Publications by authors named "William J Murphy"

342 Publications

A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination.

N Engl J Med 2021 Nov 24. Epub 2021 Nov 24.

From the Departments of Dermatology and Internal Medicine, Division of Hematology and Oncology, University of California, Davis, Sacramento (W.J.M.).

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http://dx.doi.org/10.1056/NEJMcibr2113694DOI Listing
November 2021

Whole-genome sequences shed light onto the demographic history and contemporary genetic erosion of free-ranging jaguar (Panthera onca) populations.

J Genet Genomics 2021 Nov 9. Epub 2021 Nov 9.

Pontifical Catholic University of Rio Grande do Sul, PUCRS. School of Health and Life Sciences, Porto Alegre, RS, 90619, Brazil; Instituto Pró-Carnívoros, Atibaia, SP, 12945, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.jgg.2021.10.006DOI Listing
November 2021

Mechanisms by Which Obesity Promotes Acute Graft--Host Disease in Mice.

Front Immunol 2021 11;12:752484. Epub 2021 Oct 11.

Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, United States.

The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the occurrence of acute and chronic graft--host disease (GVHD). We have recently demonstrated that obesity results in exacerbated acute gastrointestinal GVHD in both mouse models and clinical outcomes due to increased pro-inflammatory cytokine responses and microbiota alterations. We therefore wanted to delineate the role of the various parameters in obesity, adiposity, effects of high-fat (HF) diet, and the role of microbiome on GVHD pathogenesis, by taking advantage of a mouse strain resistant to diet-induced obesity (DIO). Female BALB/c mice are resistant to DIO phenotype with approximately 50% becoming DIO under HF diets. The DIO-susceptible recipients rapidly succumb to acute gut GVHD, whereas the DIO-resistant recipient littermates, which do not become obese, are partially protected from GVHD, indicating that being on HF diet alone contributes to but is not the primary driver of GVHD. Microbiome assessment revealed restricted diversity in both cohorts of mice, but coprophagy normalizes the microbiota in mice housed together. We then individually housed DIO-resistant, DIO-susceptible, and lean control mice. Notably, each of the individually housed groups demonstrates marked restricted diversity that has been shown to occur from the stress of single housing. Despite the restricted microbiome diversity, the GVHD pathogenesis profile remains consistent in the group-housed mice, with the lean control single-housed mice exhibiting no acute GVHD and DIO-resistant recipients showing again partial protection. These results demonstrate that the deleterious effects of obesity on acute gut GVHD are critically dependent on adiposity with the HF diet also playing a lesser role, and the microbiome alterations with obesity instead appear to fuel ongoing acute GVHD processes.
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http://dx.doi.org/10.3389/fimmu.2021.752484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542879PMC
October 2021

Comparative Immunogenomics of Canine Natural Killer Cells as Immunotherapy Target.

Front Immunol 2021 14;12:670309. Epub 2021 Sep 14.

Department of Surgery, University of California Davis, Sacramento, CA, United States.

Natural killer (NK) cells are key effectors of the innate immune system, but major differences between human and murine NK cells have impeded translation. Outbred dogs offer an important link for studies of NK biology and immunotherapy. We analyzed gene expression of putative NK populations from healthy dogs and dogs with naturally-occurring cancers examining differential gene expression across multiple conditions, including steady-state, activation with cytokines and co-culture, and activation with inhaled IL-15 in dogs receiving IL-15 immunotherapy. We also compared dog, mouse and human CD3-NKp46+ NK cells using a novel orthologous transcriptome. Distinct transcriptional profiles between NK populations exist between conditions and versus treatments. In cross-species analysis, canine NK cells were globally more similar to human NK cells than mice. These data define canine NK cell gene expression under multiple conditions and across species, filling an important gap in translational NK studies.
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http://dx.doi.org/10.3389/fimmu.2021.670309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476892PMC
October 2021

Persistence and expansion of cryptic endangered red wolf genomic ancestry along the American Gulf coast.

Mol Ecol 2021 Sep 29. Epub 2021 Sep 29.

Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.

Admixture and introgression play a critical role in adaptation and genetic rescue that has only recently gained a deeper appreciation. Here, we explored the geographical and genomic landscape of cryptic ancestry of the endangered red wolf that persists within the genome of a ubiquitous sister taxon, the coyote, all while the red wolf has been extinct in the wild since the early 1980s. We assessed admixture across 120,621 single nucleotiode polymorphism (SNP) loci genotyped in 293 canid genomes. We found support for increased red wolf ancestry along a west-to-east gradient across the southern United States associated with historical admixture in the past 100 years. Southwestern Louisiana and southeastern Texas, the geographical zone where the last red wolves were known prior to extinction in the wild, contained the highest and oldest levels of red wolf ancestry. Further, given the paucity of inferences based on chromosome types, we compared patterns of ancestry on the X chromosome and autosomes. We additionally aimed to explore the relationship between admixture timing and recombination rate variation to investigate gene flow events. We found that X-linked regions of low recombination rates were depleted of introgression, relative to the autosomes, consistent with the large X effect and enrichment with loci involved in maintaining reproductive isolation. Recombination rate was positively correlated with red wolf ancestry across coyote genomes, consistent with theoretical predictions. The geographical and genomic extent of cryptic red wolf ancestry can provide novel genomic resources for recovery plans targeting the conservation of the endangered red wolf.
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http://dx.doi.org/10.1111/mec.16200DOI Listing
September 2021

Rapid macrosatellite evolution promotes X-Linked hybrid male sterility in a feline interspecies cross.

Mol Biol Evol 2021 Sep 14. Epub 2021 Sep 14.

Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, 77843.

The sterility or inviability of hybrid offspring produced from an interspecific mating results from incompatibilities between parental genotypes that are thought to result from divergence of loci involved in epistatic interactions. However, attributes contributing to the rapid evolution of these regions also complicates their assembly, thus discovery of candidate hybrid sterility loci is difficult and has been restricted to a small number of model systems. Here we reported rapid interspecific divergence at the DXZ4 macrosatellite locus in an interspecific cross between two closely related mammalian species: the domestic cat (Felis silvestris catus) and the Jungle cat (Felis chaus). DXZ4 is an interesting candidate due to its structural complexity, copy number variability, and described role in the critical yet complex biological process of X-chromosome inactivation. However, the full structure of DXZ4 was absent or incomplete in nearly every available mammalian genome assembly given its repetitive complexity. We compared highly continuous genomes for three cat species, each containing a complete DXZ4 locus, and discovered that the felid DXZ4 locus differs substantially from the human ortholog, and that it varies in copy number between cat species. Additionally, we reported expression, methylation, and structural conformation profiles of DXZ4 and the X chromosome during stages of spermatogenesis that have been previously associated with hybrid male sterility. Collectively, these findings suggest a new role for DXZ4 in male meiosis and a proposed mechanism of feline interspecific incompatibility through rapid satellite divergence.
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http://dx.doi.org/10.1093/molbev/msab274DOI Listing
September 2021

Activation status dictates the function of unlicensed natural killer cells in mice and humans.

Blood Adv 2021 10;5(20):4219-4232

Department of Dermatology, UC Davis School of Medicine, Sacramento, CA.

Natural killer (NK) cells are involved in innate defense against viral infection and cancer. NK cells can be divided into subsets based on the ability of different receptors to bind to major histocompatibility (MHC) class 1 molecules, resulting in differential responses upon activation in a process called "licensing" or "arming." NK cells expressing receptors that bind self-MHC are considered licensed due to an augmented effector lytic function capability compared with unlicensed subsets. However, we demonstrated that unlicensed NK subsets instead positively regulate the adaptive T-cell response during viral infections that are related to localization and cytokine production. In this study, the differential effects of the two types of NK subsets were contingent on the environment in viral infection and hematopoietic stem cell transplantation (HSCT) models. Infection of mice with high-dose (HD) murine cytomegalovirus (MCMC) led to a loss of licensing-associated differences, as compared with mice with low-dose (LD) infection: the unlicensed NK subset no longer localized in lymph nodes (LNs), but instead remained at the site of infection. Similarly, the patterns observed during HD infection paralleled the phenotypes of both human and mouse NK cells in an HSCT setting where NK cells exhibit an activated phenotype. However, in contrast to the effects of subset depletion in T-cell replete models, the licensed NK cell subsets still dominated antiviral responses after HSCT. Overall, our results highlight the intricate tuning of NK cells and how it affects overall immune responses with regard to licensing patterns and their dependency on the level of stimulation and activation status.
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http://dx.doi.org/10.1182/bloodadvances.2021004589DOI Listing
October 2021

Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR.

J Immunother Cancer 2021 09;9(9)

Department of Medicine and Center for Health Information Partnerships, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.
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http://dx.doi.org/10.1136/jitc-2021-002627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420733PMC
September 2021

A deep neural-network classifier for photograph-based estimation of hearing protection attenuation and fit.

J Acoust Soc Am 2021 08;150(2):1067

DFSE/EPHB/Noise & Bioacoustics Team, National Institute for Occupational Safety and Health, Cincinnati, Ohio 45226, USA.

Occupational and recreational acoustic noise exposure is known to cause permanent hearing damage and reduced quality of life, which indicates the importance of noise controls including hearing protection devices (HPDs) in situations where high noise levels exist. While HPDs can provide adequate protection for many noise exposures, it is often a challenge to properly train HPD users and maintain compliance with usage guidelines. HPD fit-testing systems are commercially available to ensure proper attenuation is achieved, but they often require specific facilities designed for hearing testing (e.g., a quiet room or an audiometric booth) or special equipment (e.g., modified HPDs designed specifically for fit testing). In this study, we explored using visual information from a photograph of an HPD inserted into the ear to estimate hearing protector attenuation. Our dataset consists of 960 unique photographs from four types of hearing protectors across 160 individuals. We achieved 73% classification accuracy in predicting if the fit was greater or less than the median measured attenuation (29 dB at 1 kHz) using a deep neural network. Ultimately, the fit-test technique developed in this research could be used for training as well as for automated compliance monitoring in noisy environments to prevent hearing loss.
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http://dx.doi.org/10.1121/10.0005820DOI Listing
August 2021

The emerging roles of the gut microbiome in allogeneic hematopoietic stem cell transplantation.

Gut Microbes 2021 Jan-Dec;13(1):1966262

Department of Dermatology, School of Medicine, University of California, Davis, CA, USA.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used for the treatment of hematologic cancers and disorders. However, graft-versus-host disease (GVHD) in which the donor immune cells attack the genetically-disparate recipient is a significant cause of morbidity. Acute GVHD is an inflammatory condition and the gastrointestinal system is a major organ affected but is also tied to beneficial graft-versus-tumor (GVT) effects. There is increasing interest on the role of the microbiome on immune function as well as on cancer progression and immunotherapy outcomes. However, there are still significant unanswered questions on the role the microbiome plays in GVHD progression or how to exploit the microbiome in GVHD prevention or treatment. In this review, concepts of HSCT with the focus on GVHD pathogenesis as well as issues in preclinical models used to study GVHD will be discussed with an emphasis on the impact of the microbiome. Factors affecting the microbiome and GVHD outcome such as obesity are also examined. The bridging of preclinical models and clinical outcomes in relation to the role of the microbiome will also be discussed along with possibilities for therapeutic exploitation.
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http://dx.doi.org/10.1080/19490976.2021.1966262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436969PMC
August 2021

A new approach method for characterizing inter-species toxicodynamic variability.

J Toxicol Environ Health A 2021 12 24;84(24):1020-1039. Epub 2021 Aug 24.

Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.

Inter-species differences in toxicodynamics are often a critical source of uncertainty in safety evaluations and typically dealt with using default adjustment factors. studies that use cells from different species demonstrated some success for estimating the relationships between life span and/or body weight and sensitivity to cytotoxicity; however, no apparent investigation evaluated the utility of these models for risk assessment. It was hypothesized that an model using dermal fibroblasts derived from diverse species and individuals might be utilized to inform the extent of inter-species and inter-individual variability in toxicodynamics. To test this hypothesis and characterize both inter-species and inter-individual variability in cytotoxicity, concentration-response cytotoxicity screening of 40 chemicals in primary dermal fibroblasts from 68 individuals of 54 diverse species was conducted. Chemicals examined included drugs, environmental pollutants, and food/flavor/fragrance agents; most of these were previously assessed either or for inter-species or inter-individual variation. Species included humans, the typical preclinical species and representatives from other orders of mammals and birds. Data demonstrated that both inter-species and inter-individual components of variability contribute to the observed differences in sensitivity to cell death. Further, it was found that the magnitude of the observed inter-species and inter-individual differences was chemical-dependent. This study contributes to the paradigm shift in risk assessment from reliance on toxicity testing to higher-throughput or alternative approaches, extending the strategy to replace use of default adjustment factors with experimental characterization of toxicodynamic inter-individual variability and to also address toxicodynamic inter-species variability.
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http://dx.doi.org/10.1080/15287394.2021.1966861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530970PMC
December 2021

Increased efficacy of dual pro-inflammatory cytokine blockade on acute GVHD while maintaining GVT effects.

Blood 2021 Aug 23. Epub 2021 Aug 23.

University of California, Davis, Sacramento, California, United States.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut GVHD occurs with marked increases in pro-inflammatory cytokines (including TNF and IL-6), which we recently demonstrated was exacerbated in obesity resulting in severe gastrointestinal pathology. Given the pleiotropic and overlapping effects of these two cytokines, we assessed the impact of dual TNF and IL-6R blockade on GVHD as well as graft-versus tumor (GVT) effects in different mouse GVHD models. Early administration of combined blockade resulted in greater protection and survival from acute gut GVHD compared to single blockade regimens and even development of later chronic skin GVHD. Importantly, double cytokine blockade preserved GVT effects reinforcing that GVT and GVHD can be delineated and may result in greater efficacy in allo-HSCT.
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http://dx.doi.org/10.1182/blood.2021011216DOI Listing
August 2021

Genome-Wide SNPs Clarify a Complex Radiation and Support Recognition of an Additional Cat Species.

Mol Biol Evol 2021 Oct;38(11):4987-4991

PUCRS, Escola de Ciências da Saúde e da Vida, Laboratório de Biologia Genômica e Molecular, Porto Alegre, RS, Brazil.

Phylogenetic reconstruction and species delimitation are often challenging in the case of recent evolutionary radiations, especially when postspeciation gene flow is present. Leopardus is a Neotropical cat genus that has a long history of recalcitrant taxonomic problems, along with both ancient and current episodes of interspecies admixture. Here, we employ genome-wide SNP data from all presently recognized Leopardus species, including several individuals from the tigrina complex (representing Leopardus guttulus and two distinct populations of Leopardus tigrinus), to investigate the evolutionary history of this genus. Our results reveal that the tigrina complex is paraphyletic, containing at least three distinct species. While one can be assigned to L. guttulus, the other two remain uncertain regarding their taxonomic assignment. Our findings indicate that the "tigrina" morphology may be plesiomorphic within this group, which has led to a longstanding taxonomic trend of lumping these poorly known felids into a single species.
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http://dx.doi.org/10.1093/molbev/msab222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557425PMC
October 2021

Genomic architecture constrained placental mammal X Chromosome evolution.

Genome Res 2021 Aug 22;31(8):1353-1365. Epub 2021 Jul 22.

Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843, USA.

Susumu Ohno proposed that the gene content of the mammalian X Chromosome should remain highly conserved due to dosage compensation. X Chromosome linkage (gene order) conservation is widespread in placental mammals but does not fall within the scope of Ohno's prediction and may be an indirect result of selection on gene content or selection against rearrangements that might disrupt X-Chromosome inactivation (XCI). Previous comparisons between the human and mouse X Chromosome sequences have suggested that although single-copy X Chromosome genes are conserved between species, most ampliconic genes were independently acquired. To better understand the evolutionary and functional constraints on X-linked gene content and linkage conservation in placental mammals, we aligned a new, high-quality, long-read X Chromosome reference assembly from the domestic cat (incorporating 19.3 Mb of targeted BAC clone sequence) to the pig, human, and mouse assemblies. A comprehensive analysis of annotated X-linked orthologs in public databases demonstrated that the majority of ampliconic gene families were present on the ancestral placental X Chromosome. We generated a domestic cat Hi-C contact map from an F1 domestic cat/Asian leopard cat hybrid and demonstrated the formation of the bipartite structure found in primate and rodent inactivated X Chromosomes. Conservation of gene order and recombination patterns is attributable to strong selective constraints on three-dimensional genomic architecture necessary for superloop formation. Species with rearranged X Chromosomes retain the ancestral order and relative spacing of loci critical for superloop formation during XCI, with compensatory inversions evolving to maintain these long-range physical interactions.
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http://dx.doi.org/10.1101/gr.275274.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327908PMC
August 2021

The urgent need for more basic research on SARS-Cov2 infection and vaccines in assessing potential psychoneurological effects using maternal immune activation (MIA) and other preclinical modeling.

Authors:
William J Murphy

Brain Behav Immun 2021 10 1;97:1-3. Epub 2021 Jul 1.

Departments of Dermatology and Internal Medicine, UC Davis School of Medicine, Sacramento, CA, United States. Electronic address:

The rapid development and application of different SARS-Cov2 vaccines world-wide has resulted in impressive efficacy and protection from this deadly pandemic. However, the existence of different and continuously developing vaccine candidates coupled with the likelihood of continued application due to both waning immune responses and emergence of viral mutants, means that more basic research regarding their efficacy and continued application are needed. This is particularly true with use of preclinical models involving effects when given during pregnancy. The substantial body of data on the impact of maternal immune activation (MIA) on neurologic development and behavior in the progeny necessitates the need to have all vaccine candidates, particularly when inducing strong toll receptor (TLR) responses, involving these models. Use of other preclinical models involving autoimmunity and allergy coupled with incorporation of human modifying variables of aging and obesity should also be applied to better reflect the heterogeneity of the general population and potential off-target effects that may arise. Additionally, the use of human ACE2 receptor transgenic mouse models can shed insights given the differential tissues expression at different stages in development. However, to foster these types of basic research studies involving different vaccine products, initiatives must first be implemented and supported at the governmental level even while clinical data still accumulates.
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http://dx.doi.org/10.1016/j.bbi.2021.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247198PMC
October 2021

Skin-Resident β2AR Signaling Delays Burn Wound Healing.

J Invest Dermatol 2021 08 2;141(8):2098-2101.e4. Epub 2021 Mar 2.

Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, California, USA; Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2021.02.010DOI Listing
August 2021

Mouse Preclinical Cancer Immunotherapy Modeling Involving Anti-PD-1 Therapies Reveals the Need to Use Mouse Reagents to Mirror Clinical Paradigms.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95817, USA.

Immune checkpoint inhibition (ICI) has emerged as one of the most powerful tools to reverse cancer induced immune suppression. Monoclonal antibodies (mAbs) targeting programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) are FDA-approved and their clinical use is rapidly expanding. As opposed to the clinical paradigm, which can result in significant responses and toxicities, it has been difficult to reproduce these effects preclinically using mouse models. In large part, this is due to models, which employ rapidly growing ex vivo cultured transplantable tumor cell lines engrafted into young naïve inbred laboratory mice. However, another issue concerns the use and repeated application of xenogeneic reagents in mice (i.e., rat or hamster mAbs directed against mouse antigens at variance with clinical use of human or humanized mAbs). Building on our previous studies demonstrating that repeated administration of commonly used xenogeneic anti-PD-1 mAbs derived from both rat and hamster can induce fatal hypersensitivity in some tumor-bearing mice, we sought to compare these result with the effects of a mouse anti-mouse PD-1 mAb. Application of a murine anti-mouse PD-1 (clone: MuDX400) did not result in lethal anaphylaxis in the 4T1 tumor model. It also displayed superior antitumor effects in this and other tumor models, as it did not induce neutralizing antibody responses against the anti-PD-1 mAb, such as were observed when using xenogeneic anti-PD1 mAbs. These results demonstrate that more accurate preclinical modeling necessitates the use of mouse reagents mirroring the clinical scenario to ascertain long-term effects or toxicities, while avoiding xenogeneic responses, which do not occur clinically. Furthermore, these studies suggest a direct mechanism, whereby preclinical murine studies have often failed to recapitulate the clinical efficacy and toxicity of single agent checkpoint inhibition.
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http://dx.doi.org/10.3390/cancers13040729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916633PMC
February 2021

HER2 Overexpression and Amplification in Feline Pulmonary Carcinoma.

Vet Pathol 2021 May 19;58(3):527-530. Epub 2021 Jan 19.

9296University of Bologna, Bologna, Italy.

HER2 is overexpressed, amplified, and mutated in a subset of human lung cancer. The aim of this study was to investigate HER2 protein overexpression and gene amplification in feline pulmonary carcinomas. Thirteen pulmonary carcinomas were selected and TTF-1 and HER2 expression was evaluated by immunohistochemistry. Fluorescence in situ hybridization (FISH) was performed with a probe and a BAC probe for the feline chromosome E1p1.12-p1.11 region. Twelve adenocarcinomas and 1 squamous cell carcinoma were diagnosed. TTF-1 was positive in 7 carcinomas (58%). HER2 was overexpressed in 2 (15%), equivocal in 5 (38%), and negative in 6 cases (46%). FISH analysis of was indeterminate in 2 cases. Three pulmonary carcinomas (27%) had amplification and 8 cases were not amplified (73%). The significant correlation between HER2 protein overexpression and gene amplification are promising preliminary data, but study of additional cases is needed to confirm HER2 as a target for possible innovative treatments.
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http://dx.doi.org/10.1177/0300985820988147DOI Listing
May 2021

Ultracontinuous Single Haplotype Genome Assemblies for the Domestic Cat (Felis catus) and Asian Leopard Cat (Prionailurus bengalensis).

J Hered 2021 03;112(2):165-173

Veterinary Integrative Biosciences, Texas A&M University, College Station, TX.

In addition to including one of the most popular companion animals, species from the cat family Felidae serve as a powerful system for genetic analysis of inherited and infectious disease, as well as for the study of phenotypic evolution and speciation. Previous diploid-based genome assemblies for the domestic cat have served as the primary reference for genomic studies within the cat family. However, these versions suffered from poor resolution of complex and highly repetitive regions, with substantial amounts of unplaced sequence that is polymorphic or copy number variable. We sequenced the genome of a female F1 Bengal hybrid cat, the offspring of a domestic cat (Felis catus) x Asian leopard cat (Prionailurus bengalensis) cross, with PacBio long sequence reads and used Illumina sequence reads from the parents to phase >99.9% of the reads into the 2 species' haplotypes. De novo assembly of the phased reads produced highly continuous haploid genome assemblies for the domestic cat and Asian leopard cat, with contig N50 statistics exceeding 83 Mb for both genomes. Whole-genome alignments reveal the Felis and Prionailurus genomes are colinear, and the cytogenetic differences between the homologous F1 and E4 chromosomes represent a case of centromere repositioning in the absence of a chromosomal inversion. Both assemblies offer significant improvements over the previous domestic cat reference genome, with a 100% increase in contiguity and the capture of the vast majority of chromosome arms in 1 or 2 large contigs. We further demonstrated that comparably accurate F1 haplotype phasing can be achieved with members of the same species when one or both parents of the trio are not available. These novel genome resources will empower studies of feline precision medicine, adaptation, and speciation.
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http://dx.doi.org/10.1093/jhered/esaa057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006817PMC
March 2021

Impact of Diabetes Prevention Guideline Adoption on Health Outcomes: A Pragmatic Implementation Trial.

J Acad Nutr Diet 2021 10 3;121(10):2090-2100.e1. Epub 2020 Dec 3.

Nutrition and Dietetics Data Science Center, Research International and Scientific Affairs with the Academy of Nutrition and Dietetics, Chicago, IL. Electronic address:

Limited research exists to evaluate nutrition guideline impact on clinical practice and patient health outcomes. In this study we investigate (1) the impact of guideline training on the implementation of the diabetes prevention Evidence-Based Nutrition Practice Guideline (EBNPG), and (2) the relationship between EBNPG congruence and resulting health outcomes in patients with prediabetes. We conducted an implementation study in which registered dietitian nutritionists (RDNs) provided nutrition care with 3-month follow-up to 102 pre-diabetes patients before and after a professional training on the implementation of the Diabetes Prevention EBNPG. Using the RDNs' Nutrition Care Process (NCP) documentation, we measured percent guideline congruence and health outcomes (body weight, waist circumference, fasting glucose, glycosylated hemoglobin), and modeled health outcomes. Guideline congruence improved after training by 4.3% (P < 0.05). However, no significant associations were observed between guideline training, or guideline congruence and health outcomes. Our model showed a reduction in waist circumference (2.1 ± 0.92 cm; P = 0.023), and body weight (-1.78 ± 0.55 kg; P = 0.001) throughout the course of the study. Training of nutrition professionals improved congruence to EBNPG for Diabetes Prevention. Nevertheless, improved guideline congruence did not impact related health outcomes. Standard care including nutrition intervention resulted in body weight and waist circumference reductions. Future research needs to further address the impact of evidence-based guidelines on outcomes in all areas of practice.
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http://dx.doi.org/10.1016/j.jand.2020.11.001DOI Listing
October 2021

Re-Examining the Paradigm of Impaired Healing in the Aged Murine Excision Wound Model.

J Invest Dermatol 2021 04 28;141(4S):1071-1075.e4. Epub 2020 Nov 28.

Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA; Dermatology Section, VA Northern California Health Care System, Sacramento, California, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.10.022DOI Listing
April 2021

Obesity induces gut microbiota alterations and augments acute graft-versus-host disease after allogeneic stem cell transplantation.

Sci Transl Med 2020 11;12(571)

Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.

The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by acute and chronic graft-versus-host disease (GVHD). The impact of obesity on allo-HSCT outcomes is poorly understood. Here, we report that obesity had a negative and selective impact on acute gut GVHD after allo-HSCT in mice with diet-induced obesity (DIO). These animals exhibited increased gut permeability, endotoxin translocation across the gut, and radiation-induced gastrointestinal damage after allo-HSCT. After allo-HSCT, both male and female DIO mouse recipients showed increased proinflammatory cytokine production and expression of the GVHD marker ST2 (IL-33R) and MHC class II molecules; they also exhibited decreased survival associated with acute severe gut GVHD. This rapid-onset, obesity-associated gut GVHD depended on donor CD4 T cells and occurred even with a minor MHC mismatch between donor and recipient animals. Retrospective analysis of clinical cohorts receiving allo-HSCT transplants from unrelated donors revealed that recipients with a high body mass index (BMI, >30) had reduced survival and higher serum ST2 concentrations compared with nonobese transplant recipients. Assessment of both DIO mice and allo-HSCT recipients with a high BMI revealed reduced gut microbiota diversity and decreased Clostridiaceae abundance. Prophylactic antibiotic treatment protected DIO mouse recipients from endotoxin translocation across the gut and increased inflammatory cytokine production, as well as gut pathology and mortality, but did not protect against later development of chronic skin GVHD. These results suggest that obesity-induced alterations of the gut microbiota may affect GVHD after allo-HSCT in DIO mice, which could be ameliorated by prophylactic antibiotic treatment.
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http://dx.doi.org/10.1126/scitranslmed.aay7713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525601PMC
November 2020

Phylogenomics and the Genetic Architecture of the Placental Mammal Radiation.

Annu Rev Anim Biosci 2021 02 23;9:29-53. Epub 2020 Nov 23.

Department of Evolution, Ecology and Organismal Biology, University of California, Riverside, California 92521, USA.

The genomes of placental mammals are being sequenced at an unprecedented rate. Alignments of hundreds, and one day thousands, of genomes spanning the rich living and extinct diversity of species offer unparalleled power to resolve phylogenetic controversies, identify genomic innovations of adaptation, and dissect the genetic architecture of reproductive isolation. We highlight outstanding questions about the earliest phases of placental mammal diversification and the promise of newer methods, as well as remaining challenges, toward using whole genome data to resolve placental mammal phylogeny. The next phase of mammalian comparative genomics will see the completion and application of finished-quality, gapless genome assemblies from many ordinal lineages and closely related species. Interspecific comparisons between the most hypervariable genomic loci will likely reveal large, but heretofore mostly underappreciated, effects on population divergence, morphological innovation, and the origin of new species.
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http://dx.doi.org/10.1146/annurev-animal-061220-023149DOI Listing
February 2021

Sequence analysis in reveals pervasiveness of X-Y arms races in mammalian lineages.

Genome Res 2020 12 18;30(12):1716-1726. Epub 2020 Nov 18.

Whitehead Institute, Cambridge, Massachusetts 02142, USA.

Studies of Y Chromosome evolution have focused primarily on gene decay, a consequence of suppression of crossing-over with the X Chromosome. Here, we provide evidence that suppression of X-Y crossing-over unleashed a second dynamic: selfish X-Y arms races that reshaped the sex chromosomes in mammals as different as cattle, mice, and men. Using super-resolution sequencing, we explore the Y Chromosome of (bull) and find it to be dominated by massive, lineage-specific amplification of testis-expressed gene families, making it the most gene-dense Y Chromosome sequenced to date. As in mice, an X-linked homolog of a bull Y-amplified gene has become testis-specific and amplified. This evolutionary convergence implies that lineage-specific X-Y coevolution through gene amplification, and the selfish forces underlying this phenomenon, were dominatingly powerful among diverse mammalian lineages. Together with Y gene decay, X-Y arms races molded mammalian sex chromosomes and influenced the course of mammalian evolution.
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http://dx.doi.org/10.1101/gr.269902.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706723PMC
December 2020

PD-1 Blockade Reverses Obesity-Mediated T Cell Priming Impairment.

Front Immunol 2020 29;11:590568. Epub 2020 Oct 29.

Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, United States.

Despite obesity reaching pandemic proportions, its impact on antigen-specific T cell responses is still unclear. We have recently demonstrated that obesity results in increased expression of PD-1 on T cells, and checkpoint blockade targeting PD-1/PD-L1 surprisingly resulted in greater clinical efficacy in cancer therapy. Adverse events associated with this therapy center around autoimmune reactions. In this study, we examined the impact of obesity on T cell priming and on autoimmune pathogenesis using the mouse model experimental autoimmune encephalomyelitis (EAE), which is mediated by autoreactive myelin-specific T cells generated after immunization. We observed that diet-induced obese (DIO) mice had a markedly delayed EAE onset and developed milder clinical symptoms compared to mice on control diet (CD). This delay was associated with impaired generation of myelin-specific T cell numbers and concurrently correlated with increased PD-L1 upregulation on antigen-presenting cells in secondary lymphoid organs. PD-1 blockade during the priming stage of EAE restored disease onset and severity and increased numbers of pathogenic CD4+ T cells in the central nervous system (CNS) of DIO mice to similar levels to those of CD mice. Administration of anti-PD-1 after onset of clinical symptoms did not increase EAE pathogenesis demonstrating that initial priming is the critical juncture affected by obesity. These findings demonstrate that obesity impairs antigen-specific T cell priming, but this can be reversed with PD-1 blockade. Our results further suggest that PD-1 blockade may increase the risk of autoimmune toxicities, particularly in obesity.
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http://dx.doi.org/10.3389/fimmu.2020.590568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658608PMC
July 2021

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas.

J Immunother Cancer 2020 11;8(2)

Surgery, University of California Davis School of Medicine, Sacramento, California, USA

Purpose: Given the unmet need for novel immunotherapy in soft tissue sarcoma (STS), we sought to characterize the phenotype and function of intratumoral natural killer (NK) and T cells to identify novel strategies to augment tumor-infiltrating lymphocyte (TIL) function.

Experimental Design: Using prospectively collected specimens from dogs and humans with sarcomas, archived specimens, and The Cancer Genome Atlas (TCGA) data, we evaluated blood and tumor NK and T cell phenotype and function and correlated those with outcome. We then assessed the effects of interleukin 15 (IL-15) stimulation on both NK and T cell activation and TIGIT upregulation. Finally, we evaluated cytotoxic effects of IL-15 combined with TIGIT blockade using a novel anti-TIGIT antibody.

Results: TILs were strongly associated with survival outcome in both archived tissue and TCGA, but higher TIL content was also associated with higher TIGIT expression. Compared with blood, intratumoral NK and T cells showed significantly higher expression of both activation and exhaustion markers, in particular TIGIT. Ex vivo stimulation of blood and tumor NK and T cells from patients with STS with IL-15 further increased both activation and exhaustion markers, including TIGIT. Dogs with metastatic osteosarcoma receiving inhaled IL-15 also exhibited upregulation of activation markers and TIGIT. Ex vivo, combined IL-15 and TIGIT blockade using STS blood and tumor specimens significantly increased cytotoxicity against STS targets.

Conclusion: Intratumoral NK and T cells are prognostic in STS, but their activation is marked by significant upregulation of TIGIT. Our data suggest that combined IL-15 and TIGIT blockade may be a promising clinical strategy in STS.
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http://dx.doi.org/10.1136/jitc-2020-001355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651745PMC
November 2020

IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation.

Cancers (Basel) 2020 Oct 29;12(11). Epub 2020 Oct 29.

Department of Dermatology, University of California, Davis, Sacramento, CA 95817, USA.

The failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathways involved in immune evasion in cancer, strategies that induce a faster reconstitution of key immune effector cells are needed. Natural killer (NK) cells mediate potent anti-tumor effector functions and are the first immune cells to repopulate after HSCT. TGF-β is a potent immunosuppressive cytokine that can impede both the development and function of immune cells. Here, we evaluated the use of an immunotherapeutic regimen that combines low dose of IL-2, an NK cell stimulatory signal, with TGF-β neutralization, in order to accelerate NK cell reconstitution following congenic HSCT in mice by providing stimulatory signals yet also abrogating inhibitory ones. This therapy led to a marked expansion of NK cells and accelerated NK cell maturation. Following HSCT, mature NK cells from the treated recipients displayed an activated phenotype and enhanced anti-tumor responses both in vitro and in vivo. No overt toxicities or adverse effects were observed in the treated recipients. However, these stimulatory effects on NK cell recovery were predicated upon continuous treatment as cessation of treatment led to return to baseline levels and to no improvement of overall immune recovery when assessed at later time-points, indicating strict regulatory control of the NK cell compartment. Overall, this study still demonstrates that therapies that combine positive and negative signals can be plausible strategies to accelerate NK cell reconstitution following HSCT and augment anti-tumor efficacy.
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http://dx.doi.org/10.3390/cancers12113189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692743PMC
October 2020

A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism.

PLoS Genet 2020 10 22;16(10):e1008926. Epub 2020 Oct 22.

Division of Animal Sciences, School of Medicine, University of Missouri, Columbia, Missouri, United States of America.

The domestic cat (Felis catus) numbers over 94 million in the USA alone, occupies households as a companion animal, and, like humans, suffers from cancer and common and rare diseases. However, genome-wide sequence variant information is limited for this species. To empower trait analyses, a new cat genome reference assembly was developed from PacBio long sequence reads that significantly improve sequence representation and assembly contiguity. The whole genome sequences of 54 domestic cats were aligned to the reference to identify single nucleotide variants (SNVs) and structural variants (SVs). Across all cats, 16 SNVs predicted to have deleterious impacts and in a singleton state were identified as high priority candidates for causative mutations. One candidate was a stop gain in the tumor suppressor FBXW7. The SNV is found in cats segregating for feline mediastinal lymphoma and is a candidate for inherited cancer susceptibility. SV analysis revealed a complex deletion coupled with a nearby potential duplication event that was shared privately across three unrelated cats with dwarfism and is found within a known dwarfism associated region on cat chromosome B1. This SV interrupted UDP-glucose 6-dehydrogenase (UGDH), a gene involved in the biosynthesis of glycosaminoglycans. Importantly, UGDH has not yet been associated with human dwarfism and should be screened in undiagnosed patients. The new high-quality cat genome reference and the compilation of sequence variation demonstrate the importance of these resources when searching for disease causative alleles in the domestic cat and for identification of feline biomedical models.
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http://dx.doi.org/10.1371/journal.pgen.1008926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581003PMC
October 2020

Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses.

Blood 2021 02;137(8):1090-1103

Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.
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http://dx.doi.org/10.1182/blood.2020005628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907720PMC
February 2021

Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells.

Nat Commun 2020 09 14;11(1):4591. Epub 2020 Sep 14.

Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, USA.

Although the efficacy of cancer radiotherapy (RT) can be enhanced by targeted immunotherapy, the immunosuppressive factors induced by radiation on tumor cells remain to be identified. Here, we report that CD47-mediated anti-phagocytosis is concurrently upregulated with HER2 in radioresistant breast cancer (BC) cells and RT-treated mouse syngeneic BC. Co-expression of both receptors is more frequently detected in recurrent BC patients with poor prognosis. CD47 is upregulated preferentially in HER2-expressing cells, and blocking CD47 or HER2 reduces both receptors with diminished clonogenicity and augmented phagocytosis. CRISPR-mediated CD47 and HER2 dual knockouts not only inhibit clonogenicity but also enhance macrophage-mediated attack. Dual antibody of both receptors synergizes with RT in control of syngeneic mouse breast tumor. These results provide the evidence that aggressive behavior of radioresistant BC is caused by CD47-mediated anti-phagocytosis conjugated with HER2-prompted proliferation. Dual blockade of CD47 and HER2 is suggested to eliminate resistant cancer cells in BC radiotherapy.
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http://dx.doi.org/10.1038/s41467-020-18245-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490264PMC
September 2020
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