Multi-antigen intranasal vaccine protects against challenge with sarbecoviruses and prevents transmission in hamsters.

Immunization programs against SARS-CoV-2 with commercial intramuscular vaccines prevent disease but are less efficient in preventing infections. Mucosal vaccines can provide improved protection against transmission, ideally for different variants of concern (VOCs) and related sarbecoviruses. Here, we report a multi-antigen, intranasal vaccine, NanoSTING-SN (NanoSTING-Spike-Nucleocapsid), eliminates virus replication in both the lungs and the nostrils upon challenge with the pathogenic SARS-CoV-2 Delta VOC.

An intranasal nanoparticle STING agonist protects against respiratory viruses in animal models.

Respiratory viral infections cause morbidity and mortality worldwide. Despite the success of vaccines, vaccination efficacy is weakened by the rapid emergence of viral variants with immunoevasive properties. The development of an off-the-shelf, effective, and safe therapy against respiratory viral infections is thus desirable.

Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma.

Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC.

Enhancing oral delivery of plant-derived vesicles for colitis.

Plant-derived vesicles (PDVs) are attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract.

Defective DNA polymerase beta invoke a cytosolic DNA mediated inflammatory response.

Base excision repair (BER) has evolved to maintain the genomic integrity of DNA following endogenous and exogenous agent induced DNA base damage. In contrast, aberrant BER induces genomic instability, promotes malignant transformation and can even trigger cancer development. Previously, we have shown that deoxyribo-5'-phosphate (dRP) lyase deficient DNA polymerase beta (POLB) causes replication associated genomic instability and sensitivity to both endogenous and exogenous DNA damaging agents.

Rules of engagement: Promoting academic-industry partnership in the era of digital pathology and artificial intelligence.

Academic industry partnership (AIP) represents an important alliance between academic researchers and industry that helps translate technology and complete the innovation cycle within academic health systems. Despite diverging missions and skillsets the culture for academia and industry is changing in response to the current digital era which is spawning greater collaboration between physicians and businesses in this marketplace. In the field of pathology, this is further driven by the fact that traditional funding sources cannot keep pace with the innovation needed in digital pathology and artificial intelligence.

Detection of high antibodies titers against rat leukemia virus in an outbreak of reproductive disorders and lymphomas in Wistar rats.

Young female Wistar rats from a specific pathogen free breeding colony presented an outbreak of infertility along with neurological symptoms and malignant lymphomas. We evaluated the presence and the potential role of the rat leukemia virus (RaLV) in the disease because these clinical signs could be compatible with a retrovirus. RaLV is a mammalian type C endogenous retrovirus initially isolated from in vitro Sprague-Dawley rat embryo cultures.

Role of Base Excision Repair in Innate Immune Cells and Its Relevance for Cancer Therapy.

Innate immunity is critical for immediate recognition and elimination of invading pathogens or defense against cancer cell growth. Dysregulation of innate immune systems is associated with the pathogenesis of different types of inflammatory diseases, including cancer. In addition, the maintenance of innate immune cells' genomic integrity is crucial for the survival of all organisms.

Streptozotocin-induced hyperglycemia alters the cecal metabolome and exacerbates antibiotic-induced dysbiosis.

It is well established in the microbiome field that antibiotic (ATB) use and metabolic disease both impact the structure and function of the gut microbiome. But how host and microbial metabolism interacts with ATB susceptibility to affect the resulting dysbiosis remains poorly understood. In a streptozotocin-induced model of hyperglycemia (HG), we use a combined metagenomic, metatranscriptomic, and metabolomic approach to profile changes in microbiome taxonomic composition, transcriptional activity, and metabolite abundance both pre- and post-ATB challenge.

SPINDOC binds PARP1 to facilitate PARylation.

SPINDOC is tightly associated with the histone H3K4me3 effector protein SPIN1. To gain a better understanding of the biological roles of SPINDOC, we identified its interacting proteins. Unexpectedly, SPINDOC forms two mutually exclusive protein complexes, one with SPIN1 and the other with PARP1.

Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer.

Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24) drives spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24 metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24 gene signature reveals strong correlation with human MpBC tumors and MpBC patient-derived xenograft (PDX) models.

Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time.

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics.

Society of Toxicologic Pathology Digital Pathology and Image Analysis Special Interest Group Article*: Opinion on the Application of Artificial Intelligence and Machine Learning to Digital Toxicologic Pathology.

Toxicologic pathology is transitioning from analog to digital methods. This transition seems inevitable due to a host of ongoing social and medical technological forces. Of these, artificial intelligence (AI) and in particular machine learning (ML) are globally disruptive, rapidly growing sectors of technology whose impact on the long-established field of histopathology is quickly being realized.

Mutation in DNA Polymerase Beta Causes Spontaneous Chromosomal Instability and Inflammation-Associated Carcinogenesis in Mice.

DNA polymerase beta (Pol β) is a key enzyme in the base excision repair (BER) pathway. Pol β is mutated in approximately 40% of human tumors in small-scale studies. The 5´-deoxyribose-5-phosphate (dRP) lyase domain of Pol β is responsible for DNA end tailoring to remove the 5' phosphate group.

Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies.

(WW domain containing oxidoreductase) expression loss is common in various cancers and characteristic of poor prognosis. Deletions, translocations, and loss of expression affecting the gene are a common feature of various B cell neoplasms such as certain B cell lymphomas and multiple myeloma. However, the role of this common abnormality in B cell tumor initiation and/or progression has not been defined.

PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice.

Background & Aims: The peroxisome proliferator-activated receptor delta (PPARD) regulates cell metabolism, proliferation, and inflammation and has been associated with gastric and other cancers. Villin-positive epithelial cells are a small population of quiescent gastric progenitor cells. We expressed PPARD from a villin promoter to investigate the role of these cells and PPARD in development of gastric cancer.

Mouse Models of Overexpression Reveal Distinct Oncogenic Roles for Different Type I Protein Arginine Methyltransferases.

Protein arginine methyltransferases (PRMT) are generally not mutated in diseased states, but they are overexpressed in a number of cancers, including breast cancer. To address the possible roles of PRMT overexpression in mammary gland tumorigenesis, we generated Cre-activated PRMT1, CARM1, and PRMT6 overexpression mouse models. These three enzymes are the primary type I PRMTs and are responsible for the majority of the asymmetric arginine methylation deposited in the cells.

Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway.

Agonist antibodies targeting the T-cell costimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across preclinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist-driven tumor immunity from hepatotoxicity.

Sleeve gastrectomy improves glucose homeostasis in Zucker diabetic fatty rats.

Background: Bariatric surgery improves glucose homeostasis, but the mechanism of action is poorly understood. The aim of this study was to assess the effect of sleeve gastrectomy (SG) on glucose homeostasis in two obese populations of rats.

Methods: Two strains of rats [Zucker fatty (ZF) and Zucker diabetic fatty (ZDF)] were each divided into two groups: sham and SG.

Partial small bowel resection with sleeve gastrectomy increases adiponectin levels and improves glucose homeostasis in obese rodents with type 2 diabetes.

Background: The aim of this study was to examine the effect of small bowel resection with and without sleeve gastrectomy on glucose homeostasis in an obese rodent model of type 2 diabetes.

Methods: Zucker diabetic fatty rats were randomized into three surgical groups: Sham, small bowel resection, and small bowel resection with sleeve gastrectomy (BRSG). Weight and fasting glucose levels were measured at randomization and monitored after surgery.

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump.

Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs.

Suspected systemic calcinosis and calciphylaxis in 5 horses.

Five horses were presented with signs of myopathy along with systemic malaise, hyperfibrinogenemia, hyperphosphatemia, and an elevated calcium phosphorus product (Ca*P). Postmortem findings were consistent with systemic calcinosis, a syndrome of calcium deposition in the tissue of organs including lungs, kidneys, muscle, and heart that has not been previously described in horses.

Stillborn infant with calcified chorionic epithelium, corneal scarring, and pericarditis.

This autopsy of a stillborn term infant revealed a constellation of unusual features including calcification of the chorion membrane and portions of the umbilical vascular media, extensive white matter gliosis, arthrogryposis multiplex congenita, adhesions of one eyelid to the globe, pericarditis, a miniature left foot, and a cleft palate. We hypothesized that the membrane and umbilical cord lesions resulted from an episode of resolved chorioamnionitis earlier in the pregnancy. Mare reproductive loss syndrome (MRLS) demonstrates a bacteremic infection of the amniotic cavity, pericarditis, and uniocular endophthalmitis in the mare.