Death by design: mechanism and control of apoptosis

Active cellular suicide by apoptosis plays important roles in animal development, tissue homeostasis and a wide variety of diseases, including cancer, AIDS, stroke and many neurodegenerative disorders. A central step in the execution of apoptosis is the activation of an unusual class of cysteine proteases, termed caspases, that are widely expressed as inactive zymogens. Originally, the mechanisms for regulating the caspase-based cell death programme seemed to be different in Caenorhabditis elegans, mammals and insects. However, recent results suggest that these apparent differences in the control of cell death reflect our incomplete knowledge, rather than genuine mechanistic differences between different organisms.     

Death by design: mechanism and control of apoptosis

Active cellular suicide by apoptosis plays important roles in animal development, tissue homeostasis and a wide variety of diseases, including cancer, AIDS, stroke and many neurodegenerative disorders. A central step in the execution of apoptosis is the activation of an unusual class of cysteine proteases, termed caspases, that are widely expressed as inactive zymogens. Originally, the mechanisms for regulating the caspase-based cell death programme seemed to be different in Caenorhabditis elegans, mammals and insects. However, recent results suggest that these apparent differences in the control of cell death reflect our incomplete knowledge, rather than genuine mechanistic differences between different organisms.     

Cost-Effectiveness of Breast Cancer Control Strategies in Central America: The Cases of Costa Rica and Mexico

This paper reports the most cost-effective policy options to support and improve breast cancer control in Costa Rica and Mexico. Total costs and effects of breast cancer interventions were estimated using the health care perspective and WHO-CHOICE methodology. Effects were measured in disability-adjusted life years (DALYs) averted. Costs were assessed in 2009 United States Dollars (US$). To the extent available, analyses were based on locally obtained data. In Costa Rica, the current strategy of treating breast cancer in stages I to IV at a 80% coverage level seems to be the most cost-effective with an incremental cost-effectiveness ratio (ICER) of US$4,739 per DALY averted. At a coverage level of 95%, biennial clinical breast examination (CBE) screening could improve Costa Rica''s population health twofold, and can still be considered very cost-effective (ICER US$5,964/DALY). For Mexico, our results indicate that at 95% coverage a mass-media awareness raising program (MAR) could be the most cost-effective (ICER US$5,021/DALY). If more resources are available in Mexico, biennial mammography screening for women 50–70 yrs (ICER US$12,718/DALY), adding trastuzumab (ICER US$13,994/DALY) or screening women 40–70 yrs biennially plus trastuzumab (ICER US$17,115/DALY) are less cost-effective options. We recommend both Costa Rica and Mexico to engage in MAR, CBE or mammography screening programs, depending on their budget. The results of this study should be interpreted with caution however, as the evidence on the intervention effectiveness is uncertain. Also, these programs require several organizational, budgetary and human resources, and the accessibility of breast cancer diagnostic, referral, treatment and palliative care facilities should be improved simultaneously. A gradual implementation of early detection programs should give the respective Ministries of Health the time to negotiate the required budget, train the required human resources and understand possible socioeconomic barriers.     

POPULATION PARAMETERS AND PHOTOSYNTHETIC CAPABILITIES OF CORALLINE RHODOLITHS: BIOGEOGRAPHIC IMPLICATIONS

Rhodoliths are bed forming, unattached coralline algae that incorporate large quantities of carbonate into their thalli in oceans worldwide. Lithophyllum margaritae and Neogoniolithon tricotomun are common Rhodoliths from the Gulf of California, however, little is known about their biogeographic distribution, and their ecological and physiological characteristics. As a consequence, the objective of this study was to define the temporal population dynamics, growth rates and photosynthetic capabilities of L. margaritae and N. tricotomun from the Gulf of California. The Gulf of California is characterized by annual temperature fluctuations that can exceed 20° C. Rhodolith beds exceeding one km in length were observed from the intertidal zone to a depth of approximately 20 m at the southern Gulf. Percent cover estimates for spherical unattached individuals of L. margaritae and N. tricotomun ranged from 10 to 100%. Growth rates were determined by staining the rhodoliths with Alizarine red and evaluating the linear increment of calcium carbonate after an incubation period in the field. Annual growth rates averaged 1.8 mm year⁻¹ in L. margaritae and 3.4 mm year⁻¹ in N. tricotomun , however, growth rates varied seasonally. The photosynthetic response of both species as a function of temperature was evaluated in the laboratory from 10° to 30° C. Maximum net photosynthetic rates peaked at approximately 25 to 30° C in both species, suggesting that maximum growth rates occur during the warmest months of the year. These results lead to a better understanding of the biogeographic ranges of subtidal coralline algae.     

Structural requirements for inhibitory effects of bisphenols on the activity of the sarco/endoplasmic reticulum calcium ATPase

Bisphenols (BPs) are a class of small organic compounds with widespread industrial applications. Previous studies have identified several BPs that interfere with the activity of the ion-translocating enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). In order to define the molecular determinants of BP-mediated SERCA inhibition, we conducted enzyme activity assays with rabbit SERCA to determine the inhibitory potencies of 27 commercially available BPs, which were the basis for structure–activity relationships. The most potent BPs inhibited SERCA at low micromolar concentrations and carried at their two phenyl rings multiple non-polar substituents, such as small alkyl groups or halides. Furthermore, the presence of methyl groups or a cyclohexyl group at the central carbon atom connecting the two phenyl moieties correlated with good potencies. For a characterization and visualization of enzyme/inhibitor interactions, molecular docking was performed, which suggested that hydrogen bonding with Asp254 and hydrophobic interactions were the major driving forces for BP binding to SERCA. Calcium imaging studies with a selection of BPs showed that these inhibitors were able to increase intracellular calcium levels in living human cells, a behavior consistent with that of a SERCA inhibitor.     

Shaping organisms with apoptosis

Programmed cell death is an important process during development that serves to remove superfluous cells and tissues, such as larval organs during metamorphosis, supernumerary cells during nervous system development, muscle patterning and cardiac morphogenesis. Different kinds of cell death have been observed and were originally classified based on distinct morphological features: (1) type I programmed cell death (PCD) or apoptosis is recognized by cell rounding, DNA fragmentation, externalization of phosphatidyl serine, caspase activation and the absence of inflammatory reaction, (2) type II PCD or autophagy is characterized by the presence of large vacuoles and the fact that cells can recover until very late in the process and (3) necrosis is associated with an uncontrolled release of the intracellular content after cell swelling and rupture of the membrane, which commonly induces an inflammatory response. In this review, we will focus exclusively on developmental cell death by apoptosis and its role in tissue remodeling.     

Variation in Photosynthetic Performance Relative to Thallus Microhabitat Heterogeneity in Lithothamnion australe (Rhodophyta,Corallinales) Rhodoliths

Rhodoliths are free‐living, coralline algae that create heterogeneous structure over sedimentary habitats. These fragile ecosystems are threatened by anthropogenic disturbances that reduce their size and three‐dimensional structural complexity. We investigated how physical disturbance from boat moorings affects photosynthetic performance in the rhodolith Lithothamnion australe. Photosynthetic parameters were measured for intact rhodoliths and crushed rhodolith fragments of two sizes (ca. 1 and 2 cm diameter), while chlorophyll fluorescence was measured at the surface of rhodoliths of these two sizes, between the interior branches of the larger rhodoliths, and at the surface of 52 various sized (0.4–3.5 cm diameter) rhodoliths. Gross productivity and net productivity were 15% and 36% higher, respectively, in the smaller L. australe, while respiration was 10% higher in the larger individuals. Thallus crushing reduced gross productivity by 20% and 41%, and net productivity by 9% and 14% in the smaller and larger rhodoliths, respectively. It also reduced respiration by 33% and 60% in the smaller and larger rhodoliths, respectively. Fluorescence parameters were all greater at the surface of the larger L. australe than the smaller individuals, and greater at the surface than in the interior parts of the larger individuals. Across a range of rhodolith sizes, surface fluorescence parameters were at their maxima in 1.54 to 2.32 cm diameter individuals. These results show that L. australe’s complex structure creates heterogeneity in photosynthesis and respiration between their surface and interior parts and among rhodolith sizes. This information can help predict how rhodoliths may respond to disturbance and environmental stressors.     

Immunotherapy of intraperitoneal cancer with interleukin 2 and lymphokine-activated killer cells reduces tumor load and prolongs survival in murine models

The control of malignancy disseminated within the peritoneal cavity is an important problem in the management of low-grade gastrointestinal and ovarian neoplasms. A model of peritoneal carcinomatosis in the mouse was used to investigate the potential of lymphokine-activated killer (LAK) cells and exogenous interleukin 2 (IL-2) to control intraperitoneal tumor. LAK cells are splenocytes activated in vitro by IL-2. C57BL/6 mice were injected intraperitoneally with a lethal inoculum of syngeneic MCA-105 tumor. Three days later, the established tumor was treated with adoptively transferred LAK cells and/or exogenous IL-2 administration. LAK cells alone were ineffective in reducing intraperitoneal tumor. Administration of IL-2 alone resulted in limited tumor reduction. Treatment with exogenous IL-2 in conjunction with LAK cells resulted in the greatest reduction of intraperitoneal tumor. The larger the number of LAK cells given, the greater the reduction in tumor. Frequent intraperitoneal bolus administration of IL-2 was more effective than a single daily intraperitoneal injection and intraperitoneal administration of IL-2 and LAK was more effective than systemic treatments. Marked prolongation of life was seen in mice treated with LAK cells plus exogenous IL-2. We conclude that intraperitoneal LAK cells plus exogenous IL-2 is an effective treatment regimen for reducing intraperitoneal tumor in this murine model.