Publications by authors named "Alan Wells"

236 Publications

Performance of SARS-CoV-2 antigen testing in symptomatic and asymptomatic adults: a single-center evaluation.

BMC Infect Dis 2021 Oct 18;21(1):1071. Epub 2021 Oct 18.

Department of Pathology, University of Pittsburgh, 3477 Euler Way, Clinical Laboratory Building-6th Floor, Pittsburgh, PA, 15213, USA.

Background: Antigen testing offers rapid and inexpensive testing for SARS-CoV-2 but concerns regarding performance, especially sensitivity, remain. Limited data exists for use of antigen testing in asymptomatic patients; thus, performance and reliability of antigen testing remains unclear.

Methods: 148 symptomatic and 144 asymptomatic adults were included. A nasal swab was collected for testing by Quidel Sofia SARS IFA (Sofia) as point of care. A nasopharyngeal swab was also collected and transported to the laboratory for testing by Cepheid Xpert Xpress SARS-CoV-2/Flu/RSV RT-PCR (Cepheid).

Results: Overall, Sofia had good agreement with Cepheid (> 95%) in adults, however was less sensitive. Sofia had a sensitivity of 87.8% and 33.3% for symptomatic and asymptomatic patients, respectively. Among symptomatic patients, testing > 5 days post symptom onset resulted in lower sensitivity (82%) when compared with testing within 5 days of symptom onset (90%). Of the four Sofia false-negative results in the asymptomatic cohort, 50% went on to develop COVID-19 disease within 5 days of testing. Specificity in both symptomatic and asymptomatic cohorts was 100%.

Conclusions: Sofia has acceptable performance in symptomatic adults when tested < 5 days of symptom onset. Caution should be taken when testing patients with ≥ 5 days of symptoms. The combination of low prevalence and reduced sensitivity results in relatively poor performance of in asymptomatic patients. NAAT-based diagnostic assays should be considered in when antigen testing is unreliable, particularly in symptomatic patients with > 5 days of symptom onset and asymptomatic patients.
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http://dx.doi.org/10.1186/s12879-021-06716-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521263PMC
October 2021

Preventing metastatic emergence of breast cancer.

Aging (Albany NY) 2021 10 11;13(19):22627-22628. Epub 2021 Oct 11.

Department of Pathology, Pittsburgh VA Medical Center and University of Pittsburgh, Pittsburgh, PA 15213, USA.

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http://dx.doi.org/10.18632/aging.203631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544339PMC
October 2021

Akt isoforms differentially provide for chemoresistance in prostate cancer.

Cancer Biol Med 2021 Oct 1. Epub 2021 Oct 1.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Objective: Early prostate cancer micrometastatic foci undergo a mesenchymal to epithelial reverting transition, not only aiding seeding and colonization, but also rendering the tumor cells generally chemoresistant. We previously found that upregulated E-cadherin in the epithelial micrometastases activated canonical survival pathways, including PI3K-Akt, that protected the tumor cells from death; however, the extent of protection from blocking the pathway in its entirety was modest, because different isoforms may have alternately affected cell functioning. Here, we characterized Akt isoform expressions in primary and metastatic prostate cancers, as well as their individual contributions to chemoresistance.

Methods: Akt isoforms and E-cadherin were manipulated with drugs, knocked down, and over expressed. Tumor cell killing was determined and . Overall survival was calculated from patient records and specimens.

Results: Pan-Akt inhibition sensitized tumor cells to chemotherapy, and specific blockade of Akt1 or/and Akt2 caused cells to be more chemoresponsive. Overexpression of Akt3 induced apoptosis. A low dose of Akt1 or Akt2 inhibitor enabled standard chemotherapies to significantly eradicate metastatic prostate tumors in a mouse model, acting as chemosensitizers. In human specimens, we found Akt1 and Akt2 positively correlated, whereas Akt3 inversely correlated, with the overall survival of prostate cancer patients. Akt1high/Akt2high/Akt3low tumors had the worst outcomes.

Conclusions: E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance, whereas Akt3 made cells more fragile. These findings emphasized the need to target Akt1/2, rather than pan-Akt, as a rational therapeutic approach.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0747DOI Listing
October 2021

Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer.

Br J Cancer 2021 Oct 30;125(9):1285-1298. Epub 2021 Aug 30.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations.

Methods: We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019.

Results: Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use.

Conclusion: Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.
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http://dx.doi.org/10.1038/s41416-021-01529-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548312PMC
October 2021

Connecting Primary Care Providers in Free Clinics with Specialists Via Telehealth: A Pilot Program with Three Miami Clinics.

J Health Care Poor Underserved 2021 ;32(3):1102-1109

The Medical Alumni Volunteer Expert Network (MAVEN) Project (MP) in Miami, Florida piloted primary care provider (PCP)-specialist telehealth consults in three clinics for the uninsured. Preliminary findings suggest telehealth consults may improve quality of care, provider knowledge, and confidence, and may represent innovative health care delivery for the uninsured.
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http://dx.doi.org/10.1353/hpu.2021.0116DOI Listing
September 2021

Differential Antibody Response to mRNA COVID-19 Vaccines in Healthy Subjects.

Microbiol Spectr 2021 09 4;9(1):e0034121. Epub 2021 Aug 4.

Department of Pathology, University of Pittsburghgrid.471408.egrid.21925.3d Medical Center, Pittsburgh, Pennsylvania, USA.

Knowledge about development and duration of virus-specific antibodies after COVID-19 vaccination is important for understanding how to limit the pandemic via vaccination in different populations and societies. However, the clinical utility of postvaccination testing of antibody response and selection of targeted SARS-CoV-2 antigen(s) has not been established. The results of such testing from clinical teams independent from vaccine manufacturers are also limited. Here, we report the initial results of an ongoing clinical study on evaluation of antibody response to four different SARS-CoV-2 antigens after first and second dose of Pfizer and Moderna mRNA vaccines and at later time points. We revealed a peak of antibody induction after the vaccine boosting dose with a gradual decline of antibody levels at later time. Anti-nucleocapsid antibody was not induced by spike protein-encoding vaccines and this may continue to serve as a marker of previous SARS-CoV-2 infection. No differences between the two vaccines in terms of antibody response were revealed. Age and gender dependencies were determined to be minimal within the healthy adult (but not aged) population. Our results suggest that postvaccination testing of antibody response is an important and feasible tool for following people after vaccination and selecting individuals who might require a third dose of vaccine at an earlier time point or persons who may not need a second dose due to previous SARS-CoV-2 infection. Now that authorized vaccines for COVID-19 have been widely used, it is important to understand how they induce antivirus antibodies, which antigens are targeted, how long antibodies circulate, and how personal health conditions and age may affect this humoral immunity. Here, we report induction and time course of multiple anti-SARS-CoV-2 antibody responses in healthy individuals immunized with Pfizer and Moderna mRNA vaccines. We also determined the age and gender dependence of the antibody response and compared antibody levels to responses seen in those who have recovered from COVID-19. Our results suggest the importance of screening for antibody response to multiple antigens after vaccination in order to reveal individuals who require early and late additional boosting and those who may not need second dose due to prior SARS-CoV-2 infection.
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http://dx.doi.org/10.1128/Spectrum.00341-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552678PMC
September 2021

Suboptimal Response to Coronavirus Disease 2019 Messenger RNA Vaccines in Patients With Hematologic Malignancies: A Need for Vigilance in the Postmasking Era.

Open Forum Infect Dis 2021 Jul 30;8(7):ofab353. Epub 2021 Jun 30.

Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

We measured severe acute respiratory syndrome coronavirus 2 immunoglobulin G responses in 67 patients with hematological malignancies after 2 messenger RNA vaccine doses. Forty-six percent were nonresponders; patients with B-cell chronic lymphocytic leukemia were at highest risk (77% nonresponders). Patients with hematological malignancies should continue wearing masks and socially distancing. Studies of revaccination, boosters, and humoral immune correlates of protection are needed.
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http://dx.doi.org/10.1093/ofid/ofab353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320282PMC
July 2021

A Cross-Sectional Study of SARS-CoV-2 Seroprevalence between Fall 2020 and February 2021 in Allegheny County, Western Pennsylvania, USA.

Pathogens 2021 Jun 6;10(6). Epub 2021 Jun 6.

Division of Infectious Diseases, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Seroprevalence studies are important for understanding the dynamics of local virus transmission and evaluating community immunity. To assess the seroprevalence for SARS-CoV-2 in Allegheny County, an urban/suburban county in Western PA, 393 human blood samples collected in Fall 2020 and February 2021 were examined for spike protein receptor-binding domain (RBD) and nucleocapsid protein (N) antibodies. All RBD-positive samples were evaluated for virus-specific neutralization activity. Our results showed a seroprevalence of 5.5% by RBD ELISA, 4.5% by N ELISA, and 2.5% for both in Fall 2020, which increased to 24.7% by RBD ELISA, 14.9% by N ELISA, and 12.9% for both in February 2021. Neutralization titer was significantly correlated with RBD titer but not with N titer. Using these two assays, we were able to distinguish infected from vaccinated individuals. In the February cohort, higher median income and white race were associated with serological findings consistent with vaccination. This study demonstrates a 4.5-fold increase in SARS-CoV-2 seroprevalence from Fall 2020 to February 2021 in Allegheny County, PA, due to increased incidence of both natural disease and vaccination. Future seroprevalence studies will need to include the effect of vaccination on assay results and incorporate non-vaccine antigens in serological assessments.
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http://dx.doi.org/10.3390/pathogens10060710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226606PMC
June 2021

Antibody Responses After mRNA-Based COVID-19 Vaccination in Residential Older Adults: Implications for Reopening.

J Am Med Dir Assoc 2021 Aug 12;22(8):1593-1598. Epub 2021 Jun 12.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; Clinical Laboratory, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objective: COVID-19 disproportionately impacts residents in long-term care facilities. Our objective was to quantify the presence and magnitude of antibody response in vaccinated, older adult residents at assisted living, personal care, and independent living communities.

Design: A cross-sectional quality improvement study was conducted March 15 - April 1, 2021 in the greater Pittsburgh region.

Setting And Population: Participants were older adult residents at assisted living, personal care, and independent living communities, who received mRNA-based COVID-19 vaccine. Conditions that impair immune responses were exclusionary criteria.

Methods: Sera were collected to measure IgG anti-SARS-CoV-2 antibody level with reflex to total anti-SARS-CoV-2 immunoglobulin levels, and blinded evaluation of SARS-CoV-2 pseudovirus neutralization titers. Descriptive statistics, Pearson correlation coefficients, and multiple linear regression analysis evaluated relationships between factors potentially associated with antibody levels. Spearman correlations were calculated between antibody levels and neutralization titers.

Results: All participants (N = 70) had received two rounds of vaccination and were found to have antibodies with wide variation in relative levels. Antibody levels trended lower in males, advanced age, current use of steroids, and longer length of time from vaccination. Pseudovirus neutralization titer levels were strongly correlated (P < .001) with Beckman Coulter antibody levels [D614 G NT50, r = 0.91; B.1.1.7 (UK) NT50, r = 0.91].

Conclusions And Implications: Higher functioning, healthier, residential older adults mounted detectable antibody responses when vaccinated with mRNA-based COVID-19 vaccines. Data suggests some degree of immunity is present during the immediate period following vaccination. However, protective effects remain to be determined in larger studies as clinical protection is afforded by ongoing adaptive immunity, which is known to be decreased in older adults. This study provides important preliminary results on level of population risk in older adult residents at assisted living, personal care, and independent living communities to inform reopening strategies, but are not likely to be translatable for residents in nursing homes.
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http://dx.doi.org/10.1016/j.jamda.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196346PMC
August 2021

IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment.

Front Oncol 2021 27;11:676135. Epub 2021 May 27.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States.

Metastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiological signals can drive these tumor cells to emerge. Prior studies indicated CXCR3 ligands as being the predominant signals synergistically and significantly unregulated during inflammation in the gut-liver axis. Of the CXCR3 ligands, IP-10 (CXCL10) was the most abundant, correlated significantly with shortened survival of human breast cancer patients with metastatic disease and was highest in those with triple negative (TNBC) disease. Using a complex all-human liver microphysiological (MPS) model of dormant-emergent metastatic progression, CXCR3 ligands were found to be elevated in actively growing populations of metastatic TNBC breast cancer cells whereas they remained similar to the tumor-free hepatic niche in those with dormant breast cancer cells. Subsequent stimulation of dormant breast cancer cells in the metastatic liver MPS model with IP-10 triggered their emergence in a dose-dependent manner. Emergence was indicated to occur indirectly possibly activation of the resident liver cells in the surrounding metastatic microenvironment, as stimulation of breast cancer cells with exogenous IP-10 did not significantly change their migratory, invasive or proliferative behavior. The findings reveal that IP-10 is capable of triggering the emergence of dormant breast cancer cells within the liver metastatic niche and identifies the IP-10/CXCR3 as a candidate targetable pathway for rational approaches aimed at maintaining dormancy.
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http://dx.doi.org/10.3389/fonc.2021.676135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190328PMC
May 2021

The UPMC OPTIMISE-C19 (OPtimizing Treatment and Impact of Monoclonal antIbodieS through Evaluation for COVID-19) trial: a structured summary of a study protocol for an open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization.

Trials 2021 May 25;22(1):363. Epub 2021 May 25.

UPMC Supply Chain Management/HC Pharmacy, Pittsburgh, PA, USA.

Objectives: The primary objective is to evaluate the comparative effectiveness of COVID-19 specific monoclonal antibodies (mABs) with US Food and Drug Administration (FDA) Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs.

Trial Design: Open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization PARTICIPANTS: We will evaluate patients who meet the eligibility criteria stipulated by the COVID-19 mAB EUAs who receive mABs within the UPMC Health System, including infusion centers and emergency departments. EUA eligibility criteria include patients with mild to moderate COVID-19, <10 days of symptoms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization (elderly, obese, and/or with specific comorbidities). The EUA criteria exclude patients who require oxygen for the treatment of COVID-19 and patients already hospitalized for the treatment of COVID-19. We will use data collected for routine clinical care, including data entered into the electronic medical record and from follow-up calls.

Intervention And Comparator: The interventions are the COVID-19 specific mABs authorized by the EUAs. All aspects of mAB treatment, including eligibility criteria, dosing, and post-infusion monitoring, are as per the EUAs. As a comparative effectiveness trial, all patients receive mAB treatment, and the interventions are compared against each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mAB interventions will accordingly change. From November 2020 to February 2021, FDA issued EUAs for three mAB treatments (bamlanivimab; bamlanivimab and etesevimab; and casirivimab and imdevimab), and at trial launch on March 10, 2021 we evaluated all three. Due to a sustained increase in SARS-CoV-2 variants in the United States resistant to bamlanivimab administered alone, on March 24, 2021 the U.S. Government halted distribution of bamlanivimab alone, and UPMC accordingly halted bamlanivimab monotherapy on March 31, 2021. On April 16, 2021, FDA revoked the EUA for bamlanivimab monotherapy. At the time of manuscript submission, we are therefore evaluating the two mAB treatments authorized by EUAs (bamlanivimab and etesevimab; and casirivimab and imdevimab).

Main Outcomes: The primary outcome is total hospital free days (HFD) at 28 days after mAB administration, calculated as 28 minus the number of days during the index stay (if applicable - e.g., for patients admitted to hospital after mAB administration in the emergency department) minus the number of days readmitted during the 28 days after treatment. This composite endpoint captures the number of days from the day of mAB administration to the 28 days thereafter, during which the patient is alive and free of hospitalization. Death within 28 days is recorded as -1 HFD, as the worst outcome.

Randomisation: We will start with equal allocation. Due to uncertainty in sample size, we will use a Bayesian adaptive design and response adaptive randomization to ensure ability to provide statistical inference despite variable sample size. When mABs are ordered by UPMC physicians as a generic referral order, the order is filled by UPMC pharmacy via therapeutic interchange. OPTIMISE-C19 provides the therapeutic interchange via random allocation. Infusion center operations teams and pharmacists use a mAB assignment application embedded in the electronic medical record to determine the random allocation.

Blinding (masking): This trial is open-label. However, outcome assessors conducting follow-up calls at day 28 are blinded to mAB assignment, and investigators are blinded to by-mAB aggregate outcome data until a statistical platform trial conclusion is reached.

Numbers To Be Randomised (sample Size): Sample size will be determined by case volume throughout the course of the pandemic, supply of FDA authorized mABs, and by that needed to reach a platform trial conclusion of inferiority, superiority, or futility of a given mAB. The trial will continue as long as more than one mAB type is available under EUA, and their comparative effectiveness is uncertain.

Trial Status: Protocol Version 1.0, February 24, 2021. Recruitment began March 10, 2021 and is ongoing at the time of manuscript submission. The estimated recruitment end date is February 22, 2022, though the final end date is dependent on how the pandemic evolves, mAB availability, and when final platform trial conclusions are reached. As noted above, due to U.S. Government decisions, UPMC Health System halted bamlanivimab monotherapy on March 31, 2021.

Trial Registration: ClinicalTrials.gov Identifier: NCT04790786 . Registered March 10, 2021 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05316-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144687PMC
May 2021

Suboptimal response to COVID-19 mRNA vaccines in hematologic malignancies patients.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Studies describing SARS-CoV-2 immune responses following mRNA vaccination in hematology malignancy (HM) patients are virtually non-existent. We measured SARS-CoV-2 IgG production in 67 HM patients who received 2 mRNA vaccine doses. We found that 46% of HM patients did not produce antibodies and were therefore vaccine non-responders. Patients with B-cell CLL were at a particularly high risk, as only 23% had detectable antibodies despite the fact that nearly 70% of these patients were not undergoing cancer therapy. HM patients should be counseled about the ongoing risk of COVID-19 despite vaccination. Routine measurement of post-vaccine antibodies in HM patients should be considered. Novel strategies are needed to prevent COVID-19 in these individuals.
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http://dx.doi.org/10.1101/2021.04.06.21254949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043479PMC
April 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Preprocedural SARS-CoV-2 Testing to Sustain Medically Needed Health Care Delivery During the COVID-19 Pandemic: A Prospective Observational Study.

Open Forum Infect Dis 2021 Feb 18;8(2):ofab022. Epub 2021 Jan 18.

Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Background: We implemented a preprocedural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening initiative designed to sustain health care during a time when the extent of SARS-CoV-2 infection was unknown.

Methods: This was a prospective study of patients undergoing procedures at 3 academic hospitals in Pittsburgh, Pennsylvania (April 21-June 11), and 19 community hospitals across Middle/Western Pennsylvania and Southwestern New York (May 1-June 11). Patients at academic hospitals underwent symptom screening ≤7 days preprocedure, then SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) testing 1-4 days preprocedure. A subset also underwent day-of-procedure testing. Community hospital patients underwent testing per local protocols. We report SARS-CoV-2 PCR positivity rates, impact, and barriers to testing encountered through June 11. PCR positivity rates of optional preprocedural SARS-CoV-2 testing for 2 consecutive periods following the screening initiative are also reported.

Results: Of 5881 eligible academic hospital patients, 2415 (41.1%) were tested (April 21-June 11). Lack of interest, distance, self-isolation, and nursing home/incarceration status were barriers. There were 11 PCR-positive patients (10 asymptomatic) among 10 539 patients tested (0.10%; 95% CI, 0.05%-0.19%): 3/2415 (0.12%; 95% CI, 0.02%-0.36%) and 8/8124 (0.10%; 95% CI, 0.04%-0.19%) at academic and community hospitals, respectively. Procedures were performed as scheduled in 40% (4/10) of asymptomatic PCR-positive patients. Positivity increased during subsequent coronavirus disease 2019 (COVID-19) surges: 54/34948 (0.15%; 95% CI, 0.12%-0.20%) and 101/24741 (0.41%; 95% CI, 0.33%-0.50%) PCR-positive patients from June 12-September 10 and September 11-December 15, respectively ( < .0001).

Conclusions: Implementing preprocedural PCR testing was complex and revealed low infection rates (0.24% overall), which increased during COVID-19 surges. Additional studies are needed to define the COVID-19 prevalence threshold at which universal preprocedural screening is warranted.
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http://dx.doi.org/10.1093/ofid/ofab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880268PMC
February 2021

Binding of alpha-ACTN4 to EGF receptor enables its rapid phosphorylation.

Heliyon 2021 Jan 21;7(1):e06011. Epub 2021 Jan 21.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States.

Alpha-ACTN4, a member of alpha-actinin family is critical for cell motility through its regulated binding of actin filaments. We previously found that EGF exposure of cells triggers the tyrosyl-phosphorylation of ACTN4 in fibroblasts that dramatically downregulates its binding to actin filaments. However, the exact kinase remained uncertain. In the present study, we report that the phosphorylation of ACTN4 occurs within seconds upon EGF treatments and is accomplished via direct interaction of ACTN4 with the EGF receptor. The major binding domain of ACTN4 for EGF receptor is mapped to the N-terminal 32 amino acids. A second domain minimizes the interaction, as truncation of the C-terminal tail enhances ACTN4 binding to EGF receptor. A mimetic phosphorylated ACTN4, Y4/31E, presents low binding to EGF receptor. Overexpression of EGF receptor in melanoma cell lines, also accomplishes the phosphorylation of ACTN4 in the presence of EGF. These findings suggest that the binding of ACTN4 to EGFR enables its direct and rapid phosphorylation resulting in dissociation from EGFR and decreased binding to actin filaments.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829150PMC
January 2021

Novel combination therapy reduces subconjunctival fibrosis after glaucoma filtration surgery in the rabbit model.

Clin Exp Ophthalmol 2021 Jan 10;49(1):60-69. Epub 2021 Jan 10.

McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Glaucoma filtration surgery (GFS) is limited by subconjunctival, episcleral and scleral fibrosis sealing the trabeculectomy and scarring the filtering bleb. Mitomycin-C (MMC) is commonly applied intraoperatively to the subconjunctival and/or intrascleral space to reduce scarring and promotes GFS success but is associated with postoperative scleral melting and bleb leaks. IP-10 peptide (IP-10p), an ELR-negative CXC chemokine mimetic and inhibitor of fibroblast function, may be an alternative or adjunct to current postoperative GFS treatments. This study sought to determine if IP-10p produces histological changes in tissue remodelling, vascularity and fibrosis that enhance bleb survival after GFS.

Methods: Rabbits underwent tube-assisted filtration surgery on the right eye with either: (a) IP-10p injected into bleb at time of surgery and postoperative days 2, 4 and 7, (b) intraoperative MMC or (c) intraoperative MMC plus IP-10p injected into bleb at time of surgery and postoperative days 2, 4 and 7. Left contralateral eyes were treated with balanced salt solution (BSS).

Results: IP-10p-treated blebs demonstrated reduced collagen deposition, cellularity and overall reduction of scar formation compared to BSS-control. Bleb vascularity was reduced compared to BSS-control and MMC treatment groups. Additionally, IP-10p/MMC treated eyes demonstrated an increased number of conjunctival goblet cells in bleb histology compared to the dramatic loss seen with MMC treatment alone.

Conclusions: This study demonstrates that IP-10p significantly reduces histological scarring compared to BSS or MMC alone, does not damage the conjunctiva to the extent of current standards, and may be an alternative or adjunct to MMC for those undergoing GFS.
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http://dx.doi.org/10.1111/ceo.13884DOI Listing
January 2021

ECM-regulation of autophagy: The yin and the yang of autophagy during wound healing.

Matrix Biol 2021 06 6;100-101:197-206. Epub 2021 Jan 6.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, United States; VA Pittsburgh Healthcare Systems, Pittsburgh, PA 15213, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, United States; Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, United States; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, United States. Electronic address:

Wound healing is a complex sequence of tissue protection, replacement, and reorganization leading to regenerated tissue. Disruption of any of these steps results in the process being incomplete as an ulcer or over-exuberant as a hypertrophic scar. Over the past decade, it has become evident that the extracellular matrix and associated components orchestrate this process. However, the cellular events that are induced by the extracellular matrix to accomplish wound healing remain to be defined. Herein we propose that matrix-regulated cellular macro-autophagy is key to both the tissue replacement and resolution stages of healing by directing cellular function or apoptosis. Further, disruptions in matrix turnover alter autophagic function leading to chronic wounds or scarring. While the literature that directly investigates autophagy during wound healing is sparse, the emerging picture supports our proposing a model of the centrality of the matrix-autophagy modulation as central to physiologic and pathologic healing.
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http://dx.doi.org/10.1016/j.matbio.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257752PMC
June 2021

Dysregulation of the mevalonate pathway during SARS-CoV-2 infection: An in silico study.

J Med Virol 2021 04 29;93(4):2396-2405. Epub 2020 Dec 29.

UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.

SARS-CoV-2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID-19. Prior transcriptomic studies of host cells in response to SARS-CoV-2 infection have not reported to date the effects of SARS-CoV-2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID-19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS-CoV-2, as per Blanco-Melo et al. data set (GSE147507). In light of the present findings, SARS-CoV-2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies.
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http://dx.doi.org/10.1002/jmv.26743DOI Listing
April 2021

Use of Telemedicine for the Physical Examination of Children With Fetal Alcohol Spectrum Disorders.

Alcohol Clin Exp Res 2021 02 8;45(2):409-417. Epub 2021 Feb 8.

Division of Dysmorphology and Teratology, Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, USA.

Background: The fetal alcohol spectrum disorders (FASD) are among the most prevalent causes of neurodevelopmental disorders. The diagnosis is based on assessment of prenatal alcohol exposure, specific physical features identified with a dysmorphology examination, and neurobehavioral assessment. Prompt diagnosis of affected children is necessary to provide early intervention services in a timely manner; however, the availability of diagnostic expertise is limited. We propose telemedicine (TM) as a valid and reliable mode by which the physical phenotype of FASD can be accurately assessed.

Methods: We compared face-to-face (F2F) physical examinations of the 3 key facial features and the resulting physical phenotype of the fetal alcohol syndrome (FAS) and partial FAS (pFAS), as well as 12 additional physical features seen more frequently in children with FAS than in the general population in 61 individuals with 2 different TM methods. These included a Transportable Examination Station system using a precision camera and a laptop and a Zoom secure connection system (ZOOM), using a smart phone and a tablet. We measured the percentages of agreement and the Cohen's K coefficient for each comparison.

Results: Agreements for most physical features and for the physical phenotype of FAS and pFAS were in the "almost perfect" range with some exceptions in the "substantial" range. Imprecision in measurement and subjectivity underlie lower agreement for some features, both F2F and using TM. We identified the optimal conditions for the F2F examinations in order to assure reliability using TM.

Conclusions: TM is a valid and reliable method for the examination of the physical features of FAS that may contribute to greater access to an early diagnosis of FASD in children prenatally exposed to alcohol and/or with characteristic neurobehavioral deficits.
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http://dx.doi.org/10.1111/acer.14533DOI Listing
February 2021

Variable Performance in 6 Commercial SARS-CoV-2 Antibody Assays May Affect Convalescent Plasma and Seroprevalence Screening.

Am J Clin Pathol 2021 02;155(3):343-353

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.

Objectives: Serologic detection of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is needed for definition of convalescent plasma donors, for confounding SARS-CoV-2 presentation, and for seroprevalence studies. Reliable serologic assays with independent validation are required.

Methods: Six SARS-CoV-2 antibody assays from Beckman Coulter, Euroimmun (IgG, IgA), Roche, and Siemens (Centaur, Vista) were assessed for specificity (n = 184), sensitivity (n = 154), and seroconversion in a defined cohort with clinical correlates and molecular SARS-CoV-2 results.

Results: Assay specificity was 99% or greater for all assays except the Euroimmun IgA (95%). Sensitivity at more than 21 days from symptom onset was 84%, 95%, 72%, 98%, 67%, and 96% for Beckman Coulter, Centaur, Vista, Roche, Euroimmun IgA, and Euroimmun IgG, respectively. Average day of seroconversion was similar between assays (8-10 d), with 2 patients not producing nucleocapsid antibodies during hospitalization.

Conclusions: SARS-CoV-2 nucleocapsid antibodies may be less reliably produced early in disease than spike protein antibodies. Assessment of convalescent plasma donors at more than 30 days from symptom onset and seroprevalence studies should use assays with defined sensitivity at time points of interest because not all assays detected antibodies reliably at more than 30 days.
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http://dx.doi.org/10.1093/ajcp/aqaa228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665309PMC
February 2021

Injected Versus Sponge-Applied Mitomycin C (MMC) During Modified Trabeculectomy in New Zealand White Rabbit Model.

Transl Vis Sci Technol 2020 10 20;9(11):23. Epub 2020 Oct 20.

Department of Health Promotion and Development, University of Pittsburgh School of Nursing, Pittsburgh, PA, USA.

Purpose: Mitomycin C is routinely applied during trabeculectomy surgeries to enhance bleb survival after glaucoma filtration surgery. The current approach involves placing cellulose sponges soaked in mitomycin C at a standard concentration onto bare sclera for a predetermined duration, which varies among surgeons. The purpose of this study was to compare the effects of sponge-applied versus intra-Tenon injection of mitomycin C during modified trabeculectomy.

Methods: Two groups of five New Zealand White rabbits underwent glaucoma filtration surgery with either preoperative intra-Tenon injection of mitomycin C or intraoperative application of mitomycin C using a cellulose sponge. Postoperative intraocular pressure was recorded weekly, and eyes were enucleated and sent for pathological examination and histological analysis.

Results: An intra-Tenon injection of mitomycin C resulted in decreased intraocular pressure measurements and bleb vascularity compared to the controls but increased levels compared to the sponge-applied group. Collagen deposition and cellularity were reduced and the goblet cell population was increased in the intra-Tenon injection group.

Conclusions: This study shows that an intra-Tenon injection can be an effective method for administering mitomycin C compared to the standard-of-care approach of mitomycin C being sponge applied onto bare sclera. Mitomycin C injection led to a greater reduction in intraocular pressure and inhibition of fibroblasts. The associated goblet cell population that can lead to increased mitomycin C toxicity-related morbidity was minimized with the intra-Tenon injection compared to the sponge-applied MMC treatment. Therefore, patients with ocular surface disease may benefit from an intra-Tenon injection.

Translational Relevance: This project provides a direct, qualitative assessment in an animal model of common techniques within glaucoma filtration surgery for drug delivery to improve surgical success.
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http://dx.doi.org/10.1167/tvst.9.11.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585388PMC
October 2020

A Perspective on Therapeutic Pan-Resistance in Metastatic Cancer.

Int J Mol Sci 2020 Oct 3;21(19). Epub 2020 Oct 3.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Metastatic spread represents the leading cause of disease-related mortality among cancer patients. Many cancer patients suffer from metastatic relapse years or even decades after radical surgery for the primary tumor. This clinical phenomenon is explained by the early dissemination of cancer cells followed by a long period of dormancy. Although dormancy could be viewed as a window of opportunity for therapeutic interventions, dormant disseminated cancer cells and micrometastases, as well as emergent outgrowing macrometastases, exhibit a generalized, innate resistance to chemotherapy and even immunotherapy. This therapeutic pan-resistance, on top of other adaptive responses to targeted agents such as acquired mutations and lineage plasticity, underpins the current difficulties in eradicating cancer. In the present review, we attempt to provide a framework to understand the underlying biology of this major issue.
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http://dx.doi.org/10.3390/ijms21197304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582598PMC
October 2020

Association between fetal sex and maternal plasma microRNA responses to prenatal alcohol exposure: evidence from a birth outcome-stratified cohort.

Biol Sex Differ 2020 09 10;11(1):51. Epub 2020 Sep 10.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Medical Research and Education Bldg., Texas A&M University Health Science Center, 8447 Riverside Parkway, Bryan, TX, 77807-3260, USA.

Most persons with fetal alcohol spectrum disorders (FASDs) remain undiagnosed or are diagnosed in later life. To address the need for earlier diagnosis, we previously assessed miRNAs in the blood plasma of pregnant women who were classified as unexposed to alcohol (UE), heavily exposed with affected infants (HEa), or heavily exposed with apparently unaffected infants (HEua). We reported that maternal miRNAs predicted FASD-related growth and psychomotor deficits in infants. Here, we assessed whether fetal sex influenced alterations in maternal circulating miRNAs following prenatal alcohol exposure (PAE). To overcome the loss of statistical power due to disaggregating maternal samples by fetal sex, we adapted a strategy of iterative bootstrap resampling with replacement to assess the stability of statistical parameter estimates. Bootstrap estimates of parametric and effect size tests identified male and female fetal sex-associated maternal miRNA responses to PAE that were not observed in the aggregated sample. Additionally, we observed, in HEa mothers of female, but not male fetuses, a network of co-secreted miRNAs whose expression was linked to miRNAs encoded on the X-chromosome. Interestingly, the number of significant miRNA correlations for the HEua group mothers with female fetuses was intermediate between HEa and UE mothers at mid-pregnancy, but more similar to UE mothers by the end of pregnancy. Collectively, these data show that fetal sex predicts maternal circulating miRNA adaptations, a critical consideration when adopting maternal miRNAs as diagnostic biomarkers. Moreover, a maternal co-secretion network, predominantly in pregnancies with female fetuses, emerged as an index of risk for adverse birth outcomes due to PAE.
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http://dx.doi.org/10.1186/s13293-020-00327-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488011PMC
September 2020

SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected hospitalized COVID-19 patients.

J Gen Virol 2020 11 21;101(11):1156-1169. Epub 2020 Aug 21.

Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), emerged at the end of 2019 and by mid-June 2020 the virus had spread to at least 215 countries, caused more than 8 000 000 confirmed infections and over 450 000 deaths, and overwhelmed healthcare systems worldwide. Like severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 (hACE2) as a receptor to enter cells. However, the SARS-CoV-2 spike (S) glycoprotein has a novel insertion that generates a putative furin cleavage signal and this has been postulated to expand the host range. Two low-passage (P) strains of SARS-CoV-2 (Wash1 : P4 and Munich : P1) were cultured twice in Vero E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1 : P6 and minor variants in the Munich : P3 strain. Cleavage of the S glycoprotein in SARS-CoV-2-infected Vero E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated that the S glycoprotein reached the cell surface. Since the S protein is a major antigenic target for the development of neutralizing antibodies, we investigated the development of neutralizing antibody titres in serial serum samples obtained from COVID-19 human patients. These were comparable regardless of the presence of an intact or deleted furin cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either or pathogenesis studies.
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http://dx.doi.org/10.1099/jgv.0.001481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879561PMC
November 2020

Prostate cancer liver metastasis: Dormancy and resistance to therapy.

Semin Cancer Biol 2021 Jun 12;71:2-9. Epub 2020 Jul 12.

Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Electronic address:

Liver metastasis causes nearly half of death from solid tumors. Metastatic lesions, to the liver in particular, can become detectable years or decades after primary tumor removal, leaving an uncertain long-term prognosis in patients. Prostate cancer (PCa), a prominent metastatic dormant cancer, has the worst prognosis when found in the liver compared to other metastatic sites. These metastatic nodules display a therapy resistance in the liver pro-metastatic microenvironment; the resistance appears to be conferred by both dormancy and independent of dormancy when the nodules emerge. Within the review, the molecular underpinnings of how the liver aids and protects PCa cells seeding, colonization and resistance will be discussed.
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http://dx.doi.org/10.1016/j.semcancer.2020.07.004DOI Listing
June 2021

Leveraging Bayesian networks and information theory to learn risk factors for breast cancer metastasis.

BMC Bioinformatics 2020 Jul 10;21(1):298. Epub 2020 Jul 10.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Even though we have established a few risk factors for metastatic breast cancer (MBC) through epidemiologic studies, these risk factors have not proven to be effective in predicting an individual's risk of developing metastasis. Therefore, identifying critical risk factors for MBC continues to be a major research imperative, and one which can lead to advances in breast cancer clinical care. The objective of this research is to leverage Bayesian Networks (BN) and information theory to identify key risk factors for breast cancer metastasis from data.

Methods: We develop the Markov Blanket and Interactive risk factor Learner (MBIL) algorithm, which learns single and interactive risk factors having a direct influence on a patient's outcome. We evaluate the effectiveness of MBIL using simulated datasets, and compare MBIL with the BN learning algorithms Fast Greedy Search (FGS), PC algorithm (PC), and CPC algorithm (CPC). We apply MBIL to learn risk factors for 5 year breast cancer metastasis using a clinical dataset we curated. We evaluate the learned risk factors by consulting with breast cancer experts and literature. We further evaluate the effectiveness of MBIL at learning risk factors for breast cancer metastasis by comparing it to the BN learning algorithms Necessary Path Condition (NPC) and Greedy Equivalent Search (GES).

Results: The averages of the Jaccard index for the simulated datasets containing 2000 records were 0.705, 0.272, 0.228, and 0.147 for MBIL, FGS, PC, and CPC respectively. MBIL, NPC, and GES all learned that grade and lymph_nodes_positive are direct risk factors for 5 year metastasis. Only MBIL and NPC found that surgical_margins is a direct risk factor. Only NPC found that invasive is a direct risk factor. MBIL learned that HER2 and ER interact to directly affect 5 year metastasis. Neither GES nor NPC learned that HER2 and ER are direct risk factors.

Discussion: The results involving simulated datasets indicated that MBIL can learn direct risk factors substantially better than standard Bayesian network learning algorithms. An application of MBIL to a real breast cancer dataset identified both single and interactive risk factors that directly influence breast cancer metastasis, which can be investigated further.
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http://dx.doi.org/10.1186/s12859-020-03638-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350636PMC
July 2020

SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients.

bioRxiv 2020 Jun 22. Epub 2020 Jun 22.

Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

SARS-CoV-2, the causative agent of COVID-19, emerged at the end of 2019 and by mid-June 2020, the virus has spread to at least 215 countries, caused more than 8,000,000 confirmed infections and over 450,000 deaths, and overwhelmed healthcare systems worldwide. Like SARS-CoV, which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 (hACE2) as a receptor to enter cells. However, the SARS-CoV-2 spike (S) glycoprotein has a novel insertion that generates a putative furin cleavage signal and this has been postulated to expand the host range. Two low passage (P) strains of SARS-CoV-2 (Wash1: P4 and Munich: P1) were cultured twice in Vero-E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1: P6 and minor variants in the Munich: P3 strain. Cleavage of the S glycoprotein in SARS-CoV-2-infected Vero-E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated the S glycoprotein reached the cell surface. Since the S protein is a major antigenic target for the development of neutralizing antibodies we investigated the development of neutralizing antibody titers in serial serum samples obtained from COVID-19 human patients. These were comparable regardless of the presence of an intact or deleted furin cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either or pathogenesis studies.
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http://dx.doi.org/10.1101/2020.06.19.154930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325173PMC
June 2020

Assessing Immune Response to SARS-CoV-2 Infection.

Immunotargets Ther 2020 11;9:111-114. Epub 2020 Jun 11.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

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http://dx.doi.org/10.2147/ITT.S264138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295455PMC
June 2020

Integrative microphysiological tissue systems of cancer metastasis to the liver.

Semin Cancer Biol 2021 Jun 21;71:157-169. Epub 2020 Jun 21.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA; VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, USA; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.

The liver is the most commonly involved organ in metastases from a wide variety of solid tumors. The use of biologically and cellularly complex liver tissue systems have shown that tumor cell behavior and therapeutic responses are modulated within the liver microenvironment and in ways distinct from the behaviors in the primary locations. These microphysiological systems have provided unexpected and powerful insights into the tumor cell biology of metastasis. However, neither the tumor nor the liver exist in an isolated tissue situation, having to function within a complete body and respond to systemic events as well as those in other organs. To examine the influence of one organ on the function of other tissues, microphysiological systems are being linked. Herein, we discuss extending this concept to tumor metastases by integrating complex models of the primary tumor with the liver metastatic environment. In addition, inflammatory organs and the immune system can be incorporated into these multi-organ systems to probe the effects on tumor behavior and cancer treatments.
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http://dx.doi.org/10.1016/j.semcancer.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750290PMC
June 2021
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