Lung tissue damage, histologically similar to protease induced lung lesions, has been previously demonstrated in animals exposed to the plasticizer, di-(2-ethylhexyl)phthalate (DEHP). In an attempt ...to identify the mechanism responsible for this damage, we have examined the effect of DEHP on alveolar macrophages. Serum solubilized DEHP has a significant effect on both the phagocytosis of latex particles and lysosomal enzyme released from rabbit alveolar macrophages. Pre-exposure to 2 mg% of DEHP caused a 2-fold increase in the rate of phagocytosis and an 8-fold and 10-fold increase, respectively, in the release of the lysosomal hydrolases beta-glucuronidase and acid phosphatase. Although exposure to 2 mg% DEHP caused an 8-fold increase in in vitro cell death, pre-exposure to DEHP had only minimal effect on death during subsequent cell culture, as indicated by measurement of dye exclusion and the release of the cytosolic enzyme lactate dehydrogenase. The relationship between the DEHP induced increase in lysosomal enzyme release from alveolar macrophages and the pathological and histological effects of DEHP on pulmonary tissue is discussed, particularly with respect to patients receiving multiple blood transfusions.
Although strides have been made in the diagnosis and treatment of cancer in the past few decades, advanced, metastatic cancer remains extremely difficult to treat. Obviously, a major hurdle in ...improving survival is the treatment or prevention of metastatic disease, either to eliminate it completely or to contain it like other chronic diseases. To reach the metastatic stage, the cancer cells undergo many and various changes in the usual regulatory mechanisms governing cellular proliferation and apoptosis, resulting in great heterogeneity. Therein lies the challenge in developing appropriate and effective combination therapies for metastatic disease that utilize multiple mechanisms to overcome resistance to cell death. In this chapter, the relatively new cytotoxic taxane docetaxel will be discussed in the context of its current role in treating metastatic cancer and its future role in combination with novel, molecularly targeted chemotherapeutic agents.
Research presented at the Vancouver Autophagy Symposium (VAS) 2014 suggests that autophagy's influence on health and disease depends on tight regulation and precision targeting of substrates. ...Discussions recognized a pressing need for robust biomarkers that accurately assess the clinical utility of modulating autophagy in disease contexts. Biomarker discovery could flow from investigations of context-dependent triggers, sensors, and adaptors that tailor the autophagy machinery to achieve target specificity. In his keynote address, Dr. Vojo Deretic (University of New Mexico) described the discovery of a cargo receptor family that utilizes peptide motif-based cargo recognition, a mechanism that may be more precise than generic substrate tagging. The keynote by Dr. Alec Kimmelman (Harvard Medical School) emphasized that unbiased screens for novel selective autophagy factors may accelerate the development of autophagy-based therapies. Using a quantitative proteomics screen for de novo identification of autophagosome substrates in pancreatic cancer, Kimmelman's group discovered a new type of selective autophagy that regulates bioavailable iron. Additional presentations revealed novel autophagy regulators and receptors in metabolic diseases, proteinopathies, and cancer, and outlined the development of specific autophagy inhibitors and treatment regimens that combine autophagy modulation with anticancer therapies. VAS 2014 stimulated interdisciplinary discussions focused on the development of biomarkers, drugs, and preclinical models to facilitate clinical translation of key autophagy discoveries.
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