Survival Threshold Research Articles

Quality Investing and Pricing Strategies by Startups: Impacts of Demand Uncertainties and Capital Constraint

Investing in product quality for future growths or conserving cash flow to avoid bankruptcy is an important trade-off faced by many capital-constrained startups. Focusing on the trade-off, this paper proposes a two-stage model where a startup firm must earn profit above the survival threshold by the end of every stage. Considering impacts of the uncertainty of demand responsiveness to quality (DRQ), market shocks, and survival threshold, a hedge with price setting and quality investing is established against the bankruptcy risk. Besides, this paper stresses the necessity of identifying the operational decisions of startups under both profit-seeking and survival-seeking objectives. Results illustrate that, under stochastic environment, the profit-seeking startup makes conservative (aggressive) investment on quality by setting lower (higher) price and investing in lower (higher) quality than the deterministic case, while the survival-seeking startup always sets its price linked to quality in positive direction. In addition, the profit-seeking startup always improves its investment on quality when either the mean or the variance of DRQ increase, while the survival-seeking startup reduces its investment when either the mean of DRQ increases to a certain level or the variance of DRQ increases. Other factors are also examined. Finally, this paper provides the startup managers some guidance on the quality investing strategy under capital constraints.

Allee effect acting on the prey species in a Leslie–Gower predation model

We study the consequences of an Allee effect acting on the prey species in a Leslie–Gower predator–prey model. For this goal we make extensive use of analytical tools from dynamical systems theory complemented with a numerical bifurcation analysis. By studying the dynamics at infinity under a suitable compactification we prove that the model is well-posed in the sense that all the solutions are bounded. We provide a thorough analysis of the number and stability of equilibrium points. In particular, the origin is a non-hyperbolic equilibrium and presents different regimes of local (un)stability depending on certain conditions on the model parameters. In addition, we find curves of homoclinic, Hopf, and saddle–node bifurcations around a Bogdanov–Takens point. In this process, our findings indicate that the survival threshold for both populations in the two-dimensional phase space can be either a limit cycle, a homoclinic orbit, or the stable manifold of a saddle-equilibrium.

Role of Circulating Tumor Cells as Prognostic Marker in Patients with Gestational Choriocarcinoma

Background: To investigate whether circulating tumor cells (CTCs) are detectable in patients with gestational choriocarcinoma (GC) and evaluate the prognostic value of CTC enumeration. Methods: In this multicenter study, the presence of CTCs was examined in 180 GC patients using a semi-automated NanoVelcro system, among whom 106 patients underwent CTC re-evaluation after one cycle of chemotherapy. Findings: Approximately 96% of the GC patients contained ≥2 CTCs in 7.5 mL of blood. The number of CTCs per 7.5 mL of blood was much higher in patients with distant metastases (n=95; range, 0 to 104) than in patients without distant metastases (n=85; range, 0 to 6). Applying a 90-patient training and 90-patient validation cohort, a cutoff value of ≥6 CTCs was defined as the prognostic threshold for progression-free survival (PFS) and overall survival (OS). The presence of ≥6 CTCs was significantly associated with worse PFS and OS (both P<0.001). A multivariate analysis showed that the CTC number (≥6 CTCs) was the strongest predictor of OS (hazard ratio [HR], 15.8; 95% confidence interval [CI], 4.3-57.9; P<0.001). The number of CTCs decreased after one cycle of chemotherapy; univariate analyses demonstrated that the CTC count after the first chemotherapy cycle was a strong predictor for OS (HR, 36.1; 95% CI, 4.8-271.5; P<0.001). Interpretation: CTCs are a promising prognostic factor for GC. The absolute CTC count after one cycle of chemotherapy in the context of this disease is a strong predictor of chemotherapy response. Funding: This work was supported by grants from the National Natural Science Foundation of China (30900650, 81372501, 81572260 and 81773299), the Guangdong Natural Science Foundation (2011B031800025, S2012010008378, 2015A030313036 and 2015A030313036), and the Guangzhou and Guangdong/Guangzhou Science and Technology Planning Program (2014J4100132, 2012B031800115, 2013B02180021, 2015A020214010, 2016A020215055, 201704020094, 16ykjc08 and 2015ykzd07). Declaration of Interest: No potential conflicts of interest were disclosed. Ethical Approval: Our study was approved by the Medical Ethics Committee of each independent center.

Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial

Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2-10·7) with pembrolizumab and 8·3 months (7·6-9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66-1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. Merck Sharp & Dohme, a subsidiary of Merck & Co.

Top-down and bottom-up controls on southern New England salt marsh crab populations.

Southern New England salt marsh vegetation and habitats are changing rapidly in response to sea-level rise. At the same time, fiddler crab (Uca spp.) distributions have expanded and purple marsh crab (Sesarma reticulatum) grazing on creekbank vegetation has increased. Sea-level rise and reduced predation pressure drive these changing crab populations but most studies focus on one species; there is a need for community-level assessments of impacts from multiple crab species. There is also a need to identify additional factors that can affect crab populations. We sampled crabs and environmental parameters in four Rhode Island salt marshes in 2014 and compiled existing data to quantify trends in crab abundance and multiple factors that potentially affect crabs. Crab communities were dominated by fiddler and green crabs (Carcinus maenas); S. reticulatum was much less abundant. Burrow sizes suggest that Uca is responsible for most burrows. On the marsh platform, burrows and Carcinus abundance were negatively correlated with elevation, soil moisture, and soil percent organic matter and positively correlated with soil bulk density. Uca abundance was negatively correlated with Spartina patens cover and height and positively correlated with Spartina alterniflora cover and soil shear strength. Creekbank burrow density increased dramatically between 1998 and 2016. During the same time, fishing effort and the abundance of birds that prey on crabs decreased, and water levels increased. Unlike in other southern New England marshes where recreational overfishing is hypothesized to drive increasing marsh crab abundance, we propose that changes in crab abundance were likely unrelated to recreational finfish over-harvest; instead, they better track sea-level rise and changing abundances of alternate predators, such as birds. We predict that marsh crab abundance will continue to expand with ongoing sea-level rise, at least until inundation thresholds for crab survival are exceeded.

Comparison of heavy metals, parasites and histopathology in sculpins (Myoxocephalus spp.) from two sites at a lead-zinc mine in North East Greenland

The former lead-zinc mine at Mestersvig, Greenland, continues to contaminate the surrounding environment despite its operations ceasing over 50 years ago. Elevated concentrations of heavy metals are found in water, sediment and biota in the terrestrial, freshwater and marine environments. To shed light on the present contamination and its potential effects on local fish we investigated gill and liver histology of sculpins (Myoxocephalus spp.) around the former mining area. Two species of sculpins were caught; shorthorn sculpins (M. scorpius; n = 16) and fourhorn sculpins (M. quadricornis; n = 17) at a contaminated site, Nyhavn, and shorthorn sculpins (M. scorpius; n = 25) at the reference site. In a previous study we found histopathological changes in the tissues of the sculpins, and we suspected this to be related to elevated heavy metal tissue concentrations. Concentrations of Fe, Hg, Mn, Pb, Se and Zn were significantly higher in sculpins at Nyhavn compared to the reference site. Reference NOED and LOEC thresholds for biochemistry, tissue lesions, growth, survival and reproduction for hepatic Hg, As, Cd and Pb from the ERED database were exceeded in both sculpin species. Histopathological investigations of the sculpins gills revealed significant increases in the prevalence of hyperplastic epithelium, inflammation, intensity of neutral and total mucus cells and chloride cells along with an increased infection of colonial Peritricha. At the contaminated Nyhavn site, fourhorn sculpins had a significantly higher prevalence of chondroplastic tissue and intensity of neutral, mixed and total mucus cells in the gills compared to the shorthorn sculpins. The data indicate that both sculpin species could be useful indicator species for environmental monitoring of metal pollution in Arctic areas. However, confounding effects of gender and species should be investigated further. Effects on other biomarkers as well as baseline measurements should be included in future environmental monitoring efforts around mining activities in Greenland.

An Alternative Formulation for a Distributed Delayed Logistic Equation

We study an alternative single species logistic distributed delay differential equation (DDE) with decay-consistent delay in growth. Population oscillation is rarely observed in nature, in contrast to the outcomes of the classical logistic DDE. In the alternative discrete delay model proposed by Arino et al. (J Theor Biol 241(1):109-119, 2006), oscillatory behavior is excluded. This study adapts their idea of the decay-consistent delay and generalizes their model. We establish a threshold for survival and extinction: In the former case, it is confirmed using Lyapunov functionals that the population approaches the delay modified carrying capacity; in the later case the extinction is proved by the fluctuation lemma. We further use adaptive dynamics to conclude that the evolutionary trend is to make the mean delay in growth as short as possible. This confirms Hutchinson's conjecture (Hutchinson in Ann N Y Acad Sci 50(4):221-246, 1948) and fits biological evidence.

Abstract P3-12-05: Serum levels of the active tamoxifen metabolite Z-4OHtam is predictive of long-term survival in luminal B subtype of breast cancer patients

Abstract Background Tamoxifen (tam) is the main adjuvant endocrine treatment option in premenopausal breast cancer (BC) patients comprising luminal-like tumors. However, a significant proportion of tam-users will experience a relapse within 15 years of primary surgery. We postulate that some patients do not achieve the full clinical benefit of tam due to inter-individual differences in the metabolism of the drug and that the clinical relevance of this may be different between molecular subtypes of BC. Here, we have compared the prognostic value of threshold levels of active tam metabolites in PAM50 luminal (lum) A and B molecular subtypes. Material and Methods A number of 64 lum-like BC patients who were relapse-free 3 years after surgery, were retrospectively analyzed in the observational Oslo1 study. All patients received 20 mg tamoxifen daily for 5 years. Serum was obtained at the time of the 3 years follow-up. A sensitive and accurate LC-MS/MS method was developed and validated for the detection and quantification of tam and 9 metabolites in human serum. The median follow-up time from serum sampling to BC death or last follow-up was 13.9 years (0.6-16.5). Recurrence score and molecular subtype of the patients were determined on FFPE-tumor samples using the PAM50 classification algorithm. Results A linear trend was identified for the correlation between active metabolite Z-4OHtam and BCSS (p=0.021, HR=0.64, CI95=0.43–0.93). There was no linear association between the remaining metabolites and BC outcome. We further explored the possible association between survival and concentration thresholds for the active metabolites Z-4OHtam and Z-endoxifen and identified supervised cut off values representing low concentrations for Z-4OHtam (≤3.26 nM) and Z-endoxifen (≤9.00 nM). BC patients with low Z-4OHtam had a BCSS of 33.3% compared to 82.8% in patients with Z-4OHtam &amp;gt;3.26 nM (p&amp;lt;0.001, logrank; HR=6.83, CI 95=2.09-22.36). Lum status (A vs B; HR=5.50, CI95= 1.66-18.25) and Z-4OHtam concentration status (high vs low; HR=6.05, CI95=1.74-21.06) were the only factors left in the final multivariable model. A log-linear relationship between the ROR score and BCSS (p=0.002, HR=1.09, CI95=1.03–1.15) was identified after adjustment of clinically relevant variables and lum status was highly prognostic, (Lum A vs B; p=0.001, HR=5.2, CI=1.72-15.46). Therefore, we wanted to compare the prognostic value of the Z-4OHtam threshold in patients subgroups stratified by lum status. Low concentrations of Z-4OHtam were associated with poorer survival for patients in the lum B group only (HR=4.94, CI 95=1.16-21-02). For the lum A patients no significant association was found. Discussion Low levels (≤ 3.26 nM) of the active tam metabolite Z-4OHtam was associated with a poorer long-term outcome in tam-treated BC patients. However, when grouping patients according to the PAM50-based molecular subtype, this was only significant in patients belonging to the lum B subtype. Our results suggest that higher levels of active tam metabolites and thus better ER blockage are more important in the more aggressive lum B subtype. Citation Format: Helland T, Søiland H, Hustad S, Lash TL, Kvaløy JT, Renolen A, Borgen E, Bifulco E, Henne N, Lien EA, Mellgren G, Naume B, Janssen EA. Serum levels of the active tamoxifen metabolite Z-4OHtam is predictive of long-term survival in luminal B subtype of breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-05.

Mangrove swamp expansion controlled by climate since 1988: a case study in the Nanliu River Estuary, Guangxi, Southwest China

In the Nanliu River Estuary of Guangxi, China, the naturally expanding process of a mangrove swamp (primarily consist of Aegiceras corniculatum) over past decades is studied by satellite images. From 1988 to 2013, the area of studied mangrove swamp increased significantly from 60 hm2 to 134 hm2. The expanding process is not gradual and the significant expansion only took place in some special periods. To reveal the dynamic of mangrove swamp expansion, the evolution of tidal flat elevation and the climate change in past decades are studied respectively. The hydrodynamic condition and nutrient supply are also analysed. The study results show that the climate factors of typhoon intensity and annual minimum temperature are crucial for controlling mangrove expansion. A large number of mangrove seedlings on bare tidal flats can survive only in special climate optimum periods, which are continuous years of low typhoon intensity and high annual minimum temperature. In past decades, the scarcity of climate optimum periods resulted in a non-gradual process of mangrove expanding and a time lag of 30 years between the elevation reaching the low threshold for mangrove seedling survival and the eventual emergance of the mangrove. Compared with the climate factors, the hydrodynamic condition and nutrient supply are not important factors affecting mangrove expansion. In the future, combined with global warming, the enhanced frequency and energy of landing typhoons will most likely restrain the further expansion of this mangrove swamp.

Asymptotic properties of a stochastic chemostat including species death rate

This paper deals with a stochastic system which models the population dynamics of a chemostat including species death rate. On the basis of the theory on Markov semigroup, we demonstrate that the probability densities of the distributions for the solutions are absolutely continuous. The densities will convergence in L1 to an invariant density or weakly convergence to a singular measure under appropriate conditions. We also give the sufficient criteria for extinction exponentially of the species. To be specific, when D1&gt;D and the strength of perturbation is relatively small, we derive a precise threshold for the species survival.

Altered cropping pattern and cultural continuation with declined prosperity following abrupt and extreme arid event at ~4,200 yrs BP: Evidence from an Indus archaeological site Khirsara, Gujarat, western India

Archaeological sites hold important clues to complex climate-human relationships of the past. Human settlements in the peripheral zone of Indus culture (Gujarat, western India) are of considerable importance in the assessment of past monsoon-human-subsistence-culture relationships and their survival thresholds against climatic stress exerted by abrupt changes. During the mature phase of Harappan culture between ~4,600–3,900yrsBP, the ~4,100±100yrsBP time slice is widely recognized as one of the major, abrupt arid-events imprinted innumerous well-dated palaeo records. However, the veracity of this dry event has not been established from any archaeological site representing the Indus (Harappan) culture, and issues concerning timing, changes in subsistence pattern, and the likely causes of eventual abandonment (collapse) continue to be debated. Here we show a significant change in crop-pattern (from barley-wheat based agriculture to ‘drought-resistant’ millet-based crops) at ~4,200 yrs BP, based on abundant macrobotanical remains and C isotopes of soil organic matter (δ13CSOM) in an archaeological site at Khirsara, in the Gujarat state of western India. The crop-change appears to be intentional and was likely used as an adaptation measure in response to deteriorated monsoonal conditions. The ceramic and architectural remains of the site indicate that habitation survived and continued after the ~4,200yrsBP dry climatic phase, but with declined economic prosperity. Switching to millet-based crops initially helped inhabitants to avoid immediate collapse due to climatic stresses, but continued aridity and altered cropping pattern led to a decline in prosperity levels of inhabitants and eventual abandonment of the site at the end of the mature Harappan phase.

Best dispersal strategies in spatially heterogeneous environments: optimization of the principal eigenvalue for indefinite fractional Neumann problems.

We study the positive principal eigenvalue of a weighted problem associated with the Neumann spectral fractional Laplacian. This analysis is related to the investigation of the survival threshold in population dynamics. Our main result concerns the optimization of such threshold with respect to the fractional order [Formula: see text], the case [Formula: see text] corresponding to the standard Neumann Laplacian: when the habitat is not too fragmented, the principal positive eigenvalue can not have local minima for [Formula: see text]. As a consequence, the best strategy for survival is either following the diffusion with [Formula: see text] (i.e. Brownian diffusion), or with the lowest possible s (i.e. diffusion allowing long jumps), depending on the size of the domain. In addition, we show that analogous results hold for the standard fractional Laplacian in [Formula: see text], in periodic environments.

Range And Roosting Ecology of the Little Brown Bat,Myotis lucifugus, In Interior and Northern Alaska

Very little is known about the range and ecology of the Little Brown Bat (Myotis lucifugus) in Alaska and how the species continues to persist in a region where temperatures fall below their predicted threshold for winter survival. Establishing a baseline of current distribution is critical to monitoring potential population shifts. We hypothesized that persistence of the Little Brown Bat in interior and northern Alaska is dependent on the ability of bats to gain sufficient mass over a short summer with limited darkness, and on the availability of human structures for roosting in areas where temperatures are likely too low for roosting in natural structures. To describe the roosting ecology of bats in interior and northern Alaska, we combined traditional ecological knowledge, outreach through citizen science, and sampling using roost studies and telemetry. Activity outside of the roost was positively related to length of time between sunset and sunrise. Fat gained through summer in interior Alaska constituted 21% of body mass in fall prior to dispersal. Radio-tracked bats migrated short distances (<100 km) to areas where human structures were the most likely hibernacula. We conclude that Little Brown Bats use human structures to offset the constraints of cold temperatures and short foraging seasons in interior Alaska.

A multi-species synthesis of physiological mechanisms in drought-induced tree mortality.

Widespread tree mortality associated with drought has been observed on all forested continents and global change is expected to exacerbate vegetation vulnerability. Forest mortality has implications for future biosphere-atmosphere interactions of carbon, water and energy balance, and is poorly represented in dynamic vegetation models. Reducing uncertainty requires improved mortality projections founded on robust physiological processes. However, the proposed mechanisms of drought-induced mortality, including hydraulic failure and carbon starvation, are unresolved. A growing number of empirical studies have investigated these mechanisms, but data have not been consistently analysed across species and biomes using a standardized physiological framework. Here, we show that xylem hydraulic failure was ubiquitous across multiple tree taxa at drought-induced mortality. All species assessed had 60% or higher loss of xylem hydraulic conductivity, consistent with proposed theoretical and modelled survival thresholds. We found diverse responses in non-structural carbohydrate reserves at mortality, indicating that evidence supporting carbon starvation was not universal. Reduced non-structural carbohydrates were more common for gymnosperms than angiosperms, associated with xylem hydraulic vulnerability, and may have a role in reducing hydraulic function. Our finding that hydraulic failure at drought-induced mortality was persistent across species indicates that substantial improvement in vegetation modelling can be achieved using thresholds in hydraulic function.

Maximize surgical resection beyond contrast-enhancing boundaries in newly diagnosed glioblastoma multiforme: is it useful and safe? A single institution retrospective experience.

The extent of surgical resection (EOR) has been recorded as conditioning outcome in glioblastoma multiforme (GBM) patients but no significant improvements were recorded in survival. The study aimed to evaluate the impact of EOR on survival, investigating the role of fluid-attenuated inversion recovery (FLAIR) abnormalities removal. 282 newly diagnosed GBM patients were treated with surgery followed by concurrent and adjuvant chemo-radiotherapy. The EOR was defined as: SUPr, in case of resection amounting to 100% of enhanced and FLAIR areas; gross total (GTR) in case of resection between 90 and 100% of enhanced areas with variable amount of FLAIR abnormalities; sub-total (STR), between 10 and 89%; biopsy (B) <10%. FLAIR-RTV was dichotomized in percentage values to identify the best separation threshold for progression free survival (PFS) and overall survival (OS). SUPr was obtained in 21 patients (7.4%), GTR in 60 (21.3%), STR in 143 (50.7%) and biopsy only in 58 (20.6%). The median, 1, 2-year PFS were 10.4 ± 0.4 months, 39.0 ± 3.0, and 17.0 ± 2.0%; the median, 1, 2-year OS were 14.5 ± 0.5 months, 63.3 ± 3.0, and 23.1 ± 3.1%. EOR was significantly influencing survival (p < 0.001). The median, 1, 2-year OS were 28.6 ± 5.2 months, 90.0 ± 6.0, 71.0 ± 10.0% for patients underwent SUPr vs. 16.2 ± 1.2 months, 81.0 ± 5.0, 24.0 ± 6.0% for GTR. The FLAIR removal threshold conditioning survival was 45%. Minor complications were recorded in 14 (5%) patients and major in 8 (2.8%). surgical resection beyond contrast-enhancing boundaries could represent a promising strategy to improve outcome in GBM patients. The identification of a FLAIR-RTV threshold can be useful in clinical practice and it was recorded as factor influencing survival.

Effective combined water and sideband suppression for low-speed tissue and in vivo MAS NMR.

High-resolution magic angle spinning (HR-MAS) NMR is a powerful technique that can provide metabolic profiles and structural constraints on intact biological and environmental samples such as cells, tissues and living organisms. However, centripetal force from fast spinning can lead to a loss of sample integrity. In analyses focusing on structural organization, metabolite compartmentalization or in vivo studies, it is critical to keep the sample intact. As such, there is growing interest in slow spinning studies that preserve sample longevity. In this study, for example, reducing the spinning rate from 2500 to 500Hz during the analysis of a living freshwater shrimp increased the 100% survivability threshold from ~14 to 40h. Unfortunately, reducing spinning rate decreases the intensity of the isotropic signals and increases both the intensity and number of spinning sidebands, which mask spectral information. Interestingly, water suppression approaches such as excitation sculpting and W5 WATERGATE, which are effective at higher spinning rates, fail at lower spinning rates (<2500Hz) while simpler approaches such as presaturation are not able to effectively suppress water when the ratio of water to biomass is very high, as is the case in vivo. As such there is a considerable gap in NMR approaches which can be used to suppress water signals and sidebands in biological samples at lower spinning rates. This research presents simple but practically important sequences that combine PURGE water suppression with both phase-adjusted spinning sidebands and an analogue of TOSS termed TOSS.243. The result is simple and effective water and sideband suppression even in extremely dilute samples in pure water down to ~100Hz spinning rate. The approach is introduced, described and applied to a range of samples including, ex vivo worm tissue, Daphnia magna (water fleas), and in vivo Hyalella azteca (shrimp).

Population-based study to re-evaluate optimal lymph node yield in colonic cancer.

It is well established that lymph node (LN) yield in colonic cancer resection has prognostic significance, although optimal numbers are not clear. Here, LN thresholds associated with both LN positivity and survival were evaluated in a single population-based data set. Treatment records were linked to the Ontario Cancer Registry to identify a 25 per cent random sample of all patients with stage II/III colonic cancer between 2002 and 2008. Multivariable regression and Cox models evaluated factors associated with LN positivity and cancer-specific survival (CSS) respectively. Optimal thresholds were obtained using sequential regression analysis. On adjusted analysis of 5508 eligible patients, younger age (P < 0·001), left-sided tumours (P = 0·003), higher T category (P < 0·001) and greater LN yield (relative risk 0·89, 95 per cent c.i. 0·81 to 0·97; P = 0·007) were associated with a greater likelihood of LN positivity. Regression analyses with multiple thresholds suggested no substantial increase in LN positivity beyond 12-14 LNs. Cox analysis of stage II disease showed that lower LN yield was associated with a significant increase in the risk of death from cancer (CSS hazard ratio range 1·55-1·74; P < 0·001) compared with a greater LN yield, with no significant survival benefit beyond a yield of 20 LNs. Similarly, for stage III disease, a lower LN yield was associated with an increase in the risk of death from cancer (CSS hazard ratio range 1·49-2·20; P < 0·001) versus a large LN yield. In stage III disease, there was no observed LN threshold for survival benefit in the data set. There is incongruity in the optimal LN evaluation for colonic cancer. Although the historically stated threshold of 12 LNs may ensure accurate staging in colonic cancer, thresholds for optimal survival are associated with far greater yields.

Predicting Outcomes of Hormone and Chemotherapy in the MolecularTaxonomy ofBreast CancerInternationalConsortium (METABRIC) Study by Biochemically-inspired Machine Learning.

Genomic aberrations and gene expression-defined subtypes in the large METABRIC patient cohort have been used to stratify and predict survival. The present study used normalized gene expression signatures of paclitaxel drug response to predict outcome for different survival times in METABRIC patients receiving hormone (HT) and, in some cases, chemotherapy (CT) agents. This machine learning method, which distinguishes sensitivity vs. resistance in breast cancer cell lines and validates predictions in patients; was also used to derive gene signatures of other HT (tamoxifen) and CT agents (methotrexate, epirubicin, doxorubicin, and 5-fluorouracil) used in METABRIC. Paclitaxel gene signatures exhibited the best performance, however the other agents also predicted survival with acceptable accuracies. A support vector machine (SVM) model of paclitaxel response containing genes ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2, SLCO1B3, TUBB1, TUBB4A, and TUBB4Bwas 78.6% accurate in predicting survival of 84 patients treated with both HT and CT (median survival ≥ 4.4 yr). Accuracy was lower (73.4%) in 304 untreated patients. The performance of other machine learning approaches was also evaluated at different survival thresholds. Minimum redundancy maximum relevance feature selection of a paclitaxel-based SVM classifier based on expression of genes BCL2L1, BBC3, FGF2, FN1,and TWIST1was 81.1% accurate in 53 CT patients. In addition, a random forest (RF) classifier using a gene signature ( ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2,SLCO1B3, TUBB1, TUBB4A,and TUBB4B) predicted >3-year survival with 85.5% accuracy in 420 HT patients. A similar RF gene signature showed 82.7% accuracy in 504 patients treated with CT and/or HT. These results suggest that tumor gene expression signatures refined by machine learning techniques can be useful for predicting survival after drug therapies.

Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer

Endoplasmic reticulum (ER) stress initiates an important mechanism for cell adaptation and survival, named the unfolded protein response (UPR). Severe or chronic/prolonged UPR can breach the threshold for survival and lead to cell death. There is a fundamental gap in knowledge on the molecular mechanism of how chronic ER stress is stimulated and leads to cell death in pancreatic ductal adenocarcinoma (PDAC). Our study shows that downregulating specificity protein 1 (Sp1), a transcription factor that is overexpressed in pancreatic cancer, activates UPR and results in chronic ER stress. In addition, downregulation of Sp1 results in its decreased binding to the ER stress response element present in the promoter region of Grp78, the master regulator of ER stress, thereby preventing homeostasis. We further show that inhibition of Sp1, as well as induction of ER stress, leads to lysosomal membrane permeabilization (LMP), a sustained accumulation of cytosolic calcium, and eventually cell death in pancreatic cancer.

Significant survival advantage of high pulmonary vein index and the presence of native pulmonary artery in pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries: results from preoperative computed tomography angiography.

The prognosis of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (PA-VSD-MAPCAs) after surgery shows substantial clinical heterogeneity and predictors for outcomes are lacking. This study aimed to assess the predictive value of preoperative cardiac computed tomography angiography (CTA) for survival in patients with PA-VSD-MAPCAs. We retrospectively analysed PA-VSD-MAPCA patients with preoperative CTA who underwent both right ventricular outflow tract reconstruction and MAPCA unifocalization ( n = 24) or pulmonary artery rehabilitation ( n = 28). The end-point was overall survival. Prognostic values of CTA were assessed using Cox univariate and multivariate analyses. The significant threshold of independent parameters was calculated using receiver-operating characteristic (ROC) curves. During a median follow-up of 1145 days, a total of 13 deaths were observed. Multivariate analysis identified a high pulmonary vein index (PVI) [hazard ratio (HR) = 0.03; 95% confidence interval (CI): 0.03, 0.28; P < 0.01] and the presence of native pulmonary artery (HR = 0.06; 95% CI: 0.10, 0.35; P < 0.01) as independent positive predictors of better survival. The area under the ROC curve for PVI was 0.79 ( P < 0.01), and a cut-off point of 438 mm 2 /m 2 was deemed the significant threshold for survival (sensitivity 92%, specificity 72%). Preoperational high PVI and native pulmonary artery presence were significant morphologic predictors of a positive survival advantage in PA-VSD-MAPCA patients. A PVI ≥438 mm 2 /m 2 may be a reliable positive prognosticator that could improve the decision-making strategy for PA-VSD-MAPCA patients.