Publications by authors named "Andrew D Miller"

226 Publications

Parental Acceptance of Children's Storytelling Robots: A Projection of the Uncanny Valley of AI.

Front Robot AI 2021 19;8:579993. Epub 2021 May 19.

The School of Informatics and Computing, Indiana University, Indianapolis, IN, United States.

Parent-child story time is an important ritual of contemporary parenting. Recently, robots with artificial intelligence (AI) have become common. Parental acceptance of children's storytelling robots, however, has received scant attention. To address this, we conducted a qualitative study with 18 parents using the research technique design fiction. Overall, parents held mixed, though generally positive, attitudes toward children's storytelling robots. In their estimation, these robots would outperform screen-based technologies for children's story time. However, the robots' potential to adapt and to express emotion caused some parents to feel ambivalent about the robots, which might hinder their adoption. We found three predictors of parental acceptance of these robots: context of use, perceived agency, and perceived intelligence. Parents' speculation revealed an uncanny valley of AI: a nonlinear relation between the human likeness of the artificial agent's mind and affinity for the agent. Finally, we consider the implications of children's storytelling robots, including how they could enhance equity in children's access to education, and propose directions for research on their design to benefit family well-being.
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http://dx.doi.org/10.3389/frobt.2021.579993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172185PMC
May 2021

Postmortem diagnoses of spinal ataxia in 316 horses in California.

J Am Vet Med Assoc 2021 Jun;258(12):1386-1393

Objective: To determine period prevalences of postmortem diagnoses for spinal cord or vertebral column lesions as underlying causes of ataxia (spinal ataxia) in horses.

Animals: 2,861 client-owned horses (316 with ataxia [ataxic group] and 2,545 without ataxia [control group]).

Procedures: The medical records database of the University of California-Davis Veterinary Medical Teaching Hospital was searched to identify horses necropsied between January 1, 2005, and December 31, 2017. Results were compared between the ataxic and control groups and between various groups of horses in the ataxic group. Period prevalences were determined for the most common causes of ataxia.

Results: 2,861 horses underwent full necropsy, and the period prevalences for the most common definitive diagnoses for ataxia were 2.7% (77/2,861) for cervical vertebral compressive myelopathy (CVCM), 1.3% (38/2,861) for equine neuroaxonal dystrophy or equine degenerative myeloencephalopathy (eNAD-EDM), and 0.9% (25/2,861) for trauma; the period prevalence of ataxia of unknown origin was 2.0% (56/2,861). Horses in the ataxic group (vs the control group) were more likely to have been warmblood horses (OR, 2.70) and less likely to have been Arabian horses (OR, 0.53). In the ataxic group, horses < 5 (vs ≥ 5) years of age had greater odds of CVCM (OR, 2.82) or eNAD-EDM (OR, 6.17) versus trauma or ataxia of unknown origin. Horses in the ataxic group with CVCM were more likely Thoroughbreds (OR, 2.54), whereas horses with eNAD-EDM were more likely American Quarter Horses (OR, 2.95) and less likely Thoroughbreds (OR, 0.11).

Conclusions And Clinical Relevance: Results indicated that breed distributions differed for horses with CVCM versus eNAD-EDM; therefore, breed should be considered in the clinical evaluation of spinal ataxia in horses.
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http://dx.doi.org/10.2460/javma.258.12.1386DOI Listing
June 2021

Title: The Children's Oncology Planning for Emergencies (COPE) Tool: Prototyping with Caregivers of Children with Cancer.

AMIA Annu Symp Proc 2020 25;2020:896-905. Epub 2021 Jan 25.

Indiana University, Indianapolis, IN.

As part of a larger project to co-design and create a mHealth tool to support caregivers of children with cancer, we performed a pilot, qualitative study. For this portion of the project, we engaged with caregivers of children with cancer to co-create and refine a low-fidelity prototype of the Children's Oncology Planning for Emergencies mHealth tool. Testing was accomplished through recorded semi-structured interviews with each caregiver as they interacted with a low-fidelity wireframe using Adobe Xd. Through the engagement of our key stakeholders, we were able to refine the COPE tool to provide the key elements they desired including pertinent patient medical information, checklist for planning when seeking urgent care, and coordination of care with the medical team and other caregivers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075434PMC
January 2021

Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors.

Cancers (Basel) 2021 Apr 23;13(9). Epub 2021 Apr 23.

Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.

Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance. Mixed nonseminomas often contain pluripotent embryonal carcinoma (EC) cells, the cancer stem cells (CSCs) of these tumors. We hypothesized that differentiation therapy, a treatment strategy which aims to induce differentiation of tumor-propagating CSCs to slow tumor growth, could effectively treat mixed nonseminomas without significant toxicity. The FDA-approved antipsychotic thioridazine and the agricultural antibiotic salinomycin are two drugs previously found to selectively target CSCs, and here we report that these agents differentiate EC cells in vitro and greatly reduce their tumorigenic potential in vivo. Using a novel transformed induced pluripotent stem cell allograft model and a human xenograft model, we show that thioridazine extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors. These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics.
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http://dx.doi.org/10.3390/cancers13092045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122873PMC
April 2021

Review of Histological Grading Systems in Veterinary Medicine.

Vet Pathol 2021 Mar 26:300985821999831. Epub 2021 Mar 26.

Department of Veterinary Medicine (DIMEVET), University of Milano, Lodi (LO), Italy.

Tumor grading is a method to quantify the putative clinical aggressiveness of a neoplasm based on specific histological features. A good grading system should be simple, easy to use, reproducible, and accurately segregate tumors into those with low versus high risk. The aim of this review is to summarize the histological and, when available, cytological grading systems applied in veterinary pathology, providing information regarding their prognostic impact, reproducibility, usefulness, and shortcomings. Most of the grading schemes used in veterinary medicine are developed for common tumor entities. Grading systems exist for soft tissue sarcoma, osteosarcoma, multilobular tumor of bone, mast cell tumor, lymphoma, mammary carcinoma, pulmonary carcinoma, urothelial carcinoma, renal cell carcinoma, prostatic carcinoma, and central nervous system tumors. The prognostic relevance of many grading schemes has been demonstrated, but for some tumor types the usefulness of grading remains controversial. Furthermore, validation studies are available only for a minority of the grading systems. Contrasting data on the prognostic power of some grading systems, lack of detailed instructions in the materials and methods in some studies, and lack of data on reproducibility and validation studies are discussed for the relevant grading systems. Awareness of the limitations of grading is necessary for pathologists and oncologists to use these systems appropriately and to drive initiatives for their improvement.
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http://dx.doi.org/10.1177/0300985821999831DOI Listing
March 2021

Antiviral Activity of Vacuolar ATPase Blocker Diphyllin against SARS-CoV-2.

Microorganisms 2021 Feb 25;9(3). Epub 2021 Feb 25.

Department of Virology, Veterinary Research Institute, CZ-62100 Brno, Czech Republic.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a causative agent of the pandemic coronavirus disease 2019 (COVID-19), which has resulted in over two million deaths worldwide to date. Diphyllin and diphyllinosides are known as natural blockers of cellular vacuolar ATPases, and so can act as inhibitors of the pH-dependent fusion of viral envelopes with host cell endosomal membranes. Such pH-dependent fusion is a critical early step during the SARS-CoV-2 replication cycle. Accordingly, the anti-SARS-CoV-2 profiles and cytotoxicities of diphyllin, diphyllinoside cleistanthin B, and two structurally related compounds, helioxanthin 8-1 and helioxanthin 5-4-2, are evaluated here using in vitro cell-based assay systems. Neither helioxanthin exhibits any obvious anti-SARS-CoV-2 effects in vitro. By contrast diphyllin and cleistanthin B do exhibit anti-SARS-CoV-2 effects in Vero cells, with respective 50% effective concentrations (EC) values of 1.92 and 6.51 µM. Diphyllin displays anti-SARS-CoV-2 effect also in colorectal adenocarcinoma (CaCo-2) cells. Moreover, when diphyllin is added at various times post infection, a significant decrease in viral titer is observed in SARS-CoV-2-infected Vero cells, even at high viral multiplicities of infection. Importantly, neither diphyllin nor cleistanthin B are found cytotoxic to Vero cells in concentrations up to 100 µM. However, the cytotoxic effect of diphyllin is more pronounced in Vero E6 and CaCo-2 cells. Overall, our data demonstrate that diphyllin and diphyllin analogues might be perfected as anti-SARS-CoV-2 agents in future preclinical studies, most especially if nanomedicine approaches may be invoked to optimize functional drug delivery to virus infected cells.
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http://dx.doi.org/10.3390/microorganisms9030471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996309PMC
February 2021

"There's a problem, now what's the solution?": suggestions for technologies to support the menopausal transition from individuals experiencing menopause and healthcare practitioners.

J Am Med Inform Assoc 2021 Feb 14. Epub 2021 Feb 14.

Department of Biobehavioral Nursing and Health Informatics, University of Washington School of Nursing, Seattle, Washington, USA.

Objective: To elicit novel ideas for informatics solutions to support individuals through the menopausal transition. (Note: We use "individuals experiencing menopause" and "experiences" rather than "symptoms" when possible to counter typical framing of menopause as a cisgender women's medical problem.).

Methods: A participatory design study was conducted 2015-2017 in the Western US. Two sessions were held with individuals experiencing menopause recruited from the general public; and 3 sessions with healthcare practitioners (HCPs) including nurses, physicians, and complementary and integrative health (CIH) practitioners were held. Participants designed technologies addressing informational needs and burdensome experiences. HCPs reflected on designs from participants experiencing menopause. Directed content analysis was used to analyze transcripts.

Results: Eight individuals experiencing menopause (n = 4 each session) and 18 HCPs (n = 10 CIH, n = 3 nurses, n = 5 physicians) participated. All participants provided ideas for solution purpose, hardware, software, features and functions, and data types. Individuals experiencing menopause designed technologies to help understand and prevent burdensome menopause experiences. HCPs designed technologies for tracking and facilitating communication. Compared to nurses and physicians, CIH practitioners suggested designs reframing menopause as a positive experience and accounted for the complex lives of individuals experiencing menopause, including stigma; these ideas corresponded to comments made by participants experiencing menopause. Participants from both populations were concerned about data confidentiality and technology accessibility.

Conclusions: Participant generated design ideas included novel ideas and incorporated existing technologies. This study can inform the development of new technologies or repurposing of existing technologies to support individuals through the menopausal transition.
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http://dx.doi.org/10.1093/jamia/ocaa178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883989PMC
February 2021

Disparities in hepatic copper concentrations determined by atomic absorption spectroscopy, inductively coupled plasma mass spectrometry, and digital image analysis of rhodanine-stained sections in dogs.

J Am Vet Med Assoc 2021 Feb;258(4):395-406

Objective: To investigate disparities in hepatic copper concentrations determined by atomic absorption spectroscopy (AAS), inductively coupled plasma mass spectrometry (ICP-MS), and digital image analysis of rhodanine-stained sections.

Animals: 516 dogs.

Procedures: Medical records of dogs for which hepatic biopsy specimens had been submitted between January 1999 and December 2019 for evaluation of copper content were reviewed. Paired hepatic copper concentrations obtained with digital image analysis and AAS or ICP-MS were compared, and Spearman rank correlation coefficients were calculated to test for correlations between qualitative copper accumulation scores and hepatic copper concentrations. For dogs for which ≥ 4 rhodanine-stained hepatic sections were available, intraindividual variation in copper distribution across hepatic sections was evaluated.

Results: Median hepatic copper concentrations obtained with digital image analysis exceeded concentrations obtained with AAS or ICP-MS. Concentrations were also higher in older dogs (≥ 9 years vs < 9 years), dogs of breeds with a typical body weight ≥ 20 kg (44 lb), and dogs with necroinflammatory changes or uneven copper distribution. Qualitative copper accumulation scores were significantly associated with hepatic copper concentrations; however, the correlation between qualitative score and concentration obtained with digital image analysis ( = 0.94) was higher than the correlation between qualitative score and concentration obtained with AAS ( = 0.75) or ICP-MS ( = 0.57). The coefficient of variation for hepatic copper concentrations obtained with digital image analysis was significantly higher for dogs with higher hepatic copper concentrations.

Conclusions And Clinical Relevance: Results suggested that spectroscopic-spectrometric analysis of hepatic biopsy specimens commonly underestimated the concentration obtained by digital image analysis of rhodanine-stained sections.
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http://dx.doi.org/10.2460/javma.258.4.395DOI Listing
February 2021

Canine Gliomatosis Cerebri: Morphologic and Immunohistochemical Characterization Is Supportive of Glial Histogenesis.

Vet Pathol 2021 Mar 28;58(2):293-304. Epub 2020 Dec 28.

5922Cornell University, Ithaca, NY, USA.

Gliomatosis cerebri (GC) is a glioma subtype with diffuse neuroparenchymal infiltration without architectural distortion. GC was first used in human neuropathology and remained controversial until its elimination from the diagnostic lexicon in 2016. GC is currently defined as a diffuse growth pattern of glioma rather than a distinct entity. In this article, we characterize 24 cases of canine GC and classify these neoplasms as diffuse gliomas. Selected cases of canine GC were reviewed and immunolabeled for oligodendrocyte lineage transcription factor 2 (Olig2), glial fibrillary acidic protein (GFAP), and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase). The mean age of affected dogs was 7 years, and 9 were brachycephalic. Gross lesions (8 cases) consisted mainly of parenchymal swelling. Histologically, of the 24 cases, there was widespread infiltration of neoplastic cells with astrocytic (12 cases), oligodendroglial (8 cases), or mixed morphology (4 cases) in the brain (18 cases), spinal cord (4 cases), or both (2 cases). Secondary structures occurred across different tumor grades and were not restricted to high-grade neoplasms. Astrocytic neoplasms had moderate nuclear immunolabeling for Olig2 and robust cytoplasmic immunolabeling for GFAP. Oligodendroglial neoplasms had robust nuclear immunolabeling for Olig2, moderate or absent cytoplasmic immunolabeling for GFAP, and moderate cytoplasmic immunolabeling for CNPase. Tumors with mixed morphology had robust nuclear immunolabeling for Olig2 and variable cytoplasmic immunolabeling for GFAP and CNPase. Morphologic and immunohistochemical features confirmed a glial histogenesis for all tumors and allowed for their classification as diffuse, low- or high-grade astrocytoma; oligodendroglioma; or undefined glioma. Further research is needed to confirm or refute the hypothesis that canine GC represents an infiltrative growth pattern of canine glioma.
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http://dx.doi.org/10.1177/0300985820980704DOI Listing
March 2021

In vivo detection of microstructural spinal cord lesions in dogs with degenerative myelopathy using diffusion tensor imaging.

J Vet Intern Med 2021 Jan 22;35(1):352-362. Epub 2020 Dec 22.

Department of Clinical Sciences, Cornell College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

Background: Degenerative myelopathy (DM) in dogs is a progressive neurodegenerative condition that causes white matter spinal cord lesions. These lesions are undetectable on standard magnetic resonance imaging (MRI), limiting diagnosis and monitoring of the disease. Spinal cord lesions cause disruption to the structural integrity of the axons causing water diffusion to become more random and less anisotropic. These changes are detectable by the technique of diffusion tensor imaging (DTI) which is highly sensitive to diffusion alterations secondary to white matter lesion development.

Objective: Perform spinal DTI on cohorts of dogs with and without DM to identify if lesions caused by DM will cause a detectable alteration in spinal cord diffusivity that correlates with neurological status.

Animals: Thirteen dogs with DM and 13 aged-matched controls.

Methods: All animals underwent MRI with DTI of the entire spine. Diffusivity parameters fractional anisotropy (FA) and mean diffusivity (MD) were measured at each vertebral level and statistically compared between groups.

Results: Dogs with DM had significant decreases in FA within the regions of the spinal cord that had high expected lesion load. Decreases in FA were most significant in dogs with severe forms of the disease and correlated with neurological grade.

Conclusions And Clinical Importance: Findings suggest that FA has the potential to be a biomarker for spinal cord lesion development in DM and could play an important role in improving diagnosis and monitoring of this condition.
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http://dx.doi.org/10.1111/jvim.16014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848345PMC
January 2021

A Review of Proliferative Vascular Disorders of the Central Nervous System of Animals.

Vet Pathol 2020 Dec 11:300985820980707. Epub 2020 Dec 11.

Cornell University, Ithaca, NY, USA.

In disease, blood vessel proliferation has many salient roles including in inflammation, when granulation tissue fills superficial defects, or in the recanalization of an occluded blood vessel. Sometimes angiogenesis goes awry-granulation can be exuberant, and plexiform proliferation of vascular components can contribute to pulmonary hypertension. This review focuses on the diverse manifestations of pathologic vascular overgrowth that occur in the brain, spinal cord, and meninges of animals from birth until old age. Entities discussed include systemic reactive angioendotheliomatosis in which glomeruloid vascular proliferations are encountered in various organs including the central nervous system (CNS). The triad of CNS vascular malformations, hamartomas, and benign vascular proliferations are an especially fraught category in which terminology overlap and the microscopic similarity of various disorders makes diagnostic classification incredibly challenging. Pathologists commonly take refuge in "CNS vascular hamartoma" despite the lack of any unique histopathologic features and we recommend that this diagnostic category be abandoned. Malformative lesions that are often confusing and have similar features; the conditions include arteriovenous malformation, cavernous angioma, venous angioma, and capillary telangiectases. Meningioangiomatosis, a benign meningovascular proliferation with dual components, is a unique entity seen most commonly in young dogs. Last, accepted neoplastic conditions range from lower-grade locally acquired growths like hemangioblastoma (a tumor of mysterious interstitial stromal cells encountered in the setting of abundant capillary vasculature proliferation), the rare hemangioendothelioma, and the highly malignant and invariably multifocal metastatic hemangiosarcoma. Additionally, this review draws on the comparative medical literature for further insights into this problematic topic in pathology.
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http://dx.doi.org/10.1177/0300985820980707DOI Listing
December 2020

Editorial: Advances in the Pathogenesis of Canine Neurologic Disease.

Front Vet Sci 2020 4;7:623. Epub 2020 Sep 4.

Department of Biomedical Sciences, Section of Anatomic Pathology, Cornell University College of Veterinary Medicine, Ithaca, NY, United States.

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http://dx.doi.org/10.3389/fvets.2020.00623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499806PMC
September 2020

Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques.

Cell 2020 11 9;183(5):1354-1366.e13. Epub 2020 Oct 9.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address:

The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546181PMC
November 2020

A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.

PLoS Genet 2020 09 28;16(9):e1009028. Epub 2020 Sep 28.

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, United States of America.

Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species.
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http://dx.doi.org/10.1371/journal.pgen.1009028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544121PMC
September 2020

SOX2 Expression in Canine Neoplasia.

Vet Pathol 2020 Sep 25:300985820960130. Epub 2020 Sep 25.

Cornell University, Ithaca, NY, USA.

SOX2 is a major transcriptional regulator of stem cell pluripotency and self-renewability. Its expression in cancer stem cells from several different tumor types in humans and rodent models directly implicates SOX2 in tumorigenicity, metastasis, drug resistance, recurrence, and poor survival. Our objective was to investigate the expression of SOX2 in canine neoplasia. Immunohistochemistry for SOX2 was performed in sets of 10 archived formalin-fixed paraffin-embedded tissues from 45 distinct canine neoplasms. Normal expression of SOX2 was evaluated in a canine tissue microarray. Strong and diffuse SOX2 intranuclear immunolabeling was consistently found in the majority of ectodermal (13/15) and endodermal tumors (5/7). Negative, variable, or inconsistent SOX2 intranuclear immunolabeling was detected in the majority of mesodermal tumors (10/16) and in tumors with dual or uncertain origin (5/7). Although further studies are necessary to understand mechanistically how SOX2 contributes to the biology of each tumor type, this study demonstrates the expression of SOX2 in a wide variety of canine cancers. In the future, screening methods based on cellular plasticity and pluripotency biomarkers may provide avenues for the rational design of therapeutic strategies that target vulnerable signals upstream or downstream of SOX2 in different cancers, and possibly offer novel clinical applications for SOX2 as a prognostic indicator.
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http://dx.doi.org/10.1177/0300985820960130DOI Listing
September 2020

Advanced Therapeutics, Vaccinations, and Precision Medicine in the Treatment and Management of Chronic Hepatitis B Viral Infections; Where Are We and Where Are We Going?

Viruses 2020 09 7;12(9). Epub 2020 Sep 7.

Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic.

The management of chronic hepatitis B virus (CHB) infection is an area of massive unmet clinical need worldwide. In spite of the development of powerful nucleoside/nucleotide analogue (NUC) drugs, and the widespread use of immune stimulators such as interferon-alpha (IFNα) or PEGylated interferon-alpha (PEG-IFNα), substantial improvements in CHB standards of care are still required. We believe that the future for CHB treatment now rests with advanced therapeutics, vaccination, and precision medicine, if all are to bring under control this most resilient of virus infections. In spite of a plethora of active drug treatments, anti-viral vaccinations and diagnostic techniques, the management of CHB infection remains unresolved. The reason for this is the very complexity of the virus replication cycle itself, giving rise to multiple potential targets for therapeutic intervention some of which remain very intractable indeed. Our review is focused on discussing the potential impact that advanced therapeutics, vaccinations and precision medicine could have on the future management of CHB infection. We demonstrate that advanced therapeutic approaches for the treatment of CHB, in the form of gene and immune therapies, together with modern vaccination strategies, are now emerging rapidly to tackle the limitations of current therapeutic approaches to CHB treatment in clinic. In addition, precision medicine approaches are now gathering pace too, starting with personalized medicine. On the basis of this, we argue that the time has now come to accelerate the design and creation of precision therapeutic approaches (PTAs) for CHB treatment that are based on advanced diagnostic tools and nanomedicine, and which could maximize CHB disease detection, treatment, and monitoring in ways that could genuinely eliminate CHB infection altogether.
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http://dx.doi.org/10.3390/v12090998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552065PMC
September 2020

Feline infectious peritonitis virus-associated rhinitis in a cat.

JFMS Open Rep 2020 Jan-Jun;6(1):2055116920930582. Epub 2020 Jun 23.

Departments of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA.

Case Summary: This report describes a cat with initial respiratory signs prior to developing fulminant feline infectious peritonitis (FIP) after adoption from an animal shelter. Histologic examination of the tissues revealed typical lesions associated with FIP in the lung, liver, large intestine and small intestine. Histologic examination of the nasal cavity revealed pyogranulomatous rhinitis. Immunohistochemistry with monoclonal antibody FIPV3-70 targeting FIP antigen in macrophages confirmed FIP and molecular analysis identified a spike protein mutation (R793S) consistent with the presence of an FIP virus. Pathological changes, immunolabeling and molecular analysis provide evidence that respiratory infection by feline coronavirus is part of the spectrum of FIP-associated disease.

Relevance And Novel Information: This report highlights nasal pathology associated with FIP through a combination of histopathology, immunohistochemistry and molecular characterization of the virus. Our work supports a little-appreciated role of the respiratory tract in FIP.
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http://dx.doi.org/10.1177/2055116920930582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313338PMC
June 2020

Chromatin run-on sequencing analysis finds that ECM remodeling plays an important role in canine hemangiosarcoma pathogenesis.

BMC Vet Res 2020 Jun 22;16(1):206. Epub 2020 Jun 22.

Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

Background: Canine visceral hemangiosarcoma (HSA) is a highly aggressive cancer of endothelial origin that closely resembles visceral angiosarcoma in humans, both clinically and histopathologically. Currently there is an unmet need for new diagnostics and therapies for both forms of this disease. The goal of this study was to utilize Chromatin run-on sequencing (ChRO-seq) and immunohistochemistry (IHC) to identify gene and protein expression signatures that may be important drivers of HSA progression.

Results: ChRO-seq was performed on tissue isolated from 17 HSA samples and 4 normal splenic samples. Computational analysis was then used to identify differentially expressed genes and these factors were subjected to gene ontology analysis. ChRO-seq analysis revealed over a thousand differentially expressed genes in HSA tissue compared with normal splenic tissue (FDR < 0.005). Interestingly, the majority of genes overexpressed in HSA tumor tissue were associated with extracellular matrix (ECM) remodeling. This observation correlated well with our histological analysis, which found that HSA tumors contain a rich and complex collagen network. Additionally, we characterized the protein expression patterns of two highly overexpressed molecules identified in ChRO-seq analysis, podoplanin (PDPN) and laminin alpha 4 (LAMA4). We found that the expression of these two ECM-associated factors appeared to be largely limited to transformed endothelial cells within the HSA lesions.

Conclusion: Outcomes from this study suggest that ECM remodeling plays an important role in HSA progression. Additionally, our study identified two potential novel biomarkers of HSA, PDPN and LAMA4. Interestingly, given that function-blocking anti-PDPN antibodies have shown anti-tumor effects in mouse models of canine melanoma, our studies raise the possibility that these types of therapeutic strategies could potentially be developed for treating canine HSA.
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http://dx.doi.org/10.1186/s12917-020-02395-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310061PMC
June 2020

SARS-CoV-2 infection protects against rechallenge in rhesus macaques.

Science 2020 08 20;369(6505):812-817. Epub 2020 May 20.

Janssen Vaccines & Prevention BV, Leiden, Netherlands.

An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.
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http://dx.doi.org/10.1126/science.abc4776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243369PMC
August 2020

Pathology of larvae and adults in dogs and cats.

Authors:
Andrew D Miller

Adv Parasitol 2020 10;109:537-544. Epub 2020 Feb 10.

Department of Biomedical Sciences, Section of Anatomic Pathology, Cornell University, Ithaca, NY, United States. Electronic address:

Endoparasitism remains a significant cause of morbidity and mortality in puppies and kittens. The ascarids of dogs and cats (Toxocara canis, Toxascaris leonina, Toxocara cati) cause significant pathology due to either larval migration or adult nematode burden within the gastrointestinal tract. This chapter will review the important pathologic events and lesions that are encountered during ascarid development in dogs and cats with emphasis given to the characteristic gross pathology lesions that are seen in affected animals.
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http://dx.doi.org/10.1016/bs.apar.2020.01.024DOI Listing
May 2021

Evaluation of canonical Hedgehog signaling pathway inhibition in canine osteosarcoma.

PLoS One 2020 29;15(4):e0231762. Epub 2020 Apr 29.

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, United of States America.

Canine osteosarcoma (OSA), the most common canine primary bone malignancy, has a highly aggressive biologic behavior. Despite current standard of care therapies, including amputation and adjuvant chemotherapy, most dogs still succumb to metastatic disease. Further investigations into molecular mechanisms and pathways driving OSA are needed to improve therapeutic options. The Hedgehog (HH) cell-signaling pathway has demonstrated involvement in human OSA. Several studies in canine OSA have found changes in expression of some HH pathway genes and demonstrated a role for HH transcription factors. However, the role of this pathway as well as the translational value of its targeting in canine OSA are still undefined. The objectives of this study were to determine the expression of HH components directly in canine OSA tissues and to evaluate the biologic impact of HH signaling inhibition in canine OSA cells. In situ hybridization was used to detect HH family mRNA expression in archived canine OSA tissues and revealed variable expression levels of these mRNAs in canine OSA tissues. The effect of a commercially available Smoothened inhibitor, vismodegib, was studied in established canine OSA cell lines. Alterations in cellular growth as well as assessment of downstream HH targets were evaluated. Although changes in cell growth were noted following Smoothened inhibition, inconsistent decreases in target gene expression were found. While treatment with vismodegib had a negative impact on canine OSA cell growth and viability, the mechanism remains unclear. Further studies are warranted to evaluate the clinical significance of canonical HH signaling in canine OSA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190150PMC
July 2020

Atrophy and Death of Nonpeptidergic and Peptidergic Nociceptive Neurons in SIV Infection.

Am J Pathol 2020 07 1;190(7):1530-1544. Epub 2020 Apr 1.

Department of Neuroscience, Temple University, Lewis Katz School of Medicine, Philadelphia, Pennsylvania. Electronic address:

HIV-associated sensory neuropathy is a common neurologic comorbidity of HIV infection and prevails in the post-antiretroviral therapy (ART) era. HIV infection drives pathologic changes in the dorsal root ganglia (DRG) through inflammation, altered metabolism, and neuronal dysfunction. Herein, we characterized specific neuronal populations in an SIV-infected macaque model with or without ART. DRG neuronal populations were identified by neurofilament H-chain 200, I-B isolectin (IB4), or tropomyosin receptor kinase A expression and assessed for cell body diameter, population size, apoptotic markers, and regeneration signaling. IB4 and tropomyosin receptor kinase A-positive neurons showed a reduced cell body size (atrophy) and decreased population size (cell death) in the DRG of SIV-infected animals compared with uninfected animals. IB4 nonpeptidergic neurons were less affected in the presence of ART. DRG neurons showed accumulation of cleaved caspase 3 (apoptosis) and nuclear-localized activating transcription factor 3 (regeneration) in SIV infection, which was significantly lower in uninfected animals and SIV-infected animals receiving ART. Nonpeptidergic neurons predominantly colocalized with cleaved caspase 3 staining. Nonpeptidergic and peptidergic neurons colocalized with nuclear-accumulated activating transcription factor 3, showing active regeneration in sensory neurons. These data suggest that nonpeptidergic and peptidergic neurons are susceptible to pathologic changes from SIV infection, and intervention with ART did not fully ameliorate damage to the DRG, specifically to peptidergic neurons.
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http://dx.doi.org/10.1016/j.ajpath.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322364PMC
July 2020

Comparative Molecular Life History of Spontaneous Canine and Human Gliomas.

Cancer Cell 2020 02;37(2):243-257.e7

Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole-genome, exome, transcriptome, and methylation sequencing of 83 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, TP53 and cell-cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA-methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.
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http://dx.doi.org/10.1016/j.ccell.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132629PMC
February 2020

Integrin α10β1-Selected Mesenchymal Stem Cells Mitigate the Progression of Osteoarthritis in an Equine Talar Impact Model.

Am J Sports Med 2020 03 31;48(3):612-623. Epub 2020 Jan 31.

Cornell University, Ithaca, New York, USA.

Background: Early intervention with mesenchymal stem cells (MSCs) after articular trauma has the potential to limit progression of focal lesions and prevent ongoing cartilage degeneration by modulating the joint environment and/or contributing to repair. Integrin α10β1 is the main collagen type II binding receptor on chondrocytes, and MSCs that are selected for high expression of the α10 subunit have improved chondrogenic potential. The ability of α10β1-selected (integrin α10) MSCs to protect cartilage after injury has not been investigated.

Purpose: To investigate integrin α10 MSCs to prevent posttraumatic osteoarthritis in an equine model of impact-induced talar injury.

Study Design: Controlled laboratory study.

Methods: Focal cartilage injuries were created on the tali of horses (2-5 years, n = 8) by using an impacting device equipped to measure impact stress. Joints were treated with 20 × 10 allogenic adipose-derived α10 MSCs or saline vehicle (control) 4 days after injury. Synovial fluid was collected serially and analyzed for protein content, cell counts, markers of inflammation (prostaglandin E2, tumor necrosis factor α) and collagen homeostasis (procollagen II C-propeptide, collagen type II cleavage product), and glycosaminoglycan content. Second-look arthroscopy was performed at 6 weeks, and horses were euthanized at 6 months. Joints were imaged with radiographs and quantitative 3-T magnetic resonance imaging. Postmortem examinations were performed, and India ink was applied to the talar articular surface to identify areas of cartilage fibrillation. Synovial membrane and osteochondral histology was performed, and immunohistochemistry was used to assess type I and II collagen and lubricin. A mixed effect model with Tukey post hoc and linear contrasts or paired tests were used, as appropriate.

Results: Integrin α10 MSC-treated joints had less subchondral bone sclerosis on radiographs ( = .04) and histology ( = .006) and less cartilage fibrillation ( = .04) as compared with control joints. On gross pathology, less India ink adhered to impact sites in treated joints than in controls, which may be explained by the finding of more prominent lubricin immunostaining in treated joints. Prostaglandin E2 concentration in synovial fluid and mononuclear cell synovial infiltrate were increased in treated joints, suggesting possible immunomodulation by integrin α10 MSCs.

Conclusion: Intra-articular administration of integrin α10 MSCs is safe, and evidence suggests that the cells mitigate the effects of joint trauma.

Clinical Relevance: This preclinical study indicates that intra-articular therapy with integrin α10 MSCs after joint trauma may be protective against posttraumatic osteoarthritis.
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http://dx.doi.org/10.1177/0363546519899087DOI Listing
March 2020

Genome-Wide Association Study and Subsequent Exclusion of as a Candidate Gene Involved in Equine Neuroaxonal Dystrophy Using Two Animal Models.

Genes (Basel) 2020 01 10;11(1). Epub 2020 Jan 10.

Department of Population, Health and Reproduction, University of California, Davis School of Veterinary Medicine, Davis, CA 95616, USA.

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder of unknown etiology. Clinical signs of neurological deficits develop within the first year of life in vitamin E (vitE) deficient horses. A genome-wide association study (GWAS) was carried out using 670,000 SNP markers in 27 case and 42 control Quarter Horses. Two markers, encompassing a 2.5 Mb region on ECA7, were associated with the phenotype ( = 2.05 × 10 and 4.72 × 10). Within this region, caytaxin () was identified as a candidate gene due to its known role in Cayman Ataxia and ataxic/dystonic phenotypes in mouse models. Whole-genome sequence data in four eNAD/EDM and five unaffected horses identified 199 associated variants within the ECA7 region. MassARRAY genotyping was performed on these variants within the GWAS population. The three variants within were not concordant with the disease phenotype. No difference in expression or alternative splicing was identified using qRT-PCR in brainstem across the transcript. mice were then used to conduct functional analysis in a second animal model. Histologic lesions were not identified in the central nervous system of mice. Additionally, supplementation of homozygous mice with 600 IU/day of dl-α-tocopheryl acetate (vitE) during gestation, lactation, and adulthood did not improve the phenotype. has therefore been excluded as a candidate gene for eNAD/EDM.
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http://dx.doi.org/10.3390/genes11010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016928PMC
January 2020

Gastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5CD44 cells.

Nat Commun 2020 01 3;11(1):84. Epub 2020 Jan 3.

Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY, 14853, USA.

Areas of a junction between two types of epithelia are known to be cancer-prone in many organ systems. However, mechanisms for preferential malignant transformation at the junction areas remain insufficiently elucidated. Here we report that inactivation of tumor suppressor genes Trp53 and Rb1 in the gastric squamous-columnar junction (SCJ) epithelium results in preferential formation of metastatic poorly differentiated neoplasms, which are similar to human gastroesophageal carcinoma. Unlike transformation-resistant antral cells, SCJ cells contain a highly proliferative pool of immature Lgr5CD44 cells, which are prone to transformation in organoid assays, comprise early dysplastic lesions, and constitute up to 30% of all neoplastic cells. CD44 ligand osteopontin (OPN) is preferentially expressed in and promotes organoid formation ability and transformation of the SCJ glandular epithelium. OPN and CD44 overexpression correlate with the worst prognosis of human gastroesophageal carcinoma. Thus, detection and selective targeting of the active OPN-CD44 pathway may have direct clinical relevance.
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http://dx.doi.org/10.1038/s41467-019-13847-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941991PMC
January 2020

Microtubule-Associated Protein 2 Expression in Canine Glioma.

Front Vet Sci 2019 15;6:395. Epub 2019 Nov 15.

Department of Biomedical Sciences, Section of Anatomic Pathology, Cornell University College of Veterinary Medicine, Ithaca, NY, United States.

Canine glioma is considered a potential model for human glioma, with recent studies of occurrence, therapy, and reclassification supporting the value of the canine model. The current diagnosis of canine glioma is based on morphologic criteria and immunohistochemistry (IHC), including oligodendrocyte transcription factor 2 (Olig2), glial fibrillary acidic protein (GFAP), and 2', 3' cyclic nucleotide phosphatase (CNPase). Microtubule-associated protein 2 (MAP2) is a proven marker of human glioma and is used to complement the diagnosis and its specific immunoreactivity pattern contributes to the differentiation of astrocytomas from other glial tumors. The objective of this study was to evaluate whether canine gliomas express MAP2 and to explore differences in the pattern of immunolabeling between different gliomas. Seventy-eight cases of canine glioma were evaluated for MAP2 expression by immunohistochemistry. A glial origin was supported by Olig2 IHC in all cases. MAP2 immunolabeling was evaluated on a semi-quantitative basis, including the percentage of immunolabeled neoplastic cells, as well as the signal intensity, distribution, and pattern of immunolabeling. MAP2 was expressed in all cases, with significant correlation between diagnosis and signal intensity ( = 0.04). MAP2 immunolabeling distribution was dominated by diffuse (34/78; 44%), followed by patchy (20/78; 26%), multifocal to coalescing (16/78; 21%), and scattered (8/78; 10%). All oligodendrogliomas (53/53; 100%) and undefined gliomas (12/12; 100%) revealed a combination of perinuclear and cytoplasmic immunolabeling, and all but 3 astrocytomas had a combination of perinuclear and cytoplasmic processes immunolabeling (10/13; 77%). Significant correlation between immunolabeling pattern and diagnosis was obtained ( = 0.001). The study demonstrates that MAP2 is expressed in canine gliomas and the pattern of expression can also be applied to help distinguish astrocytomas from oligodendrogliomas and undefined gliomas.
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http://dx.doi.org/10.3389/fvets.2019.00395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872496PMC
November 2019

Canine Primary Intracranial Cancer: A Clinicopathologic and Comparative Review of Glioma, Meningioma, and Choroid Plexus Tumors.

Front Oncol 2019 8;9:1151. Epub 2019 Nov 8.

Section of Neurology and Neurosurgery, Veterinary and Comparative Neuro-Oncology Laboratory, Department of Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, United States.

In the dog, primary intracranial neoplasia represents ~2-5% of all cancers and is especially common in certain breeds including English and French bulldogs and Boxers. The most common types of primary intracranial cancer in the dog are meningioma, glioma, and choroid plexus tumors, generally occurring in middle aged to older dogs. Much work has recently been done to understand the characteristic imaging and clinicopathologic features of these tumors. The gross and histologic landscape of these tumors in the dog compare favorably to their human counterparts with many similarities noted in histologic patterns, subtype, and grades. Data informing the underlying molecular abnormalities in the canine tumors have only begun to be unraveled, but reveal similar pathways are mutated between canine and human primary intracranial neoplasia. This review will provide an overview of the clinicopathologic features of the three most common forms of primary intracranial cancer in the dog, delve into the comparative aspects between the dog and human neoplasms, and provide an introduction to current standard of care while also highlighting novel, experimental treatments that may help bridge the gap between canine and human cancer therapies.
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http://dx.doi.org/10.3389/fonc.2019.01151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856054PMC
November 2019

New opportunities for designing effective small interfering RNAs.

Sci Rep 2019 11 6;9(1):16146. Epub 2019 Nov 6.

Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.

Small interfering RNAs (siRNAs) that silence genes of infectious diseases are potentially potent drugs. A continuing obstacle for siRNA-based drugs is how to improve their efficacy for adequate dosage. To overcome this obstacle, the interactions of antiviral siRNAs, tested in vivo, were computationally examined within the RNA-induced silencing complex (RISC). Thermodynamics data show that a persistent RISC cofactor is significantly more exothermic for effective antiviral siRNAs than their ineffective counterparts. Detailed inspection of viral RNA secondary structures reveals that effective antiviral siRNAs target hairpin or pseudoknot loops. These structures are critical for initial RISC interactions since they partially lack intramolecular complementary base pairing. Importing two temporary RISC cofactors from magnesium-rich hairpins and/or pseudoknots then kickstarts full RNA hybridization and hydrolysis. Current siRNA design guidelines are based on RNA primary sequence data. Herein, the thermodynamics of RISC cofactors and targeting magnesium-rich RNA secondary structures provide additional guidelines for improving siRNA design.
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http://dx.doi.org/10.1038/s41598-019-52303-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834666PMC
November 2019