Objectives To investigate the possible role of Vitamin D (Vit D) deficiency via unregulated inflammation in COVID-19 complications and associated mortality. Design The time-adjusted case mortality ratio (T-CMR) was estimated as the number of deceased patients on day N divided by the number of confirmed cases on day N-8. The adaptive average of T-CMR (A-CMR) was further calculated as a metric of COVID-19 associated mortality in different countries. A model based on positivity change (PC) and an estimated prevalence of COVID-19 was developed to determine countries with similar screening strategies. Mean concentration of 25-hydroxyvitamin D (25(OH)D) in elderly individuals in countries with similar screening strategies were compared to investigate the potential impact of Vit D on A-CMR. We analyzed data showing a possible association between high C-Reactive Protein (CRP) concentration (CRP greater than or equal to 1 mg/dL) and severe COVID-19. We estimated a link between Vit D status and high CRP in healthy subjects (CRP greater than or equal to 0.2 mg/dL) with an adjustment for age and income to explore the possible role of Vit D in reducing complications attributed to unregulated inflammation and cytokine production. Data Sources Daily admission, recovery, and deceased rate data for patients with COVID-19 were collected from Kaggle as of April 20, 2020. Screening data were collected from Our World in Data and official statements from public authorities. The mean concentration of 25(OH)D among the elderly for comparison with A-CMR was collected from previously published studies from different countries. Chronic factor data used in regression analysis was obtained from published articles. The correlation between Vit D and CRP was calculated based on 9,212 subject-level data from NHANES, 2009-2010. Results A link between 25(OH)D and A-CMR in the US, France, Iran and the UK (countries with similar screening status) may exist. We observed an inverse correlation (correlation coefficient ranging from -0.84 to -1) between high CRP and 25(OH)D. Age and the family income status also correlated to high CRP and subjects with higher age and lower family income presented more incidences of high CRP. Our analysis determined a possible link between high CRP and Vit D deficiency and calculated an OR of 1.8 with 95%CI (1.2 to 2.6) among the elderly (age greater than or equal to 60 yo) in low-income families and an OR of 1.9 with 95%CI (1.4 to 2.7) among the elderly (age greater than or equal to 60 yo) in high-income families. COVID-19 patient-level data shows a notable OR of 3.4 with 95%CI (2.15 to 5.4) for high CRP in severe COVID-19 patients. Conclusion Given that CRP is a surrogate marker for cytokine storm and is associated with Vit D deficiency, based on retrospective data and indirect evidence we see a possible role of Vit D in reducing complications attributed to unregulated inflammation and cytokine storm. Further research is needed to account for other factors through direct measurement of Vit D levels in COVID-19 patients.

The inhibition of apoptosis is a critical event in the development of colorectal malignancies, although the mechanism(s) remain incompletely understood. The anti-apoptotic proto-oncogene, AKT, has been implicated in the molecular pathogenesis of a variety of human malignancies; however, no data exist on the role of AKT in colon carcinogenesis. We therefore evaluated the presence of AKT in human and experimental colon neoplasms by immunohistochemistry. Normal colonic mucosa and hyperplastic polyps exhibited no significant AKT expression, in marked contrast to the dramatic AKT immunoreactivity seen in colorectal cancers (57% positive) and in both human colorectal cancer cell lines examined. Importantly, AKT was also detected in 57% of the adenomas examined, implicating overexpression of this proto-oncogene as an early event during colon carcinogenesis. Moreover, in the rodent-carcinogen model, azoxymethane (AOM)-treatment induced AKT expression in premalignant rat colonocytes. Tumors that evolve via different genetic pathways displayed a lower incidence of AKT overexpression. Indeed, only 22% of mismatch repair defective tumors and 42% of AOM-induced rodent tumors upregulated AKT. Staining with an antibody specific for AKT 2 duplicated findings with the AKT 1&2 antibody, suggesting that AKT 2 was the predominant isoform involved in colon carcinogenesis. Furthermore, utilizing an antibody that specifically recognizes the serine-473 phosphorylated form of AKT, we observed that activated AKT was detectable in the neoplastic but not normal epithelium. In summary, our immunohistochemical analysis indicates AKT overexpression occurs frequently during human colon carcinogenesis, but is less common in colon cancers with microsatellite instability. The early inhibition of apoptosis during sporadic colon carcinogenesis may be related, at least partly, to the overexpression of AKT.

Recently, there has been a major thrust to understand biological processes at the nanoscale. Optical microscopy has been exceedingly useful in imaging cell microarchitecture. Characterization of cell organization at the nanoscale, however, has been stymied by the lack of practical means of cell analysis at these small scales. To address this need, we developed a microscopic spectroscopy technique, single-cell partial-wave spectroscopy (PWS), which provides insights into the statistical properties of the nanoscale architecture of biological cells beyond what conventional microscopy reveals. Coupled with the mesoscopic light transport theory, PWS quantifies the disorder strength of intracellular architecture. As an illustration of the potential of the technique, in the experiments with cell lines and an animal model of colon carcinogenesis we show that increase in the degree of disorder in cell nanoarchitecture parallels genetic events in the early stages of carcinogenesis in otherwise microscopically/histologically normal-appearing cells. These data indicate that this advance in single-cell optics represented by PWS may have significant biomedical applications.light-scattering spectroscopy ͉ nanoarchitecture ͉ subdiffusion E xisting knowledge of changes in cell architecture in disease processes is based to a large degree on the histological examination of cells and tissue. On the other hand, it is well accepted that histological and, thus, microarchitectural, aberrations are preceded by molecular, genetic, or epigenetic changes. One may pose a question whether these events are still accompanied by alterations in cell architecture that are histologically undetectable. Indeed, the diffraction limit restricts the resolution of conventional light microscopy to, at best, 200 nm. This is larger than the sizes of the fundamental building blocks of the cell, such as membranes, cytoskeleton, ribosomes, and nucleosomes. Thus, conventional light microscopy is insensitive to changes in nanoarchitecture, which is the fundamental basis of cell organization. It is clear that the fact that a cell is histologically normal may not necessarily be equated with the cell not having nanoscale structural alterations. Cellular alterations in carcinogenesis provide an illustrative and practically important example. The process of carcinoma formation involves stepwise accumulation of genetic and epigenetic alterations in epithelial cells over a time period of many years. Dysplasia, or structural alterations detectable by microscopy, is a relatively late event in this process. From a cancerresearch perspective, it is important to recognize the earlier stages of carcinogenesis that precede histological changes. One can hypothesize that although these genetic/epigenetic aberrations have not yet resulted in histologically apparent changes, they may still be accompanied by architectural consequences that occur at the nanoscale.Therefore, it is of major importance to design optical techniques for inspecting cell nanoarchitecture. One approach to...

Objectives We present evidence for a possible role of Vitamin D (VitD) deficiency in unregulated cytokine production and inflammation leading to complications in COVID-19 patients. Design The time-adjusted case mortality ratio (T-CMR) was estimated as the ratio of deceased patients on day N to the confirmed cases on day N-8. The adaptive average of T-CMR (A-CMR) was calculated as a metric of COVID-19 associated mortality. A model based on positivity change (PC) and an estimated prevalence of COVID-19 was used to determine countries with similar screening strategies. A possible association of A-CMR with the mean concentration of 25-hydroxyvitamin D (25(OH)D) in elderly individuals in countries with similar screening strategy was investigated. We considered high C-reactive protein (CRP) in severe COVID-19 patients (CRP ≥ 1 mg/dL) as a surrogate of a cytokine storm. We considered high-sensitivity CRP (hs-CRP) in healthy subjects as hs-CRP ≥ 0.2 mg/dL. Results A link between 25(OH)D and A-CMR in countries with similar screening strategy is evidence for VitD’s possible role in reducing unregulated cytokine production and inflammation among patients with severe COVID-19. We observed an odds ratio (OR) of 1.8 with 95% confidence interval (95% CI) (1.2 to 2.6) and an OR of 1.9 with 95% CI (1.4 to 2.7) for hs-CRP in VitD deficient elderly from low-income families and high-income families, respectively. COVID-19 patient-level data show an OR of 3.4 with 95% CI (2.15 to 5.4) for high CRP in severe COVID-19 patients. Conclusion We conclude that future studies on VitD’s role in reducing cytokine storm and COVID-19 mortality are warranted.