Comparison of Omicron breakthrough infection versus monovalent SARS-CoV-2 intramuscular booster reveals differences in mucosal and systemic humoral immunity.

Our understanding of the quality of cellular and humoral immunity conferred by COVID-19 vaccination alone versus vaccination plus SARS-CoV-2 breakthrough (BT) infection remains incomplete. While the current (2023) SARS-CoV-2 immune landscape of Canadians is complex, in late 2021 most Canadians had either just received a third dose of COVID-19 vaccine, or had received their two-dose primary series and then experienced an Omicron BT. Herein we took advantage of this coincident timing to contrast cellular and humoral immunity conferred by three doses of vaccine versus two doses plus BT. Our results show thatBT infection induces cell-mediated immune responses to variants comparable to an intramuscular vaccine booster dose. In contrast, BT subjects had higher salivary immunoglobulin (Ig)G and IgA levels against the Omicron spike and enhanced reactivity to the ancestral spike for the IgA isotype, which also reacted with SARS-CoV-1. Serumneutralizing antibody levels against the ancestral strain and the variants were also higher after BT infection. Our results support the need for the development of intranasal vaccines that could emulate the enhanced mucosal and humoral immunity induced by Omicron BT without exposing individuals to the risks associated with SARS-CoV-2 infection.

Potential for supraphysiologic fluid shear stresses in a rat cemented knee replacement model.

The mechano-biologic environment associated with aseptic loosening of cemented joint replacements is not fully understood. The goal of this study was to use a preclinical rat knee arthroplasty model to explore the changes in cement-bone morphology and micromotion that occur with in vivo service. Narrow gaps between cement and bone under the tibial tray were present at early time points, and with even small magnitude micromotion, resulted in large micromotion-to-gap width ratios. These data were then used to develop models of fluid flow in the cement-bone gaps to estimate potential for high fluid shear stress (FSS). Modeling results revealed supraphysiologic (>4 Pa) FSS were possible, particularly for cases in which eccentric loading applied to the implant and if the fluid in the gap consisted of marrow or synovial fluid. The early, high FSS environment, could cause fluid-induced periprosthetic osteolysis locally, resulting in progressive loss of cement-bone fixation.

Additional Distal Femoral Resection Minimally Improves Terminal Knee Extension: A Systematic Review and Meta-Regression Challenging the Dogma.

Background: Additional distal femoral resection is a common technique to address a flexion contracture during primary total knee arthroplasty (TKA) but can lead to midflexion instability and patella baja. Prior reports regarding the magnitude of knee extension obtained with additional femoral resection have varied. This study sought to systematically review research describing the effect of femoral resection on knee extension and to perform meta-regression to estimate this relationship. Methods: A systematic review was conducted using MEDLINE, PubMed, and Cochrane databases by combining the terms ("flexion contracture" OR "flexion deformity") AND ("knee arthroplasty" OR "knee replacement") to identify 481 abstracts. In total, 7 articles reporting change in knee extension after additional femoral resection or augmentation across 184 knees were included. The mean value for knee extension, its standard deviation, and the number of knees tested were recorded for each level. Meta-regression was performed using weighted mixed-effects linear regression. Results: Meta-regression estimated that each 1mm resected from the joint line produced a 2.5° gain of extension (95% confidence interval, 1.7 to 3.2). Sensitivity analyses excluding outlying observations estimated each 1mm resected from the joint line produced a 2.0° gain of extension (95% confidence interval, 1.9 to 2.2). Conclusions: Each millimeter of additional femoral resection is likely to produce only a 2° improvement in knee extension. Thus, an additional resection of 2 mm is likely to improve knee extension by less than 5°. Alternative techniques, including posterior capsular release and posterior osteophyte resection, should be considered in correcting a flexion contracture during TKA.

The catalytic activity of the ErbB-2 receptor tyrosine kinase is essential for embryonic development.

Activation of the epidermal growth factor receptor (EGFR) family is thought to play a critical role in both embryogenesis and oncogenesis. The diverse biological activities of the EGFR family are achieved through various ligand-receptor and receptor-receptor interactions. One receptor that has been found to play a central role in this signaling network is ErbB-2/Neu, and it is considered the preferred heterodimerization partner for other members of the EGFR family. To assess the importance of the catalytic activity of ErbB-2 in embryonic development, we have generated mice expressing a kinase-dead erbB-2 cDNA under the transcriptional control of the endogenous promoter. Here, we show that mice homozygous for the kinase-dead erbB-2 allele die at midgestation and display the same spectrum of embryonic defects seen in erbB-2 knockout mutants. These observations suggest that the catalytic activity of ErbB-2 is essential for normal embryonic development.

ErbB2 is required for muscle spindle and myoblast cell survival.

Signaling mediated by ErbB2 is thought to play a critical role in numerous developmental processes. However, due to the embryonic lethality associated with the germ line inactivation of erbB2, its role in adult tissues remains largely obscure. Given the expression of ErbB2 at the neuromuscular junction, we have created a muscle-specific knockout to assess its role there. This resulted in viable mice with a progressive defect in proprioception due to loss of muscle spindles. Interestingly, a partial reduction of ErbB2 levels also reduced the number of muscle spindles. Although histological analysis of the muscle revealed an otherwise normal architecture, induction of muscle injury revealed a defect in muscle regeneration. Consistent with these observations, primary myoblasts lacking ErbB2 exhibit extensive apoptosis upon differentiation into myofibers. Taken together, these results illustrate a dual role for ErbB2 in both muscle spindle maintenance and survival of myoblasts.

Receptor tyrosine kinase signaling favors a protumorigenic state in breast cancer cells by inhibiting the adaptive immune response.

Using transgenic mouse models of breast cancer that ablate Src homology and collagen A (ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4(+) T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T cell-deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers. Finally, we define a novel ShcA-regulated immune signature that functions as an independent prognostic marker of survival in human epidermal growth factor receptor 2(+) and basal breast cancers. We reveal a novel role for tumor cell-derived ShcA in the establishment and maintenance of an immunosuppressive state.

Germ-line expression of an oncogenic erbB2 allele confers resistance to erbB2-induced mammary tumorigenesis.

We have previously shown that mammary epithelial specific expression of the activated erbB2 allele under the control of the endogenous promoter in mice resulted in the formation of mammary adenocarcinomas. To assess whether mammary tumorigenesis in this model is influenced by the developmental window of expression, we generated mice that expressed the activated erbB2 allele in the germ line. Although we were able to derive viable transgenic mice that were heterozygous for the activated erbB2 allele, mice homozygous for the activated erbB2 allele died at 12.5 days of embryogenesis. These two separate lines of mice expressed activated erbB2 at equal levels in the mammary gland. Surprisingly, unlike the tumor-prone mice expressing activated ErbB2 in the mammary epithelium, mice with the germ-line erbB2 allele failed to develop tumors. Gene expression analysis of the preneoplastic mammary glands revealed that there were a number of luminal epithelial markers expressed at higher levels in the tumor-prone mice. These data suggest either an expansion of a susceptible population in the tumor-prone mice or the loss of this population in the tumor-resistant mice. Taken together, these observations suggest that the temporal pattern of expression of activated ErbB2 is a critical determinant in mammary tumorigenesis. These results strongly suggest that there are feedback mechanisms present that can compensate for the expression of a potent oncogene.