Altered protein kinase C (PKC) isoforms in non-small cell lung cancer cells: PKCdelta promotes cellular survival and chemotherapeutic resistance

Drugs that target protein kinase C (PKC) are now being evaluated in patients with non-small cell lung cancer (NSCLC), but the role of PKC in NSCLC cells remains unclear. We report here that NSCLC cell lines show enhanced phosphorylation and altered expression of specific PKC isoforms compared with normal lung epithelial cells. PKC inhibition variably increased apoptosis, with rottlerin, a PKCdelta inhibitor, being most effective and potentiating chemotherapy-induced apoptosis, especially with trastuzumab. Consistent with PKCdelta being anti-apoptotic in NSCLC cells, transient transfection of a kinase-dead mutant of PKCdelta increased apoptosis and potentiated chemotherapy-induced apoptosis. Our studies provide a rationale for targeting PKC isoforms in NSCLC cells, especially PKCdelta.     

A model for studying epithelial attachment and morphology at the interface between skin and percutaneous devices

Percutaneous devices are indispensable in modern medicine, yet complications from their use result in significant morbidity, mortality, and cost. Bacterial biofilm at the device exit site accounts for most infections in short-term devices. We hypothesize that advanced biomaterials can be developed that facilitate attachment of skin cells to percutaneous devices, forming a seal to preclude bacterial invasion. To study the skin/biomaterial interface systematically, we first identified biomaterials with physical properties compatible with histological processing of skin. Second, we developed an organ culture system to study skin response to implants. Organ cultures implanted with porous poly(2-hydroxyethyl methacrylate) [poly(HEMA)] or polytetrafluoroethylene (PTFE) could easily be evaluated histologically with preservation of the skin/biomaterial interface. Epithelial cells migrated down the cut edges of the biomaterial in a pattern seen in marsupialization of percutaneous devices in vivo. This in vitro model maintains skin viability and allows histologic evaluation of the skin/biomaterial interface, making this a useful, inexpensive test-bed for studies of epidermal attachment to modified biomaterials.     

Microcytic anemia with iron malabsorption: An inherited disorder of iron metabolism

Two siblings were identified with severe hypoproliferative microcytic anemia and iron malabsorption, in the absence of any gastrointestinal disorder or blood loss. These children had severe microcytosis (MCV 48 fl, hemoglobin 7.5 g/dl) with decreased serum iron, elevated serum TIBC, and decreased serum ferritin, despite prolonged treatment with oral iron. An iron challenge study with an oral dose of 2 mg/kg elemental iron as ferrous sulfate documented iron malabsorption. After treatment with intravenous iron dextran, there was an absence of the expected reticulocytosis and only a partial correction of the hemoglobin, hematocrit, and microcytosis. The bone marrow was hypocellular with abnormal iron incorporation into erythroid precursor cells. This appears to be a rare form of inherited anemia characterized by iron malabsorption and disordered iron metabolism that only partially corrects after the administration of parenteral iron. These features resemble those found in the microcytic mouse (mk/mk), which also has severe microcytic anemia and iron malabsorption that partially responds to parenteral iron. © 1996 Wiley-Liss, Inc.     

Piperidine alkaloids: Human and food animal teratogens

Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogenic piperidine alkaloids include poison hemlock (Conium maculatum), lupine (Lupinus spp.), and tobacco (Nicotiana tabacum) [including wild tree tobacco (Nicotiana glauca)]. There is abundant epidemiological evidence in humans that link maternal tobacco use with a high incidence of oral clefting in newborns; this association may be partly attributable to the presence of piperidine alkaloids in tobacco products. In this review, we summarize the evidence for piperidine alkaloids that act as teratogens in livestock, piperidine alkaloid structure–activity relationships and their potential implications for human health.