Proteomic and Phosphoproteomic Reprogramming in Epithelial Ovarian Cancer Metastasis.

Epithelial ovarian cancer (EOC) is a high-risk cancer presenting with heterogeneous tumors. The high incidence of EOC metastasis from primary tumors to nearby tissues and organs is a major driver of EOC lethality. We used cellular models of spheroid formation and readherence to investigate cellular signaling dynamics in each step toward EOC metastasis. In our system, adherent cells model primary tumors, spheroid formation represents the initiation of metastatic spread, and readherent spheroid cells represent secondary tumors. Proteomic and phosphoproteomic analyses show that spheroid cells are hypoxic and show markers for cell cycle arrest. Aurora kinase B abundance and downstream substrate phosphorylation are significantly reduced in spheroids and readherent cells, explaining their cell cycle arrest phenotype. The proteome of readherent cells is most similar to spheroids, yet greater changes in the phosphoproteome show that spheroid cells stimulate Rho-associated kinase 1 (ROCK1)-mediated signaling, which controls cytoskeletal organization. In spheroids, we found significant phosphorylation of ROCK1 substrates that were reduced in both adherent and readherent cells. Application of the ROCK1-specific inhibitor Y-27632 to spheroids increased the rate of readherence and altered spheroid density. The data suggest ROCK1 inhibition increases EOC metastatic potential. We identified novel pathways controlled by Aurora kinase B and ROCK1 as major drivers of metastatic behavior in EOC cells. Our data show that phosphoproteomic reprogramming precedes proteomic changes that characterize spheroid readherence in EOC metastasis.

The Effects of Cold Exposure, Hypoxia, and Fatigue on Pistol Marksmanship and Target Engagement Decision Making in Trained Marksmen.

ABSTRACT: Segovia, M, Salmon, OF, Ugale, C, and Smith, CM. The effects of cold exposure, hypoxia, and fatigue on pistol marksmanship and target engagement decision making in trained marksmen. J Strength Cond Res 38(11): e686-e694, 2024-This study aimed to examine the effects of cold exposure, hypoxia, and fatigue on pistol marksmanship and target engagement in trained marksmen. Twelve healthy subjects (mean ± SD age: 28.8 ± 4.0 years) performed 3 testing visits under normal/normoxic [Norm 21 ] (24° C; 21% FiO 2 ), cold/normoxic [Cold 21 ] (10° C; 21% FiO 2 ), and cold/hypoxic [Cold 14 ] (10° C; FiO 2 : 14.3) conditions. Pistol marksmanship and target engagement were assessed through draw time (DT) and shoot-no-shoot (SNS) courses of fire. The 2 protocols were performed before (T preF ) and immediately after (T postF ) a sandbag deadlift fatiguing protocol. Significance was set at p < 0.05. Significant condition × time interactions ( p = 0.01-0.03) were found for accuracy SNS (SNS acc ), misses SNS (SNS miss ), and total shots SNS (SNS tot ). Follow-up analyses indicated that SNS acc increased by 14.3% ( p = 0.03), SNS miss decreased by 34.7% ( p = 0.02), and SNS tot decreased by 10.6% ( p = 0.04) from T preF to T postF during the Cold 21 condition alone. No significance was found for these in the Norm 21 ( p = 0.08-0.22) or Cold 14 ( p = 0.18-0.47) conditions. Total time (SNS T ) to completion of the SNS ( p = 0.09) and DT ( p = 0.14) showed no significance across time or condition. Significant difference across time for Cold 14 ( p = 0.03-0.02) for reaction time was found. Exercise likely resulted in increased thermogenesis that improved tactically relevant motor skills including SNS acc , decreased SNS miss , and SNS tot in Cold 21 , but not Cold 14 . The additive effect of hypoxia coupled with exercise in the Cold 14 condition did not improve tactical performance, suggesting multi-stressor environments result in competing physiological responses. Tactical strength and conditioning specialists as well as operators should aim to improve thermoregulation during Cold 21 conditions, with exercise as a possible intervention.

Neuromuscular and Muscle Tissue Hemodynamic Responses When Exposed to Normobaric Hypoxia during Lower-Body Fatiguing Muscle Actions.

OBJECTIVES: This study examined effects of acute hypoxia on the neuromuscular responses (electromyographic (EMG) amplitude and EMG frequency) and localized muscle tissue oxygenated hemoglobin (oxygenated hemoglobin (OxyHb), deoxygenated hemoglobin (DeoxyHb), total hemoglobin (TotalHb), and muscle tissue oxygenation saturation (StO2) during the process of fatigue. METHODS: Fifteen male participants (21.4±2.8yr) performed leg extension repetitions to failure at 70% 1-repetition maximum until volitional exhaustion under Normoxic (FiO2:21%) and Hypoxic (FiO2:12.9%) conditions. Electromyographic amplitude, EMG frequency, OxyHb, DeoxyHb, TotalHb, and StO2 were measured from the vastus lateralis at Initial, 20, 40, 60, 80, and 100% of the repetitions to failure. RESULTS: There was no significant difference in the patterns of responses for EMG amplitude, OxyHb, or DeoxyHb between Normoxia and Hypoxia. For EMG frequency, Hypoxia was greater than Normoxia and decreased with fatigue. TotalHb and StO2 were greater under Normoxia compared to Hypoxia. The patterns of responses for EMG amplitude, DeoxyHb, and TotalHb increased throughout the repetitions to failure. OxyHb and StO2 exhibited decreases throughout the repetitions to failure for Normoxic and Hypoxic conditions. CONCLUSION: The EMG and oxygenation measurements non-invasively suggest a sympathoexcitatory response (indicated by EMG frequency) and provided complimentary information regarding the process of fatigue in normoxic and hypoxic states.

The impact of cold, hypoxia, and physical exertion on pistol accuracy and tactical performance.

The purpose of this study was to examine the impact of independent cold and combined cold and hypoxic exposures on operational-specific task performance including pistol marksmanship, pistol magazine reload ability, and subjective and objective thermal indices before and after a whole-body physical exertional task. Twelve participants were exposed to Thermoneutral Normoxic (24 °C; FiO2 21%), Cold Normoxic (10 °C; FiO2 21%), and Cold Hypoxic (10 °C; FiO2 14%) conditions for 30min before performing pistol marksmanship at distances of 6.40 and 13.72m and a pistol magazine reload task before and after 3 sets of sandbag deadlifts at 50% body mass. Thermal perception and hand temperatures were collected before and after the physical exertion task. There were no significant differences in Pistol Accuracy performance at distances of 6.40 and 13.72m due to physical exertion, cold, or hypoxia. Following physical exertion, Pistol Accuracy was similar between Thermoneutral and Cold Normoxic conditions but lead to 17% and a 10% reduction in performance during the Cold Hypoxic condition, compared to Thermoneutral and Cold Normoxic conditions. There was no change in Pistol Accuracy for the Thermoneutral Normoxic condition. The pistol magazine reload task was not impacted by physical exertion, but there was a reduction in performance in Cold Normoxic 21% (4.04s) and Cold Hypoxic 16% (3.08s) conditions. Physical exertion did not impact hand temperature but did increase thermal perception scores for all conditions. These findings indicate that cold exposure reduced both tactical dexterity and pistol marksmanship, however, physical exertion may offset these deficits via an increase in thermal perception. Additionally, hypoxemia was the primary mediator of marksmanship performance in cold hypoxic environments following an acute bout of physical exertion. Thus, in cold mountainous environments, marksmen should be aware of their elevation and utilize brief episodes of physical activity to enhance their thermal state when marksmanship is a priority for operational success.

Changes in Neuromuscular Response Patterns After 4 Weeks of Leg Press Training During Isokinetic Leg Extensions.

ABSTRACT: Salmon, OF, Housh, TJ, Hill, EC, Keller, JL, Anders, JPV, Johnson, GO, Schmidt, RJ, and Smith, CM. Changes in neuromuscular response patterns after 4 weeks of leg press training during isokinetic leg extensions. J Strength Cond Res 37(7): e405-e412, 2023-The purpose of this study was to identify velocity-specific changes in electromyographic root mean square (EMG RMS), EMG frequency (EMG MPF), mechanomyographic RMS (MMG RMS), and MMG MPF during maximal unilateral isokinetic muscle actions performed at 60° and 240°·s -1 velocities within the right and left vastus lateralis (VL) after 4 weeks of dynamic constant external resistance (DCER) bilateral leg press training. Twelve resistance-trained men (age: mean ± SD = 21.4 ± 3.6 years) visited the laboratory 3d·wk -1 to perform resistance training consisting of 3 sets of 10 DCER leg presses. Four, three-way analysis of variance were performed to evaluate changes in neuromuscular responses (EMG RMS, EMG MPF, MMG RMS, and MMG MPF) from the right and left VL during 1 single-leg maximal isokinetic leg extension performed at 60° and 240°·s -1 before and after 4 weeks of DCER leg press training ( p < 0.05). The results indicated a 36% increase in EMG RMS for the right leg, as well as a 23% increase in MMG RMS and 10% decrease in MMG MPF after training, collapsed across velocity and leg. In addition, EMG RMS was 65% greater in the right leg than the left leg following training, whereas EMG MPF was 11% greater for the left leg than the right leg throughout training. Thus, 4 weeks of DCER leg press training provides sufficient stimuli to alter the neuromuscular activation process of the VL but not velocity-specific neuromuscular adaptations in trained males.

Implications for the conservation of deep-water corals in the face of multiple stressors: A case study from the New Zealand region.

The waters around New Zealand are a global hotspot of biodiversity for deep-water corals; approximately one sixth of the known deep-water coral species of the world have been recorded in the region. Deep-water corals are vulnerable to climate-related stressors and from the damaging effects of commercial fisheries. Current protection measures do not account for the vulnerability of deep-water corals to future climatic conditions, which are predicted to alter the distribution of suitable habitat for them. Using recently developed habitat suitability models for 12 taxa of deep-water corals fitted to current and future seafloor environmental conditions (under different future climatic conditions: SSP2 - 4.5 and SSP3 - 7.0) we explore possible levels of spatial protection using the decision-support tool Zonation. Specifically, we assess the impact of bottom trawling on predictions of current distributions of deep-water corals, and then assess the effectiveness of possible protection for deep-water corals, while accounting for habitat refugia under future climatic conditions. The cumulative impact of bottom trawling was predicted to impact all taxa, but particularly the reef-forming corals. Core areas of suitable habitat were predicted to decrease under future climatic conditions for many taxa. We found that designing protection using current day predictions alone, having accounted for the impacts of historic fishing impacts, was unlikely to provide adequate conservation for deep water-corals under future climate change. Accounting for future distributions in spatial planning identified areas which may provide climate refugia whilst still providing efficient protection for current distributions. These gains in conservation value may be particularly important given the predicted reduction in suitable habitat for deep-water corals due to bottom fishing and climate change. Finally, the possible impact that protection measures may have on deep-water fisheries was assessed using a measure of current fishing value (kg km-2 fish) and future fishing value (predicted under future climate change scenarios).

Apical Node Involvement Does Not Influence Prognosis After Potentially Curative Resection for Stage III Colorectal Cancer: A Competing Risks Analysis.

OBJECTIVE: To examine the independent prognostic value of ALN status in patients with stage III CRC. SUMMARY OF BACKGROUND DATA: Early CRC staging classified nodal involvement by level of involved nodes in the operative specimen, including both locoregional and apical node status, in contrast to the American Joint Committee on Cancer/tumor nodes metastasis (TNM) system where tumors are classified by the number of nodes involved. Whether ALN status has independent prognostic value remains controversial. METHODS: Consecutive patients who underwent curative resection for Stage III CRC from 1995 to 2012 at Concord Hospital, Sydney, Australia were studied. ALN status was classified as: (i) ALN absent, (ii) ALN present but not histologically involved, (iii) ALN present and involved. Outcomes were the competing risks incidence of CRC recurrence and CRC-specific death. Associations between these outcomes and ALN status were compared with TNM N status results. RESULTS: In 706 patients, 69 (9.8%) had an involved ALN, 398 (56.4%) had an uninvolved ALN and 239 (33.9%) had no ALN identified. ALN status was not associated with tumor recurrence [adjusted hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.84-1.26] or CRC-specific death (HR 1.14, CI 0.91-1.43). However, associations persisted between TNM N-status and both recurrence (HR 1.58, CI 1.21-2.06) and CRC-specific death (HR 1.59, CI 1.19-2.12). CONCLUSIONS: No further prognostic information was conferred by ALN status in patients with stage III CRC beyond that provided by TNM N status. ALN status is not considered to be a useful additional component in routine TNM staging of CRC.

Predicting the effects of climate change on deep-water coral distribution around New Zealand-Will there be suitable refuges for protection at the end of the 21st century?

Deep-water corals are protected in the seas around New Zealand by legislation that prohibits intentional damage and removal, and by marine protected areas where bottom trawling is prohibited. However, these measures do not protect them from the impacts of a changing climate and ocean acidification. To enable adequate future protection from these threats we require knowledge of the present distribution of corals and the environmental conditions that determine their preferred habitat, as well as the likely future changes in these conditions, so that we can identify areas for potential refugia. In this study, we built habitat suitability models for 12 taxa of deep-water corals using a comprehensive set of sample data and predicted present and future seafloor environmental conditions from an earth system model specifically tailored for the South Pacific. These models predicted that for most taxa there will be substantial shifts in the location of the most suitable habitat and decreases in the area of such habitat by the end of the 21st century, driven primarily by decreases in seafloor oxygen concentrations, shoaling of aragonite and calcite saturation horizons, and increases in nitrogen concentrations. The current network of protected areas in the region appear to provide little protection for most coral taxa, as there is little overlap with areas of highest habitat suitability, either in the present or the future. We recommend an urgent re-examination of the spatial distribution of protected areas for deep-water corals in the region, utilising spatial planning software that can balance protection requirements against value from fishing and mineral resources, take into account the current status of the coral habitats after decades of bottom trawling, and consider connectivity pathways for colonisation of corals into potential refugia.

Terrestrial dissolved organic matter inflow drives temporal dynamics of the bacterial community of a subarctic estuary (northern Baltic Sea).

Climate change is projected to cause increased inflow of terrestrial dissolved organic matter to coastal areas in northerly regions. Estuarine bacterial community will thereby receive larger loads of organic matter and inorganic nutrients available for microbial metabolism. The composition of the bacterial community and its ecological functions may thus be affected. We studied the responses of bacterial community to inflow of terrestrial dissolved organic matter in a subarctic estuary in the northern Baltic Sea, using a 16S rRNA gene metabarcoding approach. Betaproteobacteria dominated during the spring river flush, constituting ~ 60% of the bacterial community. Bacterial diversity increased as the runoff decreased during summer, when Verrucomicrobia, Betaproteobacteria, Bacteroidetes, Gammaproteobacteria and Planctomycetes dominated the community. Network analysis revealed that a larger number of associations between bacterial populations occurred during the summer than in spring. Betaproteobacteria and Bacteroidetes populations appeared to display similar correlations to environmental factors. In spring, freshly discharged organic matter favoured specialists, while in summer a mix of autochthonous and terrestrial organic matter promoted the development of generalists. Our study indicates that increased inflows of terrestrial organic matter-loaded freshwater to coastal areas would promote specialist bacteria, which in turn might enhance the transformation of terrestrial organic matter in estuarine environments.

Australian forests, megafires and the risk of dwindling carbon stocks.

Over the Austral spring and summer of 2019/20 > 7 million ha of Eucalyptus forest and woodland, including some of Australia's most carbon dense ecosystems, were burnt on the east coast of Australia. We estimated bootstrapped mean CO2 emissions of c. 0.67 Pg, with other available estimates ranging from 0.55 to 0.85 Pg. Eucalyptus forests are renowned for their ability to resist and recover from wildfire so it would be expected that emitted CO2 will be reabsorbed. The combination of drought and frequent fires is likely reducing the capacity to recover from the fire so future Australian forests may store less carbon. Broadscale prescribed burning is a widely promoted approach to reduce uncontrolled wildfires, yet the benefits for the management of carbon stores are controversial. Prescribed burning can reduce carbon losses from subsequent wildfire, yet the "carbon costs" of it may equal or outweigh the "carbon benefits" in reduced wildfire emissions. Likewise, mechanical thinning of vegetation to reduce fuel loads also carries heavy carbon costs with uncertain carbon benefits. Research involving empirical measurements, modelling and a mix of large-scale management intervention is urgently required to determine what interventions can maximise carbon storage in the face of climate change-driven fires.

Recurrence and colon cancer-specific death in patients with large bowel obstruction requiring urgent operation: a competing risks analysis.

AIM: Clinical presentation with large bowel obstruction has been proposed as a predictor of poor long-term oncological outcomes after resection for colorectal cancer. This study examines the association between obstruction and recurrence and cancer-specific death after resection for colon cancer. METHOD: Consecutive patients who underwent resection for colon cancer between 1995 and 2014 were drawn from a prospectively recorded hospital database with all surviving patients followed for at least 5 years. The outcomes of tumour recurrence and colon cancer-specific death were assessed by competing risks multivariable techniques with adjustment for potential clinical and pathological confounding variables. RESULTS: Recurrence occurred in 271 of 1485 patients who had a potentially curative resection. In bivariate analysis, obstruction was significantly associated with recurrence [hazard ratio (HR) 2.23, CI 1.52-3.26, p < 0.001] but this association became nonsignificant after adjustment for confounders (HR 1.53, CI 0.95-2.46, p = 0.080). Colon cancer-specific death occurred in 238 of 295 patients who had a noncurative resection. Obstruction was not significantly associated with cancer-specific death (HR 1.02, CI 0.72-1.45, p = 0.903). In patients who had a noncurative resection, the competing risks incidence of colon cancer-specific death was not significantly greater in obstructed than in unobstructed patients (HR 1.02, CI 0.72-1.45, p = 0.903). CONCLUSION: Whilst the immediate clinical challenge of an individual patient presenting with large bowel obstruction must be addressed by the surgeon, the patient's long-term oncological outcomes are unrelated to obstruction per se.

What Box: A task for assessing language lateralization in young children.

The assessment of active language lateralization in infants and toddlers is challenging. It requires an imaging tool that is unintimidating, quick to setup, and robust to movement, in addition to an engaging and cognitively simple language processing task. Functional Transcranial Doppler Ultrasound (fTCD) offers a suitable technique and here we report on a suitable method to elicit active language production in young children. The 34-second "What Box" trial presents an animated face "searching" for an object. The face "finds" a box that opens to reveal a to-be-labelled object. In a sample of 95 children (1 to 5 years of age), 81% completed the task-32% with ≥10 trials. The task was validated (ρ = 0.4) against the gold standard Word Generation task in a group of older adults (n = 65, 60-85 years of age), though was less likely to categorize lateralization as left or right, indicative of greater measurement variability. Existing methods for active language production have been used with 2-year-old children while passive listening has been conducted with sleeping 6-month-olds. This is the first active method to be successfully employed with infants through to pre-schoolers, forming a useful tool for populations in which complex instructions are problematic.

Suppression resource decisions are the dominant influence on containment of Australian forest and grass fires.

Fire agencies aim to contain wildfires before they impact on life, property and infrastructure and to reduce the risk of damage to the environment. Despite the large cost of suppression, there are few data on the success of suppression efforts under varying weather, fuel and resource scenarios. We examined over 2200 forest and 4600 grass fires in New South Wales, Australia to determine the dominant influences on the containment of wildfires. A random forest modelling approach was used to analyse the effect of a range of human and environmental factors. The number of suppression resources per area of fire were the dominant influence on the containment of both forest and grass fires. As fire weather conditions worsened the probability of containment decreased across all fires and as fuel loads and slope increased the probability of containment decreased for forest fires. Environmental controls limit the effectiveness of wildfire management. However, results suggest investment in suppression resources and strategic fuel management will increase the probability of containment.

Mapping and exploring variation in post-fire vegetation recovery following mixed severity wildfire using airborne LiDAR.

There is a public perception that large high-severity wildfires decrease biodiversity and increase fire hazard by homogenizing vegetation composition and increasing the cover of mid-story vegetation. But a growing literature suggests that vegetation responses are nuanced. LiDAR technology provides a promising remote sensing tool to test hypotheses about post-fire vegetation regrowth because vegetation cover can be quantified within different height strata at fine scales over large areas. We assess the usefulness of airborne LiDAR data for measuring post-fire mid-story vegetation regrowth over a range of spatial resolutions (10 × 10 m, 30 × 30 m, 50 × 50 m, 100 × 100 m cell size) and investigate the effect of fire severity on regrowth amount and spatial pattern following a mixed severity wildfire in Warrumbungle National Park, Australia. We predicted that recovery would be more vigorous in areas of high fire severity, because park managers observed dense post-fire regrowth in these areas. Moderate to strong positive associations were observed between LiDAR and field surveys of mid-story vegetation cover between 0.5-3.0 m. Thus our LiDAR survey was an apt representation of on-ground vegetation cover. LiDAR-derived mid-story vegetation cover was 22-40% lower in areas of low and moderate than high fire severity. Linear mixed-effects models showed that fire severity was among the strongest biophysical predictors of mid-story vegetation cover irrespective of spatial resolution. However much of the variance associated with these models was unexplained, presumably because soil seed banks varied at finer scales than our LiDAR maps. Dense patches of mid-story vegetation regrowth were small (median size 0.01 ha) and evenly distributed between areas of low, moderate and high fire severity, demonstrating that high-severity fires do not homogenize vegetation cover. Our results are relevant for ecosystem conservation and fire management because they: indicate that native vegetation are responsive and resilient to high-severity fire, and show the usefulness of remote sensing tools such as LiDAR to monitor post-fire vegetation recovery over large areas in situ.

Resolving future fire management conflicts using multicriteria decision making.

Management strategies to reduce the risks to human life and property from wildfire commonly involve burning native vegetation. However, planned burning can conflict with other societal objectives such as human health and biodiversity conservation. These conflicts are likely to intensify as fire regimes change under future climates and as growing human populations encroach farther into fire-prone ecosystems. Decisions about managing fire risks are therefore complex and warrant more sophisticated approaches than are typically used. We applied a multicriteria decision making approach (MCDA) with the potential to improve fire management outcomes to the case of a highly populated, biodiverse, and flammable wildland-urban interface. We considered the effects of 22 planned burning options on 8 objectives: house protection, maximizing water quality, minimizing carbon emissions and impacts on human health, and minimizing declines of 5 distinct species types. The MCDA identified a small number of management options (burning forest adjacent to houses) that performed well for most objectives, but not for one species type (arboreal mammal) or for water quality. Although MCDA made the conflict between objectives explicit, resolution of the problem depended on the weighting assigned to each objective. Additive weighting of criteria traded off the arboreal mammal and water quality objectives for other objectives. Multiplicative weighting identified scenarios that avoided poor outcomes for any objective, which is important for avoiding potentially irreversible biodiversity losses. To distinguish reliably among management options, future work should focus on reducing uncertainty in outcomes across a range of objectives. Considering management actions that have more predictable outcomes than landscape fuel management will be important. We found that, where data were adequate, an MCDA can support decision making in the complex and often conflicted area of fire management.

The potential for LiDAR technology to map fire fuel hazard over large areas of Australian forest.

Fuel load is a primary determinant of fire spread in Australian forests. In east Australian forests, litter and canopy fuel loads and hence fire hazard are thought to be highest at and beyond steady-state fuel loads 15-20 years post-fire. Current methods used to predict fuel loads often rely on course-scale vegetation maps and simple time-since-fire relationships which mask fine-scale processes influencing fuel loads. Here we use Light Detecting and Remote Sensing technology (LiDAR) and field surveys to quantify post-fire mid-story and crown canopy fuel accumulation and fire hazard in Dry Sclerophyll Forests of the Sydney Basin (Australia) at fine spatial-scales (20 × 20 m cell resolution). Fuel cover was quantified in three strata important for crown fire propagation (0.5-4 m, 4-15 m, >15 m) over a 144 km(2) area subject to varying fire fuel ages. Our results show that 1) LiDAR provided a precise measurement of fuel cover in each strata and a less precise but still useful predictor of surface fuels, 2) cover varied greatly within a mapped vegetation class of the same fuel age, particularly for elevated fuel, 3) time-since-fire was a poor predictor of fuel cover and crown fire hazard because fuel loads important for crown fire propagation were variable over a range of fire fuel ages between 2 and 38 years post-fire, and 4) fuel loads and fire hazard can be high in the years immediately following fire. Our results show the benefits of spatially and temporally specific in situ fuel sampling methods such as LiDAR, and are widely applicable for fire management actions which aim to decrease human and environmental losses due to wildfire.

The drivers of wildfire enlargement do not exhibit scale thresholds in southeastern Australian forests.

Wildfires are complex adaptive systems, and have been hypothesized to exhibit scale-dependent transitions in the drivers of fire spread. Among other things, this makes the prediction of final fire size from conditions at the ignition difficult. We test this hypothesis by conducting a multi-scale statistical modelling of the factors determining whether fires reached 10 ha, then 100 ha then 1000 ha and the final size of fires >1000 ha. At each stage, the predictors were measures of weather, fuels, topography and fire suppression. The objectives were to identify differences among the models indicative of scale transitions, assess the accuracy of the multi-step method for predicting fire size (compared to predicting final size from initial conditions) and to quantify the importance of the predictors. The data were 1116 fires that occurred in the eucalypt forests of New South Wales between 1985 and 2010. The models were similar at the different scales, though there were subtle differences. For example, the presence of roads affected whether fires reached 10 ha but not larger scales. Weather was the most important predictor overall, though fuel load, topography and ease of suppression all showed effects. Overall, there was no evidence that fires have scale-dependent transitions in behaviour. The models had a predictive accuracy of 73%, 66%, 72% and 53% accuracy at 10 ha, 100 ha, 1000 ha and final size scales. When these steps were combined, the overall accuracy for predicting the size of fires was 62%, while the accuracy of the one step model was only 20%. Thus, the multi-scale approach was an improvement on the single scale approach, even though the predictive accuracy was probably insufficient for use as an operational tool. The analysis has also provided further evidence of the important role of weather, compared to fuel, suppression and topography in driving fire behaviour.

Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer.

Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion. The initial phosphorylation site is a Tyr residue (Y14) present in the N-terminal A/B domain of P1- but not P2-driven HNF4α. Phospho-Y14 interacts with the Src SH2 domain, leading to the phosphorylation of two additional tyrosines in the ligand binding domain (LBD) in P1-HNF4α. Phosphomimetic mutants in the LBD decrease P1-HNF4α protein stability, nuclear localization and transactivation function. Immunohistochemical analysis of approximately 450 human colon cancer specimens (Stage III) reveals that P1-HNF4α is either lost or localized in the cytoplasm in approximately 80% of tumors, and that staining for active Src correlates with those events in a subset of samples. Finally, three SNPs in the human HNF4α protein, two of which are in the HNF4α F domain that interacts with the Src SH3 domain, increase phosphorylation by Src and decrease HNF4α protein stability and function, suggesting that individuals with those variants may be more susceptible to Src-mediated effects. This newly identified interaction between Src kinase and HNF4α has important implications for colon and other cancers.

KRAS mutations and CDKN2A promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer.

Colonic and rectal cancers differ in their clinicopathologic features and treatment strategies. Molecular markers such as gene methylation, microsatellite instability and KRAS mutations, are becoming increasingly important in guiding treatment decisions in colorectal cancer. However, their association with clinicopathologic variables and utility in the management of rectal cancer is still poorly understood. We analyzed CDKN2A gene methylation, CpG island methylator phenotype (CIMP), microsatellite instability and KRAS/BRAF mutations in a cohort of 381 rectal cancers with extensive clinical follow-up data. BRAF mutations (2%), CIMP-high (4%) and microsatellite instability-high (2%) were rare, whereas KRAS mutations (39%), CDKN2A methylation (20%) and CIMP-low (25%) were more common. Only CDKN2A methylation and KRAS mutations showed an association with poor overall survival but these did not remain significant when analyzed with other clinicopathologic factors. In contrast, this prognostic effect was strengthened by the joint presence of CDKN2A methylation and KRAS mutations, which independently predicted recurrence of cancer and was associated with poor overall and cancer-specific survival. This study has identified a subgroup of more aggressive rectal cancers that may arise through the KRAS-p16 pathway. It has been previously shown that an interaction of p16 deficiency and oncogenic KRAS promotes carcinogenesis in the mouse and is characterized by loss of oncogene-induced senescence. These findings may provide avenues for the discovery of new treatments in rectal cancer.

Mural and extramural venous invasion and prognosis in colorectal cancer.

BACKGROUND: Extramural venous invasion is a known independent predictor of poor prognosis after resection of colorectal adenocarcinoma, but the prognostic value of mural venous invasion alone and the association between venous invasion and prognosis within tumor stages has received little research attention. OBJECTIVE: This study aimed to determine whether associations between mural and extramural venous invasion and outcome differ among tumor stages after adjustment for other factors known to influence prognosis. DESIGN: This study is a retrospective analysis of prospectively collected data. SETTINGS: Data were drawn from a registry of 3040 consecutive patients undergoing resection between 1980 and 2005 under the care of specialist surgeons in a tertiary referral public hospital and an affiliated private hospital. A standardized protocol was used for the pathological assessment of specimens. MAIN OUTCOME MEASURES: The primary outcomes measured were overall survival, cancer-specific survival, and recurrence. RESULTS: There was no significant association between venous invasion and survival in stages A (n = 544) or B (n = 1078). In stage C (n = 899), overall survival time was significantly shorter in patients with mural invasion alone or extramural invasion (both p < 0.001) than in those without invasion, and this persisted after adjustment for other prognostic variables. Equivalent bivariate associations were found in stage D, but only the effect of extramural invasion persisted after adjustment. LIMITATIONS: Our findings arise from the experience of a single surgical group and may not be generalizable to other settings. Only hematoxylin and eosin staining was used. CONCLUSIONS: The association between venous invasion and prognosis was stage specific. Both mural venous invasion alone and extramural venous invasion independently predicted overall survival in patients with stage C tumors, but not in patients with stages A, B, or D tumors. Although mural invasion alone was rare, the separate reporting of both mural and extramural invasion in patients with stage C tumor is informative and desirable.