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Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2-5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan-Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51-4.54; p < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.

Granular media constitute the most abundant form of solid matter on Earth and beyond. When external forces are applied to a granular medium, the forces are transmitted through it via chains of contacts among grains-force chains. Understanding the spatial structure and temporal evolution of force chains constitutes a fundamental goal of granular mechanics. Here, we introduce an experimental technique, interference optical projection tomography, to study force chains in three-dimensional (3D) granular packs under triaxial shear loads and illustrate the technique with random assemblies of spheres and icosahedra. We find that, in response to an increasing vertical load, the pack of spheres forms intensifying vertical force chains, while the pack of icosahedra forms more interconnected force-chain networks. This provides microscopic insights into why particles with more angularity are more resistant to shear failure-the interconnected force-chain network is stronger (that is, more resilient to topological collapse) than the isolated force chains in round particles. The longer force chains with less branching in the pack of round particles are more likely to buckle, which leads to the macroscopic failure of the pack. This work paves the way for understanding the grain-scale underpinning of localized failure of 3D granular media, such as shear localization in landslides and stick-slip frictional motion in tectonic and induced earthquakes., Competing Interests: Competing interests statement:The authors declare no competing interest.

The postmenopausal decrease in circulating estradiol (E2) levels has been shown to contribute to several adverse physiological and psychiatric effects. To elucidate the molecular effects of E2 on the brain, we examined differential gene expression and DNA methylation (DNAm) patterns in the nonhuman primate brain following ovariectomy (Ov) and subsequent subcutaneous bioidentical E2 chronic treatment. We identified several dysregulated molecular networks, including MAPK signaling and dopaminergic synapse response, that are associated with ovariectomy and shared across two different brain areas, the occipital cortex (OC) and prefrontal cortex (PFC). The finding that hypomethylation (p = 1.6 × 10 -51 ) and upregulation (p = 3.8 × 10 -3 ) of UBE2M across both brain regions provide strong evidence for molecular differences in the brain induced by E2 depletion. Additionally, differential expression (p = 1.9 × 10 -4 ; interaction p = 3.5 × 10 -2 ) of LTBR in the PFC provides further support for the role E2 plays in the brain, by demonstrating that the regulation of some genes that are altered by ovariectomy may also be modulated by Ov followed by hormone replacement therapy (HRT). These results present real opportunities to understand the specific biological mechanisms that are altered with depleted E2. Given E2's potential role in cognitive decline and neuroinflammation, our findings could lead to the discovery of novel therapeutics to slow cognitive decline. Together, this work represents a major step toward understanding molecular changes in the brain that are caused by ovariectomy and how E2 treatment may revert or protect against the negative neuro-related consequences caused by a depletion in estrogen as women approach menopause., (© 2024. The Author(s).)

Introduction: The hippocampus is especially susceptible to age-associated neuronal pathologies, and there is concern that the age-associated rise in cortisol secretion from the adrenal gland may contribute to their etiology. Furthermore, because 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) catalyzes the reduction of cortisone to the active hormone cortisol, it is plausible that an increase in the expression of this enzyme enhances the deleterious impact of cortisol in the hippocampus and contributes to the neuronal pathologies that underlie cognitive decline in the elderly., Methods: Rhesus macaques were used as a translational animal model of human aging, to examine age-related changes in gene and protein expressions of ( HSD11B1 /HSD11B1) in the hippocampus, a region of the brain that plays a crucial role in learning and memory., Results: Older animals showed significantly ( p  < 0.01) higher base-line cortisol levels in the circulation. In addition, they showed significantly ( p  < 0.05) higher hippocampal expression of HSD11B1 but not NR3C1 and NR3C2 (i.e., two receptor-encoding genes through which cortisol exerts its physiological actions). A similar age-related significant ( p  < 0.05) increase in the expression of the HSD11B1 was revealed at the protein level by western blot analysis., Discussion: The data suggest that an age-related increase in the expression of hippocampal HSD11B1 is likely to raise cortisol concentrations in this cognitive brain area, and thereby contribute to the etiology of neuropathologies that ultimately lead to neuronal loss and dementia. Targeting this enzyme pharmacologically may help to reduce the negative impact of elevated cortisol concentrations within glucocorticoid-sensitive brain areas and thereby afford neuronal protection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lomniczi, Luna, Cervera-Juanes, Appleman, Kohama and Urbanski.)

Background: Amyloid beta (Aβ) plaque density was examined in the amygdala of rhesus macaques, to elucidate the influence of age, diet and hormonal environment., Methods: Luminex technology was used to measure cerebrospinal fluid (CSF) concentrations of Aβ 40 and Aβ 42 across three decades, while immunohistochemistry was used to examine Aβ plaque density in the amygdala., Results: Aβ 40 was found to be the predominant isoform of Aβ in the CSF, but neither Aβ 40 or Aβ 42 concentrations showed an age-related change, and the ratio of Aβ 42 to Aβ 40 showed only a marginal increase. Significantly fewer Aβ plaques were detected in the amygdala of old ovariectomized animals if they received estradiol HRT ( p < 0.001); similar results were obtained regardless of whether they had been maintained on a regular monkey chow for ∼48 months or on a high-fat, high-sugar, Western-style diet for ∼30 months., Conclusion: The results demonstrate that HRT involving estrogen can reduce Aβ plaque load in a cognitive brain region of aged non-human primates. The results from this translational animal model may therefore have clinical relevance to the treatment of AD in post-menopausal women, whether used alone, or as a supplement to current pharmacological and monoclonal antibody-based interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Appleman, Thomas, Weiss, Nilaver, Cervera-Juanes, Kohama and Urbanski.)