New Roles for Vitamin D Superagonists: From COVID to Cancer.

Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity

Novel and Known Protein Tyrosine Kinases and Their Abnormal Expression in Human Melanoma

We have used the polymerase chain reaction and Northern blotting to identify protein tyrosine kinases that may play an an important role in the process of melanoma initiation and progression. Degenerate primers from the conserved catalytic domain of tyrosine kinase genes were used to amplify and clone partial cDNA sequences from a human melanoma cell line (DX3-LT5.1) and normal human melanocytes. When the melanoma reaction products were sequenced, 13 distinct clones were found, of which one is novel to date and has provisionally been named MEK (for melanocytic kinase). Of the remaining 12 known kinases, only two, ERB-B2 and IGFI-1-R, have previously been reported in pigment cells. Reaction products from melanocytes included only eight of these 13 sequences. To test for quantitative differences in tyrosine kinase expression between normal and malignant cells, a panel of eight melanoma lines and normal melanocytes was analyzed by Northern blotting. Two tyrosine kinases (JTK-14/TIE and TYRO-9) were detected in some melanomas but were not found in normal melanocytes, whereas others, including MEK, appeared to be overexpressed in some malignant lines. A minority of kinases showed either no change or a reduction in the level of mRNA. Expression of tyrosine kinases varied independently, and individual lines contained various combinations of these enzymes. Our findings are consistent with an increased overall expression of these putative growth factor receptors during melanoma development

Lee Strasberg's Method

Lee Strasberg (1901–1982) is a divisive figure whose method of acting is often misunderstood. Few people really know what it is or how it works, or what is its true relationship to the Stanislavski System. This is due to a number of misconceptions about the nature of his training with its emphasis on the development of the sensory imagination. This paper aims to challenge some of the myths about the Method, and to clarify Strasberg’s unique contribution to actor training

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone

A study of the biochemistry and immunochemistry of differentiation of the normal epidermis and involved psoriatic epidermis

Imperial Users onl

New Roles for Vitamin D Superagonists: From COVID to Cancer.

Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity

Factors influencing the suitability of organ-cultured corneas for transplantation. Invest Ophthalmol Vis Sci 38: 16

Purpose. To assess the influence of donor and storage factors on the suitability of organcultured corneas for penetrating keratoplasty (PKP) using multifactorial regression analysis. Methods. Corneas (mean donor age, 57 years; standard deviation, 21 years) were stored by organ culture at 34°C for up to 5 weeks (mean, 22 days; standard deviation, 6 days). The endothelium was assessed by light microscopy, and corneas with <2200 cells/mm 2 were considered unsuitable for PKP. Results. Of the 9250 corneas stored between 1992 and 1994, 59% were issued for PKP, 5% were discarded because of bacterial or fungal contamination, and 30% were unsuitable for PKP owing to endothelial deficiencies. Donor age had the strongest influence on suitability for PKP: >80% of corneas from donors younger than 40 years of age were issued for PKP compared with only 45% of corneas from donors 80 years of age and older. There was an overall decline in the percentage of corneas suitable for PKP with increasing storage time, but the rate of this decline was inversely related to donor age. Cause of death and post mortem times to enucleation and to storage had only a small influence on suitability for PKP. Conclusions. Criteria based on endothelial assessment rather than on donor age allow corneas from donors of all ages, stored by organ culture for extended periods, to be used for PKP. Organ culture also allows corneas with bacterial or fungal contamination to be identified and discarded before they are grafted. Invest Ophthalmol Vis Sci. 1997; 38:16-24

Analysis of bleaching liquors by ion chromatography

"May, 1985.