Experimental Radiosensitization and Molecular Prediction of Chemoradiotherapy Response in Rectal Cancer

In Norway, the annual incidence of rectal cancer exceeds 1000 cases. Although surgery remains the principal treatment modality in this common disease, recent studies have highlighted the central role of chemoradiotherapy (CRT) in conjunction with surgical resection to optimize local control and improve outcome. Nevertheless, in locally advanced rectal cancer (LARC), tumor response to preoperative CRT may vary considerably; in addition, this treatment delays surgery and has substantial acute and long-term adverse effects. Hence, in the contemporary management of LARC, the possibility of improving CRT efficacy and predicting CRT response to enable treatment stratification would be a critical achievement. The study aims were to evaluate new drugs for radiosensitizing efficacy in relevant preclinical models and to identify functional biomarkers predictive of tumor responsiveness to preoperative CRT in LARC. Oxaliplatin is a chemotherapeutic currently under investigation in CRT trials for rectal cancer. In an experimental in vivo model of human colorectal carcinoma, however, this drug did not convincingly improve the radiosensitizing effect of a standard CRT regimen, implying that integration of oxaliplatin into combined modality treatment of rectal cancer should remain controversial when conclusive clinical evidence is lacking. On the contrary, vorinostat, a histone deacetylases inhibitor, enhanced radiation response of experimental colorectal carcinoma models as evaluated by in vitro clonogenicity and in vivo tumor growth delay, suggesting that this class of therapeutics might be a supplement to current CRT strategies in rectal cancer. Finally, recognizing that kinase activity is a predictor of radiation response in tumor models, multiplex kinase activity profiles of diagnostic tumor biopsies from LARC patients were correlated with the individual tumor responses to preoperative CRT, and kinase pathways descriptive of poor-responding tumors were identified

Egg buoyancy variability in local populations of Atlantic cod (Gadus morhua)

http://dx.doi.org/10.1007/s00227-012-1984-8Previous studies have found strong evidences for Atlantic cod (Gadus morhua) egg retention in fjords, which are caused by the combination of vertical salinity structure, estuarine circulation, and egg specific gravity, supporting small-scaled geographical differentiations of local populations. Here, we assess the variability in egg specific gravity for selected local populations of this species, that is, two fjord-spawning populations and one coastal-spawning population from Northern Norway (66–71°N/10–25°E). Eggs were naturally spawned by raised broodstocks (March to April 2009), and egg specific gravity was measured by a density-gradient column. The phenotype of egg specific gravity was similar among the three local populations. However, the associated variability was greater at the individual level than at the population level. The noted gradual decrease in specific gravity from gastrulation to hatching with an increase just before hatching could be a generic pattern in pelagic marine fish eggs. This study provides needed input to adequately understand and model fish egg dispersal

Tracking oocyte development and the timing of skipped spawning for north-east Arctic haddock (Melanogrammus aeglefinus)

The present study tracked oocyte development over 9 months and noted incidences of ‘skipping’, i.e., adults terminating their upcoming reproductive cycle, in field-caught north-east Arctic (NEA) haddock (Melanogrammus aeglefinus), currently the largest stock of this species. Applications of advanced image and histological techniques revealed the presence of cortical alveoli oocytes (CAO), which prevailed as the most advanced oocyte phase for 4–5 months. This new finding of an extended and early appearance of CAOs in this gadoid was supported by that vitellogenesis first started to appear 3 months later. The subsequent oocyte growth trajectories indicated that larger individuals [total length (TL) = 70 cm] typically spawn in the order of 3 weeks earlier than the smaller ones (TL = 40 cm). The spawning season appeared stretched over about 3 months. The majority of skipping females arrested oocyte growth at the CAO phase followed by atretic reabsorption. Compared to those individuals maturing for the spawning season, ‘skippers’ generally exhibited lower body condition, characterized also by relatively lower liver sizes at the time of the main spawning season. This study demonstrated well-developed skipping dynamics, but also that the CAO period, i.e., when skipping takes place, may be exceedingly long in this commercially valuable gadoid and that its reproductive cycle in many ways deviates from that of the data-rich, sympatric NEA cod (Gadus morhua).publishedVersio

Is it possible to photoperiod manipulate spawning time in planktivorous fish ? A long-term experiment on Atlantic herring

The oocyte development (vitellogenesis) of individual fish is highly dependent upon their physiology which is influenced by both intrinsic and extrinsic factors. Thus, if individuals encounter poor biophysical conditions, they will likely be unable to reproduce. The photoperiod is an external factor that is constant between years but with increasing intra-annual (seasonal) variation polewards. In high-latitude marine environments, several ecological processes are strongly photic entrained, e.g., the planktonic spring bloom. However, it is still unclear whether day length or planktonic peaks (feeding opportunity) is the main timer or regulator behind gametogenesis not only for teleost piscivores but also for planktivores living in these waters. Hence, we experimentally investigated the role of photoperiod steering vitellogenesis in the planktivorous Atlantic herring (Clupea harengus), rearing larvae up to the mature adult stage. We imposed a natural and 6-month offset photoperiod hypothesising that vitellogenesis is entrained by this photic zeitgeber. The results of our experiment clearly demonstrated that herring have a strong photic zeitgeber acting upon vitellogenesis according to the experienced photoperiod. Thus, the Offset Group showed a displacement in vitellogenesis of 6 months. The second hypothesis that feeding opportunities play a clear role in assisting this photic zeitgeber in Atlantic herring could be rejected. This clarification supports that the survival potential of the larvae is the main selection pressure in operation in these respects, i.e., rather than the extent of feeding opportunities of the adults.publishedVersio

Increasing temperature and prey availability affect the growth and swimming kinematics of Atlantic herring (Clupea harengus) larvae

Climate change will increase the magnitude and duration of warming events and the variability in the phenology and abundance of available prey to the early life stages of fish. These factors influence physiological, behavioral and ecological processes, impacting growth, development and survival. Using a fully factorial design with two prey-availability treatments (1200 prey items L−1 (high prey abundance) or 40 prey items L−1 (low prey abundance)) under three temperature regimes (8, 10 and 12°C), the swimming kinematics of 6-week old spring-spawning Atlantic herring larvae were examined using silhouette video photography. Higher temperatures combined with food limitation significantly decreased the growth and swimming kinematics of larval herring, with the most negative effect observed in larvae reared at 12°C and exposed to low food abundances. Specifically, larvae displayed reduced locomotory behaviors and reduced vertical movements. By contrast, larvae reared at high prey abundance and at 12°C displayed more active swimming and exploratory behavior, as evidenced by an increase in both locomotory behavior and vertical and horizontal turn angles, suggesting increased motivation to search for food. This research highlights the importance of determining to what degree fish larvae are sensitive to changes in temperature and how these changes might be further influenced by food availability.publishedVersio

Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition

BACKGROUND: The tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death. METHODS: Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed. RESULTS: In addition to G(2)/M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G(1 )phase cells). In contrast, histone acetylation was associated with complete depletion of the G(1 )population of cells with functional p53 but accumulation of both G(1 )and G(2)/M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G(2)/M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified. CONCLUSION: In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified

Experimental parameterisation of principal physics in buoyancy variations of marine teleost eggs

It is generally accepted that the high buoyancy of pelagic marine eggs is due to substantial influx of water across the cell membrane just before ovulation. Here we further develop the theoretical basis by applying laboratory observations of the various components of the fertilized egg in first-principle equations for egg specific gravity (ρegg) followed by statistical validation. We selected Atlantic cod as a model animal due to the affluent amount of literature on this species, but also undertook additional dedicated experimental works. We found that specific gravity of yolk plus embryo is central in influencing ρegg and thereby the buoyancy. However, our established framework documents the effect on ρegg of the initial deposition of the heavy chorion material in the gonad prior to spawning. Thereafter, we describe the temporal changes in ρegg during incubation: Generally, the eggs showed a slight rise in ρegg from fertilization to mid-gastrulation followed by a gradual decrease until full development of main embryonic organs just before hatching. Ontogenetic changes in ρegg were significantly associated with volume and mass changes of yolk plus embryo. The initial ρegg at fertilization appeared significantly influenced by the chorion volume fraction which is determined by the combination of the final chorion volume of the oocyte and of the degree of swelling (hydrolyzation) prior to spawning. The outlined principles and algorithms are universal in nature and should therefore be applicable to fish eggs in general

Bio-physical properties of Norwegian coastal cod eggs

Vertical distribution of fish eggs and larvae is a key factor for transport and retention of the offspring, and for problems linked to mixing/separation between populations, and hence for mechanism maintaining genetic differentiation among local populations, in combination with high site fidelity and natal homing of older cod. The vertical distribution is determined by the combined effects of local salinity structure of the ambient water and by the specific gravity of the eggs. The specific gravity of the eggs is determined their bio-physical characteristics. We have studied bio-physical properties of Norwegian Coastal cod (Gadus morhua) eggs from different areas (Porsangen, Tysfjord, and Helgeland)