadis.2020.165770DOI Listing
July 2020

From Network Positions to Language Use: Understanding the Effects of Brokerage and Closure Structures from a Linguistic Perspective.

Health Commun 2020 Mar 3:1-8. Epub 2020 Mar 3.

Department of Communication, University of California.

We investigated cancer survivors' interactions on an online breast cancer support forum, focusing on how the network structures of brokerage and closure relate to the types of support received and to the language used in posts. Data came through the extraction of 1,443 forum members' online networks. Automated linguistic analysis was carried out on the 27,248 threads these survivors made and the 336,151 replies they received. Survivors' brokerage and closure levels were positively correlated with the use of positive affective words in their posts, a linguistic marker of well-being. Different network positions fostered different types of support in the community. Specifically, people bridging unconnected users (the broker role) were more likely to receive informational support whereas people in closely knit groups (the closure role) were more likely to receive emotional support. Theoretical, methodological, and practical implications are examined.
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http://dx.doi.org/10.1080/10410236.2020.1731776DOI Listing
March 2020

Identification of gene signature for treatment response to guide precision oncology in clear-cell renal cell carcinoma.

Sci Rep 2020 02 6;10(1):2026. Epub 2020 Feb 6.

Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

Clear-cell renal cell carcinoma (ccRCC) is a common therapy resistant disease with aberrant angiogenic and immunosuppressive features. Patients with metastatic disease are treated with targeted therapies based on clinical features: low-risk patients are usually treated with anti-angiogenic drugs and intermediate/high-risk patients with immune therapy. However, there are no biomarkers available to guide treatment choice for these patients. A recently published phase II clinical trial observed a correlation between ccRCC patients' clustering and their response to targeted therapy. However, the clustering of these groups was not distinct. Here, we analyzed the gene expression profile of 469 ccRCC patients, using featured selection technique, and have developed a refined 66-gene signature for improved sub-classification of patients. Moreover, we have identified a novel comprehensive expression profile to distinguish between migratory stromal and immune cells. Furthermore, the proposed 66-gene signature was validated using a different cohort of 64 ccRCC patients. These findings are foundational for the development of reliable biomarkers that may guide treatment decision-making and improve therapy response in ccRCC patients.
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http://dx.doi.org/10.1038/s41598-020-58804-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005147PMC
February 2020

Effect of hyperglycaemia and diabetes on acute myocardial ischaemia-reperfusion injury and cardioprotection by ischaemic conditioning protocols.

Br J Pharmacol 2020 12 9;177(23):5312-5335. Epub 2020 Mar 9.

The Hatter Cardiovascular Institute, University College London, London, UK.

Diabetic patients are at increased risk of developing coronary artery disease and experience worse clinical outcomes following acute myocardial infarction. Novel therapeutic strategies are required to protect the myocardium against the effects of acute ischaemia-reperfusion injury (IRI). These include one or more brief cycles of non-lethal ischaemia and reperfusion prior to the ischaemic event (ischaemic preconditioning [IPC]) or at the onset of reperfusion (ischaemic postconditioning [IPost]) either to the heart or to extracardiac organs (remote ischaemic conditioning [RIC]). Studies suggest that the diabetic heart is resistant to cardioprotective strategies, although clinical evidence is lacking. We overview the available animal models of diabetes, investigating acute myocardial IRI and cardioprotection, experiments investigating the effects of hyperglycaemia on susceptibility to acute myocardial IRI, the response of the diabetic heart to cardioprotective strategies e.g. IPC, IPost and RIC. Finally we highlight the effects of anti-hyperglycaemic agents on susceptibility to acute myocardial IRI and cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.
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http://dx.doi.org/10.1111/bph.14993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680002PMC
December 2020

Blood biomarkers as surrogate endpoints of treatment responses to aerobic exercise and cognitive training (ACT) in amnestic mild cognitive impairment: the blood biomarkers study protocol of a randomized controlled trial (the ACT Trial).

Trials 2020 Jan 6;21(1):19. Epub 2020 Jan 6.

School of Nursing, University of Minnesota, 5-140 WDH, 308 Harvard St SE, Minneapolis, MN, 55455, USA.

Background: Alzheimer's disease (AD) is an epidemic with tremendous public health impacts because there are currently no disease-modifying therapeutics. Randomized controlled trials (RCTs) for prevention of AD dementia often use clinical endpoints that take years to manifest (e.g., cognition) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI]). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive, but little is known about their value as surrogate endpoints for treatment responses in the prevention of AD dementia.

Methods: The objective of this study is to investigate blood neuropathological, neurodegenerative, and neurotrophic biomarkers as surrogate endpoints for treatment responses to three interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise, cognitive training, and combined aerobic exercise and cognitive training (ACT). We chose these three sets of biomarkers for their unique mechanistic associations with AD pathology, neurodegeneration and neurogenesis. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 2 × 2 factorial phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n = 128). In this ACT Trial blood biomarkers study, we will enroll 120 ACT Trial participants with aMCI and measure blood biomarkers at baseline and at 3, 6, 12, and 18 months. The goals are to (1) determine the effect of interventions on blood biomarkers over 6 months, (2) evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months, and (3, exploratory) examine blood biomarkers as surrogate endpoints for predicting brain MRI biomarker responses to interventions over 18 months.

Discussion: This study aims to identify new blood biomarkers that can track cognitive decline or AD-related brain atrophy among patients with aMCI subjected to a regimen of aerobic exercise and cognitive training. Findings from this study will drive the further use of blood biomarkers in developing effective prevention and treatment strategies for AD dementia.

Trial Registration: ClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.
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http://dx.doi.org/10.1186/s13063-019-3798-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943901PMC
January 2020

Thromboembolic risk with IVIg: Incidence and risk factors in patients with inflammatory neuropathy.

Neurology 2020 02 18;94(6):e635-e638. Epub 2019 Dec 18.

From the National Hospital of Neurology and Neurosurgery (J.S., C.E., S.S.-G., M.P.L., A.C.); MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases (M.K., A.R., H.M., M.M.R.), UCL Institute of Neurology; Department of Cardiology (R.B.), University College London Hospital; and Department of Neuroimmunology (M.P.L.), Institute of Neurology, London, UK.

Our objective was to evaluate whether IV immunoglobulin (IVIg) increases the risk of thromboembolic events in neurology outpatients with inflammatory neuropathies, as there is conflicting evidence supporting this hypothesis, mainly from non-neurologic cohorts. We investigated this question over 30 months in our cohort of patients with inflammatory neuropathies receiving regular IVIg and found a greater incidence of arterial and venous thromboembolic events than population-based rates determined by hospital admissions data. Vascular risk factors were more common in the event group but there were no IVIg administration factors that contributed to the risk. This study suggests that IVIg may have a small but contributory role in determining thromboembolic risk in the inflammatory neuropathy cohort and more evidence is required before it is clear whether the current primary prevention guidelines are appropriate in this group of patients.
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http://dx.doi.org/10.1212/WNL.0000000000008742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136065PMC
February 2020

PD-L1 Expression in Pediatric Low-Grade Gliomas Is Independent of BRAF V600E Mutational Status.

J Neuropathol Exp Neurol 2020 01;79(1):74-85

Division of Pediatric Oncology, Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Baltimore, Maryland (AMM, EHR); Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota (WRB); Department of Pathology, Division of Neuropathology, Johns Hopkins School of Medicine, Baltimore, Maryland (MY, BP, AA, LA, EHR, CGE); Department of Molecular and Cell Biology, The Johns Hopkins University, Krieger School of Arts and Sciences, Baltimore, Maryland (LH); Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy (ELE); and Department of Neurosurgery, Division of Neurosurgical Oncology (ML), Johns Hopkins School of Medicine, Baltimore, Maryland.

To evaluate a potential relationship between BRAF V600E mutation and PD-L1 expression, we examined the expression of PD-L1 in pediatric high- and low-grade glioma cell lines as well as a cohort of pediatric low-grade glioma patient samples. Half of the tumors in our patient cohort were V600-wildtype and half were V600E mutant. All tumors expressed PD-L1. In most tumors, PD-L1 expression was low (<5%), but in some cases over 50% of cells were positive. Extent of PD-L1 expression and immune cell infiltration was independent of BRAF V600E mutational status. All cell lines evaluated, including a BRAF V600E mutant xenograft, expressed PD-L1. Transient transfection of cell lines with a plasmid expressing mutant BRAF V600E had minimal effect on PD-L1 expression. These findings suggest that the PD-1 pathway is active in subsets of pediatric low-grade glioma as a mechanism of immune evasion independent of BRAF V600E mutational status. Low-grade gliomas that are unresectable and refractory to traditional therapy are associated with significant morbidity and continue to pose a treatment challenge. PD-1 pathway inhibitors may offer an alternative treatment approach. Clinical trials will be critical in determining whether PD-L1 expression indicates likely therapeutic benefit with immune checkpoint inhibitors.
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http://dx.doi.org/10.1093/jnen/nlz119DOI Listing
January 2020

Psychosis Remitted After Ependymoma Resection in a School-Aged Child.

J Neuropsychiatry Clin Neurosci Summer 2020;32(3):305-308. Epub 2019 Dec 4.

The Departments of Psychiatry (Jules-Dole, Borden, Chambers, Salpekar), Neurosurgery (Uribe-Cardenas), Pathology (Bell, Raabe), and Neurology (Salpekar) and the Division of Oncology, Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center (McReynolds, Raabe), Johns Hopkins University School of Medicine, Baltimore; the Department of Neurological Surgery, Cornell University, New York (Uribe-Cardenas); the Department of Neurologic Surgery, Mayo Clinic, Rochester Minn. (Ahn); and the Kennedy Krieger Institute, Baltimore (Salpekar).

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http://dx.doi.org/10.1176/appi.neuropsych.19070147DOI Listing
December 2019

A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer.

Gynecol Oncol 2020 01 29;156(1):23-31. Epub 2019 Nov 29.

Moffitt Cancer Center, Tampa, FL, USA.

Objective: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer.

Methods: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d.

Results: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm.

Conclusions: Addition of ralimetinib to GC resulted in a modest improvement in PFS.
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http://dx.doi.org/10.1016/j.ygyno.2019.11.006DOI Listing
January 2020

Characteristics of Gastroenteritis Outbreaks in Australia, 2001 to 2016.

Foodborne Pathog Dis 2020 05 18;17(5):308-315. Epub 2019 Nov 18.

OzFoodNet, Communicable Diseases Branch, Queensland Health, Brisbane, Australia.

spp. are a globally important cause of bacterial gastroenteritis, with Australia experiencing higher rates of illness than many comparable high-income countries. Despite the high disease incidence, outbreaks of campylobacteriosis in Australia are infrequently detected and reported. We examined the epidemiology of outbreaks in Australia, with particular emphasis on assessing transmission routes and evidence as reported during public health investigations. A national register of enteric and foodborne disease outbreaks was used to summarize data on all outbreaks reported in Australia between 2001 and 2016. Outbreak data were reviewed and analyzed for trends over time. Additional information was sought from state and territory epidemiologists, to validate transmission routes. A total of 84 outbreaks were reported, with 51 (61%) being classified as foodborne. Specific food vehicles were identified for 33 (65%) outbreaks, with 28 (85%) implicating chicken or chicken-containing dishes. Although no increase in the proportion of foodborne outbreaks was observed, examination of specific food vehicles demonstrated a significant increase in outbreaks because of poultry-liver containing foods ( = 0.04). One quarter of all 1042 outbreak-associated cases occurred in aged-care facilities (ACFs), including 17 associated hospitalizations and three deaths. After review of evidence data, 23 outbreaks (27%) were determined to have an unknown route of transmission, including 10 (43%) outbreaks occurring in ACFs. spp. remain a less commonly reported cause of gastroenteritis outbreaks in Australia. Although many reported outbreaks can be linked to foodborne transmission, over a quarter were unable to identify either a food vehicle or transmission source, particularly for outbreaks occurring in aged care. Increased efforts to improve evidence collection and understanding of transmission dynamics for outbreaks of campylobacteriosis, particularly in aged care, are required.
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http://dx.doi.org/10.1089/fpd.2019.2731DOI Listing
May 2020

A rare case of circulating melanoma cells in peripheral blood.

Blood 2019 10;134(16):1359

University of Arizona.

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http://dx.doi.org/10.1182/blood.2019002625DOI Listing
October 2019

Effects of public versus media responsibility messages on stigmatization of people with schizophrenia in an American adult sample.

Soc Psychiatry Psychiatr Epidemiol 2020 Jul 23;55(7):917-927. Epub 2019 Oct 23.

Department of Communication, University of California Davis, One Shields Ave., Davis, CA, 95616, USA.

Purpose: People with mental illness suffer from the consequences of stigma. Interventions to reduce stigma should focus on alternative approaches that target false beliefs toward mental disorders. The effectiveness of two messages to reduce stigma toward schizophrenia was tested: a traditional public responsibility message that attributes stigma to public misunderstandings, and an alternative media responsibility message that attributes stigma to bias in media representations.

Methods: An experiment with Americans (N = 448) randomly assigned to a public responsibility message, a media responsibility message, or a control condition. Participants in the two message conditions completed measures of guilt and reactance toward the media. Perceptions of personal responsibility and dangerousness, and social rejection intentions were assessed for all participants.

Results: Both messages lowered perceptions of dangerousness and social rejection intentions, relative to control. The media responsibility generated more reactance toward the media than the public responsibility approach, but not more guilt. Reactance did not mediate message effects. Perceptions of personal responsibility were reduced after exposure to the public responsibility message, but only for participants with no prior contact with mental illness.

Conclusions: Both approaches reduced perceptions of dangerousness and social rejection intentions. Stigma reduction campaigns might segment the audience based on prior contact.
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http://dx.doi.org/10.1007/s00127-019-01788-6DOI Listing
July 2020

Developing a Highly Specific Biomarker for Germ Cell Malignancies: Plasma miR371 Expression Across the Germ Cell Malignancy Spectrum.

J Clin Oncol 2019 11 25;37(33):3090-3098. Epub 2019 Sep 25.

BC Cancer, Vancouver Centre, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: Our objective was to evaluate operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumor.

Patients And Methods: One hundred eleven male patients with a history of or newly diagnosed germ cell tumors were evaluable. Biospecimens obtained before confirmed clinical events were analyzed for miR371 expression with blinding of providers and laboratory personnel to analytic results or clinical status, respectively. Cases (patients with clinically confirmed active germ cell malignancy [aGCM]) and controls (patients with no clinically confirmed aGCM) were assigned over the course of the management. Patients were assigned risk status (high, low, or moderate) based on the composite clinical picture at time points in management.

Results: Considering all cases and controls and results of prospectively obtained biosamples analyzed for miR371 expression, 46 (35%) of 132 samples had clinically confirmed aGCM over the course of management; 44 (96%) of these 46 patients had plasma miR371 expression (true positives) with no false positives. Two (4%) of 46 patients had no miRNA expression despite pathologic confirmation of aGCM (false negatives). Plasma miR371 expression in confirmed aGCM had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively. Interpretation of sensitivity and negative predictive value is limited by modest follow-up. Specificity and sensitivity were 100% and 98%, 100% and 92%, and 100% and 97% in the low-, moderate-, and high-risk groups, respectively, with a median follow-up time of 15 months.

Conclusion: Plasma miR371 expression predicts aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 await longer follow-up for more complete definition, the findings of a highly specific liquid biopsy strongly support moving forward with large-scale, real-world clinical trials to further define full operating characteristics and to identify clinical utility and areas of patient benefit.
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http://dx.doi.org/10.1200/JCO.18.02057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351323PMC
November 2019