A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models.

RNA vaccines have demonstrated efficacy against SARS-CoV-2 in humans, and the technology is being leveraged for rapid emergency response. In this report, we assessed immunogenicity and, for the first time, toxicity, biodistribution, and protective efficacy in preclinical models of a two-dose self-amplifying messenger RNA (SAM) vaccine, encoding a prefusion-stabilized spike antigen of SARS-CoV-2 Wuhan-Hu-1 strain and delivered by lipid nanoparticles (LNPs). In mice, one immunization with the SAM vaccine elicited a robust spike-specific antibody response, which was further boosted by a second immunization, and effectively neutralized the matched SARS-CoV-2 Wuhan strain as well as B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta) variants. High frequencies of spike-specific germinal center B, Th0/Th1 CD4, and CD8 T cell responses were observed in mice. Local tolerance, potential systemic toxicity, and biodistribution of the vaccine were characterized in rats. In hamsters, the vaccine candidate was well-tolerated, markedly reduced viral load in the upper and lower airways, and protected animals against disease in a dose-dependent manner, with no evidence of disease enhancement following SARS-CoV-2 challenge. Therefore, the SARS-CoV-2 SAM (LNP) vaccine candidate has a favorable safety profile, elicits robust protective immune responses against multiple SARS-CoV-2 variants, and has been advanced to phase 1 clinical evaluation (NCT04758962).

Sargramostim (rhu GM-CSF) Improves Survival of Non-Human Primates with Severe Bone Marrow Suppression after Acute, High-Dose, Whole-Body Irradiation.

Exposure to acute, high-dose, whole-body ionizing radiation results in bone marrow failure (hematopoietic acute radiation syndrome with resultant infection, bleeding, anemia, and increased risk of death). Sargramostim (yeast-derived rhu GM-CSF), a yeast-derived, molecularly cloned, hematopoietic growth factor and pleiotropic cytokine supports proliferation, differentiation, maturation and survival of cells of several myeloid lineages. We evaluated the efficacy of sargramostim in non-human primates (rhesus macaques) exposed to whole-body ionizing radiation at a 50-60% lethal dose. The primary end point was day 60 survival. Non-human primates received daily subcutaneous sargramostim (7 mcg/kg/day) or control. To reflect the anticipated setting of a nuclear or radiologic event, treatment began 48 h postirradiation, and non-human primates received only moderate supportive care (no whole blood transfusions or individualized antibiotics). Sargramostim significantly increased day 60 survival to 78% (95% confidence interval, 61-90%) vs. 42% (26-59%; P = 0.0018) in controls. Neutrophil, platelet and lymphocyte recovery rates were accelerated and infection rates decreased. Improved survival when sargramostim was started 48 h postirradiation, without use of intensive supportive care, suggests sargramostim may be effective in treating humans exposed to acute, high-dose whole-body, ionizing radiation in a scenario such as a mass casualty event.

Metastatic malignant pilomatrixoma, acanthomatous ameloblastoma, and liver tumor in a dog with polyphagia, polyuria, polydipsia, and weight loss.

A 12-year-old, spayed female, Labrador dog was presented for evaluation of polyphagia, polyuria, polydipsia, weight loss of 2 months duration, and multiple cutaneous and subcutaneous masses. The dog was diagnosed with malignant pilomatrixoma with renal, lung, and lumbar metastases. This report describes an atypical presentation of malignant pilomatrixoma.

Pilomatrixoma malin avec métastases, améloblastome acanthomateux et tumeur hépatique chez une chienne avec polyphagie, polyurie, polydipsie et amaigrissement. Une chienne Labrador, âgée de 12 ans, était présentée pour l'évaluation d'une polyphagie, polyurie, polydipsie et d'un amaigrissement durant depuis 2 mois, ainsi que de multiples masses cutanées et sous-cutanées. Elle présentait un pilomatrixoma avec métastases aux reins, aux poumons et à une vertèbre lombaire. Ce rapport de cas décrit une présentation atypique de pilomatrixoma malin.(Traduit par les auteurs).

Use of magnetic resonance imaging and histopathologic findings for diagnosis of an aneurysmal bone cyst in the scapula of a cat.

CASE DESCRIPTION: An 18-month-old spayed female domestic shorthair cat was evaluated because of left thoracic limb lameness. CLINICAL FINDINGS: A firm mass was palpable in the left scapular region. On the basis of clinical signs; results of radiographic, ultrasonographic, and cytologic evaluations; and findings on magnetic resonance imaging, an aneurysmal bone cyst (ABC) of the scapula was strongly suspected. TREATMENT AND OUTCOME: Considering the large size of the mass and the poor prognosis for return to function of the left thoracic limb, amputation was elected. Histologic evaluation ruled out a malignant process and was diagnostic for ABC originating from the left scapula. The patient recovered well and was ambulatory the day after surgery. Three years after surgery, the cat was healthy. CLINICAL RELEVANCE: The combination of radiography, regional ultrasonography, and magnetic resonance imaging enabled lesion structure and cavity content evaluation. However, final diagnosis was confirmed by histologic evaluation. To our knowledge, this is the first veterinary report of the use of magnetic resonance imaging in the characterization and diagnosis of an ABC.

A primitive neuroectodermal tumor with extension into the cranial vault in a dog.

This paper reports the clinical findings, cytology, diagnostic imaging, and necropsy of an unusual case of a peripheral nervous system neoplasm which, subsequent to a 6-month clinical history, extended into the cranial vault. Necropsy and histology confirmed the diagnosis of a peripheral primitive neuroectodermal tumor.

Canine sterile neutrophilic dermatitis (resembling Sweet's syndrome) in a Dachshund.

A 6-year-old Dachshund was presented with a 2-day history of lethargy, anorexia and cutaneous erythema, edema, and multifocal erythematous papules affecting the ventral abdomen, axillae, and groin. Microscopic examination revealed a sterile neutrophilic dermatitis resembling Sweet's syndrome; however, extracutaneous lesions were not present. The condition responded rapidly to corticosteroid therapy.

Canadian Association of Neurosciences Review: prion protein and prion diseases: the good and the bad.

In the 1700's a strange new disease affecting sheep was recognized in Europe. The disease later became known as "Scrapie" and was the first of a family of similar diseases affecting a number of species that are now known as the Transmissible Spongiform Encephalopathies (TSEs). The appearance of a new disease in humans linked to the consumption of meat products from infected cattle has stimulated widespread public concern and scientific interest in the prion protein and related diseases. Nearly 300 years after the first report, these diseases still merit the descriptor "strange". This family of diseases is characterized by a unique profile of histological changes, can be transmitted as inherited or acquired diseases, as well as apparent sporadic spontaneous generation of the disease. These diseases are believed by many, to be caused by a unique protein only infectious agent. The "prion protein" (PrPC), a term first coined by Stanley Prusiner in 1982 is crucial to the development of these diseases, apparently by acting as a substrate for an abnormal disease associated form. However, aside from being critical to the pathogenesis of the disease, the function of PrPC, which is expressed in all mammals, has defied definitive description. Several roles have been proposed on the basis of in vitro studies, however, thus far, in vivo confirmation has not been forthcoming. The biological features of PrPC also seem to be unusual. Numerous mouse models have been generated in an attempt to understand the pathogenesis of these diseases. This review summarizes the current state of histological features, the etiologic agent, the normal metabolism and the function of the prion protein, as well as the limitations of the mouse models.

Prion protein protects against ethanol-induced Bax-mediated cell death in vivo.

Prion protein inhibits Bax activation and Bax-mediated cell death in primary cultures of human neurons and in MCF-7 cells. To determine whether prion protein can protect against Bax-mediated cell death in vivo, wild-type, null and prion over-expressing mice were subjected to Bax-dependent ethanol induced neuronal apoptotic cell death and the brains were immunostained for active caspase-3 as a downstream marker of Bax activation. Bax activation occurs in all ethanol-injected mice independent of their genotype. A higher level of cell death is present in ethanol-injected null mice than in wild-type and prion over-expressing mice. We conclude that prion protein protects some, but not all neurons, against Bax-mediated cell death in this experimental paradigm.

Neuroprotective functions of prion protein.

The normal function of prion protein (PrP) is usually disregarded at the expense of the more fascinating role of PrP in transmissible prion diseases. However, the normal PrP may play an important role in cellular function in the central nervous system, since PrP is highly expressed in neurons and motifs in the sequence of PrP are conserved in evolution. The finding that prion null mice do not have a significant overt phenotype suggests that the normal function of PrP is of minor importance. However, the absence of PrP in cells or in vivo contributes to an increased susceptibility to oxidative stress or apoptosis-inducing insults. An alternative explanation is that the PrP normal function is so important that it is redundant. Probing into the characteristics of PrP has revealed a number of features that could mediate important cellular functions. The neuroprotective actions so far identified with PrP are initiated through cell surface signaling, antioxidant activity, or anti-Bax function. Here, we review the characteristics of the PrP and the evidence that PrP protects against neurodegeneration and neuronal cell death.