Mornings with Art, lessons learned: feedback regulation, restriction threshold biology, and redundancy govern molecular stress responses

Work from the laboratory of Dr. Arthur B. Pardee has highlighted basic principles that govern cellular and molecular biological processes in living cells. Among the most important governing principles in cellular and molecular responses are: (i) threshold "restriction" responses, wherein a level of response is reached and a "point of no return" is achieved; (ii) feedback regulation; and (iii) redundancy. Lessons learned from the molecular biology of cellular stress responses in mammalian cancer versus normal cells after ionizing radiation (IR) or chemotherapeutic agent exposures reveal similar instances of these guiding principles in mammalian cells. Among these are the: (i) induction of cell death responses by beta-lapachone (beta-lap), a naphthoquinone anti-tumor agent that kills cancer cells via an NQO1 (i.e., X-ray-inducible protein-3, xip3)-dependent mechanism; (ii) induction of secretory clusterin (sCLU) in response to TGF-beta1 exposure, and the ability of induced sCLU protein to down-regulate TGF-beta1 signaling; and (iii) induction of DNA mismatch repair-dependent G(2) cell cycle checkpoint responses after exposure to alkylating agents. We have learned these lessons and now adopted strategies to exploit them for improved therapy. These examples will be discussed and compared to the pioneering findings of researchers in the Pardee laboratory over the years.     

Dispersion and Ecological Impact of the Invasive Freshwater Bivalve Limnoperna fortunei in the Río de la Plata Watershed and Beyond

Limnoperna fortunei is a freshwater bivalve that invaded South America through Río de la Plata estuary in 1989 and has since become a major macrofouling pest. Along the Paraná-Paraguay waterway, which hosts intense boat traffic, L. fortunei has moved upstream at an average rate of of 250 km per year. In contrast, along the Uruguay river, where boat traffic is restricted to the lowermost 200 km section, upstream colonization is almost 10-times slower. This suggests that attachment to vessels is by far the most important dispersion mechanism. It is suggested that the Amazon, Orinoco and Magdalena basins are under high risk of invasion by this mussel, especially through their estuarine gateways. All South American basins host innumerable water bodies with favorable conditions for L. fortunei’s colonization. Known ecological tolerance limits of the mussel also suggest that it may colonize much of the area from Central America to Canada, including waters that due to their low calcium contents, high temperature and pollution levels, and low oxygen are inadequate for the survival of Dreissena polymorpha. Despite it’s remarkable geographic expansion and its extremely high population densities, L. fortunei’s ecological effects have received very little attention so far. It is suggested that the 2.4-fold increase in Argentine landings of freshwater fish between 1992–1993 and 2000–2001 may be associated with the introduction of this prey species.     

Evidence of Associations between Cytokine Genes and Subjective Reports of Sleep Disturbance in Oncology Patients and Their Family Caregivers

The purposes of this study were to identify distinct latent classes of individuals based on subjective reports of sleep disturbance; to examine differences in demographic, clinical, and symptom characteristics between the latent classes; and to evaluate for variations in pro- and anti-inflammatory cytokine genes between the latent classes. Among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their FCs, growth mixture modeling (GMM) was used to identify latent classes of individuals based on General Sleep Disturbance Scale (GSDS) obtained prior to, during, and for four months following completion of radiation therapy. Single nucleotide polymorphisms (SNPs) and haplotypes in candidate cytokine genes were interrogated for differences between the two latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on GSDS group membership. Two latent classes were identified: lower sleep disturbance (88.5%) and higher sleep disturbance (11.5%). Participants who were younger and had a lower Karnofsky Performance status score were more likely to be in the higher sleep disturbance class. Variation in two cytokine genes (i.e., IL6, NFKB) predicted latent class membership. Evidence was found for latent classes with distinct sleep disturbance trajectories. Unique genetic markers in cytokine genes may partially explain the interindividual heterogeneity characterizing these trajectories.     

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

A disintegrin and metalloproteinases (ADAMs) are a recently discovered family of proteins that share the metalloproteinase domain with matrix metalloproteinases (MMPs). Among this family, structural features distinguish the membrane-anchored ADAMs and the secreted ADAMs with thrombospondin motifs referred to as ADAMTSs. By acting on a large panel of membrane-associated and extracellular substrates, they control several cell functions such as adhesion, fusion, migration and proliferation. The current review addresses the contribution of these proteinases in the positive and negative regulation of cancer progression as mainly mediated by the regulation of growth factor activities and integrin functions.     

Preoperative CEA, NSE, SCC, TPA and CYFRA 21.1 serum levels as prognostic indicators in resected non-small cell lung cancer.

In 62 patients affected by resectable non-small cell lung cancer (NSCLC) submitted to radical surgery we evaluated the prognostic significance of CEA, NSE, SCC, TPA, and CYFRA 21.1 serum levels at diagnosis, as well as the predictive ability of these tumor markers with respect to histological type and pathological stage. The group was composed of 56 male and 6 female patients; the median age was 62 years (range 29-73 years). Thirty-four patients had a histological diagnosis of adenocarcinoma and 28 of squamous cell carcinoma; with regard to pathological stage, 32 patients had stage 1, 4 patients stage II and 23 patients stage IIIA disease. A good predictive ability with respect to histological type was obtained with SCC serum levels; as for pathological stage, TPA and CYFRA 21.1 were found to have moderate predictive ability. In this series of patients, at a median follow-up of 55 months after surgery, we found that both TPA and CYFRA 21.1 serum levels at diagnosis were reliable predictors of overall survival, high values of these markers being associated with a worse prognosis.     

Cellulase Facilitated Squash Preparations of Vicia Faba Chromosomes for Quinacrine Fluorescent Staining

This paper is partially based on work performed under contract with the U. S. Atomic Energy Commission at The University of Rochester Atomic Energy Project and has bcen assigned Report No. UR-3490-238, and has also been partially supported by Grant USPHS GM0933.     

Carbohydrate translocation in sugar beet petioles in relation to petiolar respiration and adenosine 5'-triphosphate

Earlier studies have shown that the retarding effect of low petiolar temperatures on sucrose transport through sugar beet (Beta vulgaris L.) petioles is markedly time-dependent. Although the initial effect of chilling the petiole to near 0 C is severely inhibitory, translocation rates soon recover (usually within about 2 hours) to values at or near the control rate. In the present studies, selected metabolic parameters were measured simultaneously with translocation. No stoichiometric relationships among petiolar sucrose transport, petiolar respiration (CO₂ production), and calculated petiolar ATP turnover rates were evident. It appears that the major sources of energy input energizing carbohydrate transport in sieve tubes function mainly at either loading or unloading sites and not at the level of individual sieve-tube elements.     

STRUCTURAL EVIDENCE FOR A THEORY OF VEIN LOADING OF TRANSLOCATE

The ultrastructure of minor veins of Beta vulgaris was examined with reference to possible models for vein loading of translocate. Structural evidence was reviewed in the light of recent physiological observations as a basis for proposed mechanisms. Features which appeared to be of significance in formulating a model included the open, differentiated sieve plates, the predominance of organelle-rich parenchyma cells, and the branched plasmodesmata connecting sieve tubes and parenchyma cells. The resulting model views cell to cell movement of photosynthate via the symplast to the specialized parenchyma cells. The actively accumulated sucrose appears to move from the specialized parenchyma cells into the sieve tubes via plasmodesmata in the lateral and end walls.