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Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal genetic disorder that is characterized by segmental accelerated aging. The major causal mutation associated with HGPS triggers abnormal messenger RNA splicing of the lamin A gene leading to changes in the nuclear architecture. To date, two models have been proposed to explain how mutations in the lamin A gene could lead to HGPS, structural fragility and altered gene expression. We favor a compatible model that links HGPS to stem cell-driven tissue regeneration. In this model, nuclear fragility of lamin A-deficient cells increases apoptotic cell death to levels that exhaust tissues' ability for stem cell-driven regeneration. Tissue-specific differences in cell death or regenerative potential, or both, result in the tissue-specific segmental aging pattern seen in HGPS. We propose that the pattern of aging-related conditions present or absent in HGPS can provide insight into the genetic and environmental factors that contribute to normal aging.

Despite the prominence of C−N bond forming cross‐coupling reactions as a strategy to assemble molecular fragments, aminative coupling approaches, in which two fragments are assembled directly at the heteroatom, represents a rarely exploited retrosynthetic strategy. Herein, we report the design, synthesis, and implementation of an anomeric amide reagent capable of promoting highly regioselective aminative alkene‐arene and alkene‐alkene coupling reactions. This transformation follows a sequence of catalyst‐free chloroamination, N‐deprotection, and formal nitrene functionalization, all in one‐pot. Due to the simplicity of both the protocol and the building blocks required, high‐throughput experimentation (HTE) was employed, in combination with a full‐scale scope, to rapidly and efficiently explore a wide range of chemical space and determine the limits of reactivity. In addition, alternative reactivity modes from the functionalized intermediates delivered by this protocol demonstrate the divergent nature of this aminative coupling strategy. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is a neuroendocrine malignancy showing poor response to a variety of therapeutic strategies. We evaluated the antitumor activity of S- trans, trans-farnesylthiosalicylic acid (FTS), a new inhibitor of Ras signal transduction, in a newly established SCID mouse xenotransplantation model for human MCC (seven animals per group). FTS injected intraperitoneally at 5 mg/kg per day for 2 weeks up-regulated the tumor suppressor p53 and induced tumor cell apoptosis in established MCCs growing subcutaneously in SCID mice. These effects led to a statistically significant inhibition of MCC growth ( P<0.002). The mean tumor weights following FTS or control treatment were 0.32±0.15 g and 1.08±0.29 g, respectively. There was no evidence of FTS related toxicity at the effective dose used. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for MCC and possibly for other tumors that rely on tyrosine kinase signaling. [ABSTRACT FROM AUTHOR]

The purpose of this article is to present a mathematically more accurate pattern of analysis of the cost structure of the industrial enterprise, with special reference to labor costs. It goes without saying that the analysis of the cost structure has to supply the basis for subsequent analyses, principally those of the break even complex, the forecast of unit costs, the profit, the effect of declining sales prices, increasing wages etc. If one identifies the combination of different cost classes, as they may be present in the isolated first shift, and then follows their changes at different volume levels, a definite pattern of formation of unit costs and profit will be observed. But, if one identifies the combination of costs after the addition of shift and overtime work, and then again follows their changes at different times and volume levels, a different pattern in the formation of unit costs and profit will be noted. Cost variability within a business and among businesses is endless. This situation, resistant to realistic survey, requires us to try to explore, and to define, on the basis of a purposeful classification, all distinct cases of cost structures which possibly could be encountered.

This article discusses the nature and treatment of dividends under a entity concept of corporate residual equity. It was hypothesized that the main objective of the corporation after its inception is to survive, and that the corporation strives to maintain both economic and financial competence in implementing this objective. It was argued that the only significant representation made by the corporation in soliciting stockholders' capital contributions was its agreement to pay dividends when and if declared, and that capital thus contributed becomes the corporation's equity. It was advanced that the treatment of several persistent problems in corporation accounting might be rendered more consistent if the nature of corporate residual equity as thus analyzed were accepted. The corporation, in soliciting stockholders' capital contributions, agrees to pay dividends when and if declared. This suggests that both the timing and the amount of dividends are at the corporation's discretion, and that stockholders cannot force the corporation to pay dividends even though earnings are ample.

Ras transformation requires Ras membrane anchorage, which is promoted by a farnesylcysteine carboxymethyl ester and by additional sequences specific to each Ras isoform. We showed previously that S-trans,trans-farnesylthiosalicylic acid (FTS) disrupts Ras membrane anchorage and that this disturbance contributes to inhibition of cell transformation and tumor growth. Most tumor cells develop resistance to anticancer agents. Here we examined whether tumor cells develop resistance to FTS and evaluated the therapeutic potential of FTS combined with cytotoxic drugs, because oncogenic Ras promotes antiapoptotic signals in tumors of epithelial origin. We showed that Panc-1 pancreatic cancer cells, SW480 colon cancer cells, and H-ras (EJ)-transformed Rat-1 fibroblasts exposed to FTS for prolonged periods (>6 months) do not escape FTS-induced growth inhibition and do not develop drug resistance. These cells continued to express reduced amounts of Ras, exhibit a reversed phenotype, and show an altered response to the cytotoxic drugs doxorubicin and gemcitabine. FTS-treated Panc-1 or SW480 cells acquired sensitivity to the cytotoxic drugs, whereas FTS-treated EJ cells lost sensitivity to doxorubicin, reflecting the opposite effects of oncogenic Ras on the survival of epithelial cells and fibroblasts. Treatment with FTS led to a marked increase in sensitivity to gemcitabine of the formerly resistant SW480 cells and a 100-fold increase in sensitivity to gemcitabine of Panc-1 cells. Such treatment in mice with preexisting Panc-1 tumors provided a synergistic effect of FTS and gemcitabine, leading to enhanced inhibition of tumor growth and a 65% increase in survival rate.