Publications by authors named "J Chuck Harrell"

365 Publications

Breast cancer liver metastasis: current and future treatment approaches.

Clin Exp Metastasis 2021 Mar 6. Epub 2021 Mar 6.

Department of Pathology, Virginia Commonwealth University, Richmond, VA, 23298, USA.

Nearly all fatalities arising from breast tumors are attributable to distant metastases. Breast cancer liver metastasis (BCLM) is associated with poor prognoses, with the median survival time being 2 to 3 years. Tumor intrinsic subtype directs preferential metastasis to specific organs, with HER2-enriched tumors demonstrating the highest rates of metastasis to the liver, though all subtypes can grow in the liver. There is no singular established standard-of-care for BCLM; therapeutic selection is driven by histologic and molecular hallmarks of the primary tumor or biopsied metastasis samples. Given the poor prognosis of patients with hepatic spread, pre-clinical studies are necessary to identify and evaluate promising new treatment strategies. It is critical that these laboratory studies accurately recapitulate the BCLM disease process, standard progression, and histological attributes. In this review, we summarize the histologic and molecular characteristics of BCLM, evaluate the efficacy of existing surgical and medical treatment strategies, and discuss future approaches to preclinical study of BCLM.
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http://dx.doi.org/10.1007/s10585-021-10080-4DOI Listing
March 2021

Biofilm Formation, Chronic Infection, and Immunity Within the Intestine and Hepatobiliary Tract.

Front Cell Infect Microbiol 2020 2;10:624622. Epub 2021 Feb 2.

Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States.

Within the species of , there is significant diversity represented among the numerous subspecies and serovars. Collectively, these account for microbes with variable host ranges, from common plant and animal colonizers to extremely pathogenic and human-specific serovars. Despite these differences, many species find commonality in the ability to form biofilms and the ability to cause acute, latent, or chronic disease. The exact outcome of infection depends on many factors such as the growth state of , the environmental conditions encountered at the time of infection, as well as the infected host and immune response elicited. Here, we review the numerous biofilm lifestyles of (on biotic and abiotic surfaces) and how the production of extracellular polymeric substances not only enhances long-term persistence outside the host but also is an essential function in chronic human infections. Furthermore, careful consideration is made for the events during initial infection that allow for gut transcytosis which, in conjunction with host immune functions, often determine the progression of disease. Both typhoidal and non-typhoidal salmonellae can cause chronic and/or secondary infections, thus the adaptive immune responses to both types of bacteria are discussed with particular attention to the differences between Typhi, Typhimurium, and invasive non-typhoidal that can result in differential immune responses. Finally, while strides have been made in our understanding of immunity to in the lymphoid organs, fewer definitive studies exist for intestinal and hepatobiliary immunity. By examining our current knowledge and what remains to be determined, we provide insight into new directions in the field of immunity, particularly as it relates to chronic infection.
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http://dx.doi.org/10.3389/fcimb.2020.624622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885405PMC
February 2021

Prolactin Drives a Dynamic STAT5A/HDAC6/HMGN2 Cis-Regulatory Landscape Exploitable in ER+ Breast Cancer.

Endocrinology 2021 Feb 16. Epub 2021 Feb 16.

Department of Pathology, Virginia Commonwealth University, Richmond, VA USA.

The hormone, prolactin, has been implicated in breast cancer pathogenesis and regulates chromatin engagement by the transcription factor, STAT5A. STAT5A is known to inducibly bind promoters and cis-regulatory elements genome wide, though the mechanisms by which it exerts specificity and regulation of target gene expression remain enigmatic. We previously identified HDAC6 and HMGN2 as cofactors that facilitate prolactin induced, STAT5A mediated gene expression. Here, multi-condition STAT5A, HDAC6, and HMGN2 ChIP-seq with parallel condition RNA-seq are utilized to reveal the cis-regulatory landscape and cofactor dynamics underlying prolactin stimulated gene expression in breast cancer. We find that prolactin regulated genes are significantly enriched for cis-regulatory elements bound by HDAC6 and HMGN2, and that inducible STAT5A binding at enhancers, rather than promoters, conveys specificity for prolactin regulated genes. The selective HDAC6 inhibitor, ACY-241, blocks prolactin induced STAT5A chromatin engagement at cis-regulatory elements as well as a significant proportion of prolactin stimulated gene expression. We identify functional pathways known to contribute to the development and/or progression of breast cancer that are activated by prolactin and inhibited by ACY-241. Additionally, we find that the DNA sequences underlying shared STAT5A and HDAC6 binding-sites at enhancers are differentially enriched for estrogen response elements (ESR1 and ESR2 motifs) relative to enhancers bound by STAT5A alone. Gene set enrichment analysis identifies significant overlap of ERα regulated genes with genes regulated by prolactin, particularly prolactin regulated genes with promoters or enhancers co-occupied by both STAT5A and HDAC6. Lastly, the therapeutic efficacy of ACY-241 is demonstrated in in vitro and in vivo breast cancer models, where we identify synergistic ACY-241 drug combinations and observe differential sensitivity of ER + models relative to ER - models.
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http://dx.doi.org/10.1210/endocr/bqab036DOI Listing
February 2021

Unexpected PD-L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies.

EMBO Mol Med 2021 Mar 15;13(3):e12716. Epub 2021 Feb 15.

Laboratory of Novel Biologics, University of Virginia, Charlottesville, VA, USA.

Lack of effective immune infiltration represents a significant barrier to immunotherapy in solid tumors. Thus, solid tumor-enriched death receptor-5 (DR5) activating antibodies, which generates tumor debulking by extrinsic apoptotic cytotoxicity, remains a crucial alternate therapeutic strategy. Over past few decades, many DR5 antibodies moved to clinical trials after successfully controlling tumors in immunodeficient tumor xenografts. However, DR5 antibodies failed to significantly improve survival in phase-II trials, leading in efforts to generate second generation of DR5 agonists to supersize apoptotic cytotoxicity in tumors. Here we have discovered that clinical DR5 antibodies activate an unexpected immunosuppressive PD-L1 stabilization pathway, which potentially had contributed to their limited success in clinics. The DR5 agonist stimulated caspase-8 signaling not only activates ROCK1 but also undermines proteasome function, both of which contributes to increased PD-L1 stability on tumor cell surface. Targeting DR5-ROCK1-PD-L1 axis markedly increases immune effector T-cell function, promotes tumor regression, and improves overall survival in animal models. These insights have identified a potential clinically viable combinatorial strategy to revive solid cancer immunotherapy using death receptor agonism.
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http://dx.doi.org/10.15252/emmm.202012716DOI Listing
March 2021

Systemic manifestations of Ehlers-Danlos syndrome.

Proc (Bayl Univ Med Cent) 2020 Aug 26;34(1):49-53. Epub 2020 Aug 26.

H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas.

Ehlers-Danlos syndrome (EDS) is a multifaceted debilitating disease. Affected patients are at risk for complications such as joint hypermobility and cardiac disease, but the prevalence, course, and management of these conditions are not well understood. The objective of this retrospective cohort study was to investigate the demographic characteristics and systemic manifestations in EDS. We performed a retrospective analysis of 98 EDS patients seen in a physical medicine and rehabilitation clinic between January 2015 and April 2019. Charts were reviewed for demographic information, subtype of EDS, characteristics of musculoskeletal pain, and presence of certain systemic comorbid diagnoses: autonomic dysfunction, headaches/migraines, gastrointestinal conditions, cardiovascular anomalies, mast cell activation syndrome, and temporomandibular joint dysfunction. Of 98 patients, 75 were diagnosed with EDS-hypermobile type (EDS-HT); 94 patients were women, and the mean age was 36.7 years. On average, each patient reported involvement of 5.4 joints, with the shoulder, knee, and lumbar spine as the most common. The average number of comorbid systemic conditions was 2.8, of which autonomic dysfunction was the most common. This study aims to provide a better understanding of this disease to promote earlier and more accurate diagnoses to guide treatment and prevent complications.
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http://dx.doi.org/10.1080/08998280.2020.1805714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785142PMC
August 2020

Validation of Whole Slide Imaging for Intraoperative Consultation During Mohs Micrographic Surgery.

Dermatol Surg 2020 Jul 29. Epub 2020 Jul 29.

*University of Florida College of Medicine, Gainesville, Florida †Department of Dermatology, University of Florida College of Medicine, Gainesville, Florida.

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http://dx.doi.org/10.1097/DSS.0000000000002545DOI Listing
July 2020

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial.

JAMA Oncol 2021 Jan;7(1):42-50

Department of Medicine, Medical College of Wisconsin, Milwaukee.

Importance: Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.

Objective: To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML.

Design, Setting, And Participants: The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020.

Intervention: Discontinuation of TKIs.

Main Outcomes And Measures: Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR).

Results: Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs.

Conclusions And Relevance: In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies.

Trial Registration: ClinicalTrials.gov Identifier: NCT02269267.
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http://dx.doi.org/10.1001/jamaoncol.2020.5774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662490PMC
January 2021

Optimizing Precision of Hypertension Care to Maximize Blood Pressure Control: A Pilot Study Utilizing a Smartphone App to Incorporate Plasma Renin Activity Testing.

Clin Transl Sci 2020 Nov 3. Epub 2020 Nov 3.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Only half of patients with hypertension (HTN) respond to any given antihypertensive medication. Heterogeneity in pathophysiologic pathways underlying HTN is a major contributor. Personalizing antihypertensive therapy could improve blood pressure (BP) reduction. The objective of this study was to assess the effect of pragmatic implementation of a personalized plasma renin activity (PRA)-based smartphone app on improving BP reduction. Patients with untreated or treated but uncontrolled HTN were recruited. BP and PRA were measured at baseline with final BP measured at 6 months. Patient's information was entered into the app and treatment recommendations were returned. Clinicians were at liberty to follow or disregard the app's recommendations. BP levels and percent BP control among patients whose clinicians did and did not follow the app's recommendations were compared using independent t-test and Fisher's exact test, respectively. Twenty-nine European American patients were included (38% women) with mean age of 52 ± 9 years and median PRA of 1.3 ng/mL/hr (interquartile range 0.5-3.1 ng/mL/hr). Participants whose clinicians followed the app's recommendations (n = 16, 55%) as compared with those whose clinicians did not (n = 13, 45%), had a greater reduction in 6-month systolic BP (-15 ± 21 vs. -3 ± 21 mm Hg; adjusted-P = 0.1) and diastolic BP (-8 ± 8 vs. -1 ± 8 mm Hg; adjusted-P = 0.04). BP control at 6 months tended to be greater among patients whose clinicians accepted the app's recommendations vs. those whose clinicians did not (63% vs. 23%, P = 0.06). This pilot study demonstrates that acceptance of the app's recommendations was associated with a greater BP reduction. Future studies to confirm these pilot findings are warranted.
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http://dx.doi.org/10.1111/cts.12922DOI Listing
November 2020

The Roles of Autophagy and Senescence in the Tumor Cell Response to Radiation.

Radiat Res 2020 08;194(2):103-115

Departments of a Pharmacology and Toxicology.

Radiation is a critical pillar in cancer therapeutics, exerting its anti-tumor DNA-damaging effects through various direct and indirect mechanisms. Radiation has served as an effective mode of treatment for a number of cancer types, providing both curative and palliative treatment; however, resistance to therapy persists as a fundamental limitation. While cancer cell death is the ideal outcome of any anti-tumor treatment, radiation induces several responses, including apoptotic cell death, mitotic catastrophe, autophagy and senescence, where autophagy and senescence may promote cell survival. In most cases, autophagy, a conventionally cytoprotective mechanism, is a "first" responder to damage incurred from chemotherapy and radiation treatment. The paradigm developed on the premise that autophagy is cytoprotective in nature has provided the rationale for current clinical trials designed with the goal of radiosensitizing cancer cells through the use of autophagy inhibitors; however, these have failed to produce consistent results. Delving further into pre-clinical studies, autophagy has actually been shown to take diverse, sometimes opposing, forms, such as acting in a cytotoxic or nonprotective fashion, which may be partially responsible for the inconsistency of clinical outcomes. Furthermore, autophagy can have both pro- and anti-tumorigenic effects, while also having an important immune modulatory function. Senescence often occurs in tandem with autophagy, which is also the case with radiation. Radiation-induced senescence is frequently followed by a phase of proliferative recovery in a subset of cells and has been proposed as a tumor dormancy model, which can contribute to resistance to therapy and possibly also disease recurrence. Senescence induction is often accompanied by a unique secretory phenotype that can either promote or suppress immune functions, depending on the expression profile of cytokines and chemokines. Novel therapeutics selectively cytotoxic to senescent cells (senolytics) may prove to prolong remission by delaying disease recurrence in patients. Accurate assessment of primary responses to radiation may provide potential targets that can be manipulated for therapeutic benefit to sensitize cancer cells to radiotherapy, while sparing normal tissue.
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http://dx.doi.org/10.1667/RADE-20-00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482104PMC
August 2020

Ehlers-Danlos Syndrome: An Analysis of the Current Treatment Options.

Pain Physician 2020 07;23(4):429-438

H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX.

Background: Ehlers-Danlos syndrome (EDS) is a multifaceted disease that can present with a variety of types of pain. Unfortunately, both the mechanisms and treatments for pain are poorly understood. The proposed treatments for the various musculoskeletal pain syndromes in EDS have had variable success, and it becomes much more imperative to better define and evaluate the current treatment modalities in treating this debilitating disease.

Objectives: The purpose of this study was to investigate the currently available treatment modalities for patients with EDS and their efficacies in pain and symptom relief.

Study Design: Retrospective cohort study.

Setting: Institutional physical medicine and rehabilitation primary care clinic.

Methods: All patients were seen between January 2015 and April 2019, in which 98 patients with EDS were identified through retrospective chart review. Institutional review board approval was obtained, and all patients provided written consent to be included in the study. We reviewed various treatment modalities, including complimentary/alternative treatments, opioids/opioid-like medications, nonsteroidal antiinflammatory drugs, physical therapy, occupational therapy, muscle relaxants, neuropathic modulators, steroids, surgery/procedures, and acetaminophen. Treatment methods were extracted from individual patient charts, and efficacy was grouped into 3 categories: improvement, no effect, or worsened symptoms.

Results: The most common treatments used were complimentary/alternative treatments (n = 88). Occupational therapy and bracing were the most effective options with 70% of patients reporting improvement. Neuropathic modulators were the least well tolerated with 47% of patients reporting adverse effects.

Limitations: Men were a small percentage of the study. Patients were not randomized, and pain score reporting was subjective. Patient data were extracted from a single practice setting. Timing and symptom onset were not measured.

Conclusions: There is a relative paucity of published literature regarding the various treatment methods for EDS. Although our study is able to identify positive and negative trends with certain modalities, it is vital to understand that EDS is not a uniform diagnosis among patients, and that a combination of several different treatments usually is needed for optimal symptom control. Further research and investigation are necessary to develop a comprehensive treatment database for this complex condition.

Key Words: Ehlers-Danlos syndrome, pain, hypermobility, arthralgia, subluxation, genetic, physical therapy, interventional pain.
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July 2020

Single Center Trends in Acute Coronary Syndrome Volume and Outcomes During the COVID-19 Pandemic.

Cardiol Res 2020 Aug 3;11(4):256-259. Epub 2020 Jun 3.

Division of Cardiology, University of California, Los Angeles, CA, USA.

Background: The coronavirus disease 2019 (COVID-19) pandemic has greatly affected healthcare delivery across the world. In this report, we aim to further characterize the changes in cardiac catheterization at our institution, specifically in the setting of acute coronary syndrome (ACS).

Methods: We performed a retrospective analysis of patients undergoing cardiac catheterization between December 23, 2019 and April 12, 2020 at our institution. All patients with cardiac catheterizations for ACS, ST-elevation myocardial infarction (STEMI) activation, and out-of-hospital cardiac arrest (OHCA) were analyzed. Cardiac catheterization volume, as well as clinical and procedural characteristics of patients undergoing cardiac catheterization, was compared before and during the COVID-19 pandemic.

Results: Patients presenting with ACS and OHCA were similar in terms of demographics and comorbidities during both time periods. The mean monthly volume for ACS cases dropped by 26% during the pandemic, which was consistent among both unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) and STEMI cases. OHCA volume decreased significantly as well (five cases per month before to zero cases during the pandemic, P = 0.01). Among patients with STEMI, initial markers of cardiac injury, door-to-balloon time, and all-cause mortality were similar in both time periods.

Conclusions: With the start of the COVID-19 pandemic, there was a reduction in cardiac catheterization volume across the spectrum of ACS at our institution, which was consistent with reports from other centers across the globe. Patients with STEMI during the initial phase of the COVID-19 pandemic did not seem to have delays in presentation or significant differences in all-cause mortality at our institution.
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http://dx.doi.org/10.14740/cr1096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295564PMC
August 2020

New generation breast cancer cell lines developed from patient-derived xenografts.

Breast Cancer Res 2020 06 23;22(1):68. Epub 2020 Jun 23.

Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.

Background: Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. Here we describe six breast cancer cell lines derived from patient-derived xenografts (PDX) and their general characteristics.

Methods: Established breast cancer PDX were processed into cell suspensions and placed into standard 2D cell culture; six emerged into long-term passageable cell lines. Cell lines were assessed for protein expression of common luminal, basal, and mesenchymal markers, growth assessed in response to estrogens and endocrine therapies, and RNA-seq and oncogenomics testing performed to compare relative transcript levels and identify putative oncogenic drivers.

Results: Three cell lines express ER and two are also progesterone receptor (PR) positive; PAM50 subtyping identified one line as luminal A. One of the ER+PR+ lines harbors a D538G mutation in the gene for ER (ESR1), providing a natural model that contains this endocrine-resistant genotype. The third ER+PR cell line has mucinous features, a rare histologic type of breast cancer. The three other lines are ER- and represent two basal-like and a mixed ductal/lobular breast cancer. The cell lines show varied responses to tamoxifen and fulvestrant, and three were demonstrated to regrow tumors in vivo. RNA sequencing confirms all cell lines are human and epithelial. Targeted oncogenomics testing confirmed the noted ESR1 mutation in addition to other mutations (i.e., PIK3CA, BRCA2, CCND1, NF1, TP53, MYC) and amplifications (i.e., FGFR1, FGFR3) frequently found in breast cancers.

Conclusions: These new generation breast cancer cell lines add to the existing repository of breast cancer models, increase the number of ER+ lines, and provide a resource that can be genetically modified for studying several important clinical breast cancer features.
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http://dx.doi.org/10.1186/s13058-020-01300-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310532PMC
June 2020

The impact of social constraints on insomnia among African-American breast cancer survivors: The mediating role of fear of recurrence.

Psychooncology 2020 08 2;29(8):1296-1302. Epub 2020 Jul 2.

College of Medicine, Howard University, Washington, DC, USA.

Objective: Insomnia is a significant concern among African-American breast cancer survivors (BCS). Social constraints (SC)-receiving unsupportive or critical responses when expressing trauma-related emotions-and fear of recurrence (FOR) have been associated with insomnia. We examined FOR as a mediator in the relationship between SC and insomnia in African-American BCS. We hypothesized a direct effect of SC on insomnia, and an indirect effect of SC on insomnia through FOR.

Methods: Sixty-four African-American BCS completed a questionnaire assessing demographics, clinical characteristics, SC, FOR, and insomnia. Participants were an average of M = 8.41 (SD = 5.8) year survivors. The mediation was tested using PROCESS for SPSS.

Results: The direct effect of SC on insomnia was significant (direct effect = .17, SE = .08, P = .04). Moreover, the indirect effect of SC on insomnia through FOR was significant (indirect effect = .19, SE = .10, 95% CI = .05, .41).

Conclusions: Experiencing SC from family and friends could produce cognitions that impact sleep for BCS, and FOR could be one of those cognitions. Family-based models of care that emphasize the emotional needs of survivors and families could be a relevant strategy to address the SC that impacts sleep.
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http://dx.doi.org/10.1002/pon.5435DOI Listing
August 2020

Basal Cell Carcinoma Arising in Scars of Subcutaneous Port Sites.

Dermatol Surg 2020 Mar 24. Epub 2020 Mar 24.

University of Florida College of Medicine, Gainesville, Florida Department of Dermatology, University of Florida Health, Gainesville, Florida.

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http://dx.doi.org/10.1097/DSS.0000000000002393DOI Listing
March 2020

Identification of synergistic drug combinations using breast cancer patient-derived xenografts.

Sci Rep 2020 01 30;10(1):1493. Epub 2020 Jan 30.

Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA.

Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with relatively poor outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative, targeted treatment options, despite decades of major research efforts. Our studies sought to identify promising targeted therapeutic candidates for TNBC through in vitro screening of 1,363 drugs in patient-derived xenograft (PDX) models. Using this approach, we generated a dataset that can be used to assess and compare responses of various breast cancer PDXs to many different drugs. Through a series of further drug screening assays and two-drug combination testing, we identified that the combination of afatinib (epidermal growth factor receptor (EGFR) inhibitor) and YM155 (inhibitor of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5; survivin) expression) is synergistically cytotoxic across multiple models of basal-like TNBC and reduces PDX mammary tumor growth in vivo. We found that YM155 reduces EGFR expression in TNBC cells, shedding light on its potential mechanism of synergism with afatinib. Both EGFR and BIRC5 are highly expressed in basal-like PDXs, cell lines, and patients, and high expression of both genes reduces metastasis-free survival, suggesting that co-targeting of these proteins holds promise for potential clinical success in TNBC.
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http://dx.doi.org/10.1038/s41598-020-58438-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992640PMC
January 2020

The utility of the "Glowing Head" mouse for breast cancer metastasis research.

Clin Exp Metastasis 2020 04 14;37(2):241-246. Epub 2020 Jan 14.

Integrative Life Sciences Program, Virginia Commonwealth University, Richmond, VA, USA.

The expression of cellular reporters to label cancer cells, such as green fluorescent protein (GFP) and luciferase, can stimulate immune responses and effect tumor growth. Recently, a mouse model that expresses GFP and luciferase in the anterior pituitary gland was generated to tolerize mice to these proteins; the "Glowing Head" mouse. Mice were obtained from a commercial vendor, bred, and then used for tumor growth and metastasis studies. The transgene expression of luciferase was assessed within tumor-naïve mice as well as mice with mammary tumors or metastases. Tumor-free mice with white fur, compared to black fur, allowed for stronger luciferase transgene expression to be observed in the pituitary, sternum, and femur. Growth of four different luciferase-expressing mouse cancer cell lines readily occurred in the mammary gland. Though sternum expression of the luciferase transgene occurred in cancer-free mice, growth or death of luciferase positive cancer cells in the lung could be observed. Liver metastases seeded by portal vein injections of luciferase positive cancer cell lines were completely distinct from luciferase transgene expression. Though lung and brain metastasis studies have limitations, the Glowing Head mouse can be useful to inhibit immune system rejection of luciferase or GFP expressing cancer cells. This mouse model is most beneficial for studies of mammary tumors and liver metastases.
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http://dx.doi.org/10.1007/s10585-020-10020-8DOI Listing
April 2020

Eruption on the vulva and groin.

JAAD Case Rep 2020 Jan 18;6(1):6-8. Epub 2019 Dec 18.

Department of Dermatology, University of Florida College of Medicine, Gainesville, Florida.

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http://dx.doi.org/10.1016/j.jdcr.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928262PMC
January 2020

Differential contribution of cyclooxygenase to basal cerebral blood flow and hypoxic cerebral vasodilation.

Am J Physiol Regul Integr Comp Physiol 2020 02 23;318(2):R468-R479. Epub 2019 Dec 23.

Department of Kinesiology, University of Wisconsin, Madison, Wisconsin.

Cyclooxygenase (COX) is proposed to regulate cerebral blood flow (CBF); however, accurate regional contributions of COX are relatively unknown at baseline and particularly during hypoxia. We hypothesized that COX contributes to both basal and hypoxic cerebral vasodilation, but COX-mediated vasodilation is greater in the posterior versus anterior cerebral circulation. CBF was measured in 9 healthy adults (28 ± 4 yr) during normoxia and isocapnic hypoxia (fraction of inspired oxygen = 0.11), with COX inhibition (oral indomethacin, 100mg) or placebo. Four-dimensional flow magnetic resonance imaging measured cross-sectional area (CSA) and blood velocity to quantify CBF in 11 cerebral arteries. Cerebrovascular conductance (CVC) was calculated (CVC = CBF × 100/mean arterial blood pressure) and hypoxic reactivity was expressed as absolute and relative change in CVC [ΔCVC/Δ pulse oximetry oxygen saturation ()]. At normoxic baseline, indomethacin reduced CVC by 44 ± 5% ( < 0.001) and artery CSA ( < 0.001), which was similar across arteries. Hypoxia ( 80%-83%) increased CVC ( < 0.01), reflected as a similar relative increase in reactivity (% ΔCVC/-Δ) across arteries ( < 0.05), in part because of increases in CSA ( < 0.05). Indomethacin did not alter ΔCVC or ΔCVC/Δ to hypoxia. These findings indicate that ) COX contributes, in a largely uniform fashion, to cerebrovascular tone during normoxia and ) COX is not obligatory for hypoxic vasodilation in any regions supplied by large extracranial or intracranial arteries.
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http://dx.doi.org/10.1152/ajpregu.00132.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199240PMC
February 2020

Advances in the diagnosis of autoimmune bullous dermatoses.

Clin Dermatol 2019 Nov - Dec;37(6):692-712. Epub 2019 Oct 15.

Department of Dermatology, University of Florida College of Medicine, Gainesville, Florida, USA. Electronic address:

Autoimmune bullous dermatoses are defined by autoantibodies directed against adhesion proteins in the epidermis or basement membrane zone, resulting in blister formation on the skin and mucosa. Diagnosis depends on lesional biopsy for histopathology and perilesional biopsy for direct immunofluorescence. Additional diagnostic methods include indirect immunofluorescence, enzyme-linked immunosorbent assay, and immunoblot (Western blot), which may be selected in specific clinical scenarios due to improved sensitivity and/or specificity. This contribution reviews the available evidence supporting the use of each method to provide a practical reference for clinicians when diagnosing autoimmune bullous disorders. Techniques and cost are reviewed, and newer diagnostic techniques with potential for clinical application are.
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http://dx.doi.org/10.1016/j.clindermatol.2019.09.004DOI Listing
August 2020

Framework for Ethical Community Engagement (ECE) with Underserved Populations in the Rural South: A Help for Bioethics and Healthcare Promotion.

J Health Care Poor Underserved 2019 ;30(4S):91-104

Mainstream bioethics has dealt inadequately with issues of race, gender, and class that intersect and shape the life experiences of vulnerable populations in the U.S., such as Black women in the rural South who have faced bioethical and public health challenges throughout U.S. history. They have suffered from health disparities, challenges to their autonomy, inadequate access to quality health care, biomedical violations, and a healthcare system that has implicit bias and discrimination. Thus, we propose a framework for biomedical and behavioral researchers and organizations who seek to engage, ethically, such vulnerable communities. The goal of this Ethical Community Engagement (ECE) framework is to empower communities, respect autonomy, and address needs of populations that suffer from health disparities. The Tuskegee/Macon County Diabetes Coalition, formed to coordinate and share information promoting healthy living and habits among citizens of this area, is a demonstration of this ECE framework.
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http://dx.doi.org/10.1353/hpu.2019.0120DOI Listing
August 2020

Motor impairments in transient ischemic attack increase the odds of a positive diffusion-weighted imaging: A meta-analysis.

Restor Neurol Neurosci 2019 ;37(5):509-521

Department of Neurology, University of Colorado, Aurora, CO, USA.

Background: Unilateral motor impairment is a key symptom used in the diagnosis of transient ischemic attack (TIA). Diffusion-weighted imaging (DWI) is a promising diagnostic tool for detecting ischemic lesions. While both motor impairments and DWI abnormalities are linked to the diagnosis of TIA, the association between these prognostic factors is not well understood.

Objective: To examine the association between unilateral motor impairments and the odds of a positive DWI in TIA. Further, to determine whether the time between symptom onset and neuroimaging (delay to scan) influences the odds of a positive DWI.

Methods: We used PRISMA guidelines to conduct a systematic search from 1989 to 2018. We included studies that reported number of individuals with/without unilateral motor symptoms and a positive/negative DWI.

Results: Twenty-four studies from North America, Australia, Asia, and Europe were submitted to a meta-analysis. A pooled odds ratio of 1.80 (95% CI, 1.45-2.24, p = 0.00; I2 = 57.38) suggested that the odds of a positive DWI are greater in TIA individuals who experience motor symptoms as compared with those who experience no motor symptoms. Further, increasing the time delay to scan from the symptom onset (>2 days) did not influence the odds of a positive DWI as compared with an earlier scan (≤2 days).

Conclusions: The current meta-analysis provides cumulative evidence from 6710 individuals with TIA that the presence of motor symptoms increases the odds of a positive DWI by two-folds. These findings transform the clinical perception into evidence-based knowledge that motor impairments elevate the risk for brain tissue damage. Unilateral motor impairments in a cerebrovascular event should increase a physician's suspicion of detecting brain infarctions. These findings may influence the clinical management of TIA by generating faster response to motor impairments in TIA and accelerating referral to specialized stroke clinic.
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http://dx.doi.org/10.3233/RNN-190940DOI Listing
April 2020

Tuning the electronic properties of the γ-AlO surface by phosphorus doping.

Phys Chem Chem Phys 2019 Jul;21(27):15080-15088

Department of Chemistry, Rutgers University, Newark, NJ 07102, USA.

Tuning the electronic properties of oxide surfaces is of pivotal importance, because they find applicability in a variety of industrial processes, including catalysis. Currently, the industrial protocols for synthesizing oxide surfaces are limited to only partial control of the oxide's properties. This is because the ceramic processes result in complex morphologies and a priori unpredictable behavior of the products. While the bulk doping of alumina surfaces has been demonstrated to enhance their catalytic applications (i.e. hydrodesulphurization (HDS)), the fundamental understanding of this phenomenon and its effect at an atomic level remain unexplored. In our joint experimental and computational study, simulations based on Density Functional Theory (DFT), synthesis, and a variety of surface characterization techniques are exploited for the specific goal of understanding the structure-function relationship of phosphorus-doped γ-Al2O3 surfaces. Our theoretical calculations and experimental results agree in finding that P doping of γ-Al2O3 leads to a significant decrease in its work function. Our computational models show that this decrease is due to the formation of a new surface dipole, providing a clear picture of the effect of P doping at the surface of γ-Al2O3. In this study, we uncover a general paradigm for tuning support-catalyst interactions that involves electrostatic properties of doped γ-Al2O3 surface, specifically the surface dipole. Our findings open a new pathway for engineering the electronic properties of metal oxides' surfaces.
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http://dx.doi.org/10.1039/c9cp03105gDOI Listing
July 2019

Quantitative assessment of breast cancer liver metastasis expansion with patient-derived xenografts.

Clin Exp Metastasis 2019 06 8;36(3):257-269. Epub 2019 May 8.

Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall Street, Richmond, VA, 23298, USA.

Advanced breast cancer often spreads to the bone, brain, liver, and lungs. The survival time of a patient with breast cancer liver metastasis is often less than 9 months without treatment. Experimental model systems often focus on the lung as a site of metastatic relapse, and therefore, there is less of an understanding of the biological processes that occur during expansive liver metastasis growth. In these studies, 14 genetically distinct breast cancer patient-derived xenografts (PDXs) were characterized for growth in the liver after portal vein injection of cancer cells. Growth in the liver occurred in 12 of 14 models, and the relative growth rate across the PDXs was overall similar to growth in the mammary gland. Pathological and immunohistochemical analyses revealed that the proliferation rates of metastases were relatively similar as the metastases expanded until the tumors became necrotic, and then slightly lower proliferation rates were observed. There were influxes of macrophages and neutrophils as the metastases increased in size, suggesting these innate immune cells may result in differential responses to therapeutics in micrometastases compared to macrometastases. The development and characterization of these models is important as future studies can utilize this information to determine if targeted therapies can slow the progression of metastatic disease at different stages in the liver.
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http://dx.doi.org/10.1007/s10585-019-09968-zDOI Listing
June 2019

Reactive oxygen species and cyclooxygenase products explain the majority of hypoxic cerebral vasodilation in healthy humans.

Acta Physiol (Oxf) 2019 08 27;226(4):e13288. Epub 2019 May 27.

Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin.

Aim: The role of reactive oxygen species (ROS) in human cerebral blood flow (CBF) during hypoxia is largely unknown. Additionally, it is unknown whether ROS interact with cyclooxygenase-derived signals during hypoxia to increase CBF. We hypothesized ROS inhibition would reduce hypoxic CBF, and combined inhibition of cyclooxygenase (COX) and ROS would decrease hypoxic CBF more than ROS suppression alone.

Methods: We measured middle cerebral artery velocity with transcranial Doppler ultrasound in 12 healthy adults during normoxia and 2 isocapnic hypoxia trials. Intravenous ascorbic acid infusion during the first hypoxia trial suppressed ROS. Oral indomethacin inhibited COX between hypoxia trials. The second bout of hypoxia tested the combined effects of ROS and COX inhibition. Middle cerebral artery velocity was normalized for blood pressure as cerebrovascular conductance index.

Results: Hypoxia increased cerebrovascular conductance index in both trials (P < 0.05). Ascorbic acid infusion did not alter cerebrovascular conductance index during hypoxia. Combined ascorbic acid and indomethacin significantly reduced hypoxia-mediated increases in cerebrovascular conductance index from 17 ± 2 to 4 ± 1 cm s 100 mm Hg (P < 0.05).

Conclusion: ROS are not obligatory for hypoxic cerebral vasodilation. Current data indicate ROS and COX together may account for the majority of the increase in CBF through the middle cerebral artery during hypoxia. These data are the first to demonstrate compensatory hypoxic vasodilatory signalling in human cerebral circulation.
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http://dx.doi.org/10.1111/apha.13288DOI Listing
August 2019

Separation of breast cancer and organ microenvironment transcriptomes in metastases.

Breast Cancer Res 2019 03 6;21(1):36. Epub 2019 Mar 6.

Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA.

Background: The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis.

Methods: In these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability.

Results: The experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids.

Conclusions: These studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression.
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http://dx.doi.org/10.1186/s13058-019-1123-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404325PMC
March 2019

The long-term prognostic and predictive capacity of cyclin D1 gene amplification in 2305 breast tumours.

Breast Cancer Res 2019 02 28;21(1):34. Epub 2019 Feb 28.

Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.

Background: Use of cyclin D1 (CCND1) gene amplification as a breast cancer biomarker has been hampered by conflicting assessments of the relationship between cyclin D1 protein levels and patient survival. Here, we aimed to clarify its prognostic and treatment predictive potential through comprehensive long-term survival analyses.

Methods: CCND1 amplification was assessed using SNP arrays from two cohorts of 1965 and 340 patients with matching gene expression array and clinical follow-up data of over 15 years. Kaplan-Meier and multivariable Cox regression analyses were used to determine survival differences between CCND1 amplified vs. non-amplified tumours in clinically relevant patient sets, within PAM50 subtypes and within treatment-specific subgroups. Boxplots and differential gene expression analyses were performed to assess differences between amplified vs. non-amplified tumours within PAM50 subtypes.

Results: When combining both cohorts, worse survival was found for patients with CCND1-amplified tumours in luminal A (HR = 1.68; 95% CI, 1.15-2.46), luminal B (1.37; 1.01-1.86) and ER+/LN-/HER2- (1.66; 1.14-2.41) subgroups. In gene expression analysis, CCND1-amplified luminal A tumours showed increased proliferation (P < 0.001) and decreased progesterone (P = 0.002) levels along with a large overlap in differentially expressed genes when comparing luminal A and B-amplified vs. non-amplified tumours.

Conclusions: Our results indicate that CCND1 amplification is associated with worse 15-year survival in ER+/LN-/HER2-, luminal A and luminal B patients. Moreover, luminal A CCND1-amplified tumours display gene expression changes consistent with a more aggressive phenotype. These novel findings highlight the potential of CCND1 to identify patients that could benefit from long-term treatment strategies.
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http://dx.doi.org/10.1186/s13058-019-1121-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394106PMC
February 2019

Live Cell Mass Accumulation Measurement Non-Invasively Predicts Carboplatin Sensitivity in Triple-Negative Breast Cancer Patient-Derived Xenografts.

ACS Omega 2018 Dec 19;3(12):17687-17692. Epub 2018 Dec 19.

Department of Physics, Virginia Commonwealth University, 701 West Grace Street, Richmond, Virginia 23284, United States.

Prompt and repeated assessments of tumor sensitivity to available therapeutics could reduce patient morbidity and mortality by quickly identifying therapeutic resistance and optimizing treatment regimens. Analysis of changes in cancer cell biomass has shown promise in assessing drug sensitivity and fulfilling these requirements. However, a major limitation of previous studies in solid tumors, which comprise 90% of cancers, is the use of cancer cell lines rather than freshly isolated tumor material. As a result, existing biomass protocols are not obviously extensible to real patient tumors owing to potential artifacts that would be generated by the removal of cells from their microenvironment and the deleterious effects of excision and purification. In this present work, we show that simple excision of human triple-negative breast cancer (TNBC) tumors growing in immunodeficient mouse, patient-derived xenograft (PDX) models, followed by enzymatic disaggregation into single cell suspension, is enabling for rapid and accurate biomass accumulation-based predictions of in vivo sensitivity to the chemotherapeutic drug carboplatin. We successfully correlate in vitro biomass results with in vivo treatment results in three TNBC PDX models that have differential sensitivity to this drug. With a maximum turnaround time of 40 h from tumor excision to useable results and a fully-automated analysis pipeline, the assay described here has significant potential for translation to clinical practice.
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http://dx.doi.org/10.1021/acsomega.8b02224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312628PMC
December 2018

Sphingosine kinase 1 activation by estrogen receptor α36 contributes to tamoxifen resistance in breast cancer.

J Lipid Res 2018 12 12;59(12):2297-2307. Epub 2018 Oct 12.

Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of Medicine, Richmond, VA 23298

In breast cancer, 17β-estradiol (E2) plays critical roles mainly by binding to its canonical receptor, estrogen receptor (ER) α66, and eliciting genomic effects. E2 also triggers rapid, nongenomic responses. E2 activates sphingosine kinase 1 (SphK1), increasing sphingosine-1-phosphate (S1P) that binds to its receptors, leading to important breast cancer signaling. However, the E2 receptor responsible for SphK1 activation has not yet been identified. Here, we demonstrate in triple-negative breast cancer cells, which lack the canonical ERα66 but express the novel splice variant ERα36, that ERα36 is the receptor responsible for E2-induced activation of SphK1 and formation and secretion of S1P and dihydro-S1P, the ligands for S1PRs. Tamoxifen, the first-line endocrine therapy for breast cancer, is an antagonist of ERα66, but an agonist of ERα36, and, like E2, activates SphK1 and markedly increases secretion of S1P. A major problem with tamoxifen therapy is development of acquired resistance. We found that tamoxifen resistance correlated with increased SphK1 and ERα36 expression in tamoxifen-resistant breast cancer cells, in patient-derived xenografts, and in endocrine-resistant breast cancer patients. Our data also indicate that targeting this ERα36 and SphK1 axis may be a therapeutic option to circumvent endocrine resistance and improve patient outcome.
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http://dx.doi.org/10.1194/jlr.M085191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277156PMC
December 2018