CX3CR1 is a modifying gene of survival and progression in Amyotrophic Lateral Sclerosis

The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis disease (ALS), the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142sporadic [sALS] and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.21±4.82) than patients with 249V/V genotype (67.48±7.28; diff=-25.27 months 95%CI [-42.09,-8.45]; p=0.003). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff -29.78 months; 95%CI [-49.42,-10.14]; p=0.003). The same effects were also observed in the spinal sALS patients with 249I-280M haplotype (diff=-27.23 months; 95%CI [-49.83,-4.64]; p=0.018). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR= 2.32; 95IC%[1.24, 4.33]; p=0.007). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease"s symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.

Transketolase-like 1 expression is modulated during Colorectal cancer progression and metastasis formation

Background Transketolase-like 1 (TKTL1) induces glucose degradation through anaerobic pathways, even in presence of oxygen, favoring the malignant aerobic glycolytic phenotype characteristic of tumor cells. As TKTL1 appears to be a valid biomarker for cancer prognosis, the aim of the current study was to correlate its expression with tumor stage, probability of tumor recurrence and survival, in a series of colorectal cancer patients. Methodolody/Principal Findings Tumor tissues from 63 patients diagnosed with colorectal cancer at different stages of progression were analyzed for TKTL1 by immunohistochemistry. Staining was quantified by computational image analysis, and correlations between enzyme expression, local growth, lymph-node involvement and metastasis were assessed. The highest values for TKTL1 expression were detected in the group of stage III tumors, which showed significant differences from the other groups (Kruskal-Wallis test, P = 0.000008). Deeper analyses of T, N and M classifications revealed a weak correlation between local tumor growth and enzyme expression (Mann-Whitney test, P = 0.029), a significant association of the enzyme expression with lymph-node involvement (Mann-Whitney test, P = 0.0014) and a significant decrease in TKTL1 expression associated with metastasis (Mann-Whitney test, P = 0.0004). Conclusions/Significance To our knowledge, few studies have explored the association between variations in TKTL1 expression in the primary tumor and metastasis formation. Here we report downregulation of enzyme expression when metastasis appears, and a correlation between enzyme expression and regional lymph-node involvement in colon cancer. This finding may improve our understanding of metastasis and lead to new and more efficient therapies against cancer.

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

Background: During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia.

Effectiveness of early detection on breast cancer mortality reduction in Catalonia (Spain)

Background: At present, it is complicated to use screening trials to determine the optimal age intervals and periodicities of breast cancer early detection. Mathematical models are an alternative that has been widely used. The aim of this study was to estimate the effect of different breast cancer early detection strategies in Catalonia (Spain), in terms of breast cancer mortality reduction (MR) and years of life gained (YLG), using the stochastic models developed by Lee and Zelen (LZ). Methods: We used the LZ model to estimate the cumulative probability of death for a cohort exposed to different screening strategies after T years of follow-up. We also obtained the cumulative probability of death for a cohort with no screening. These probabilities were used to estimate the possible breast cancer MR and YLG by age, period and cohort of birth. The inputs of the model were: incidence of, mortality from and survival after breast cancer, mortality from other causes, distribution of breast cancer stages at diagnosis and sensitivity of mammography. The outputs were relative breast cancer MR and YLG. Results: Relative breast cancer MR varied from 20% for biennial exams in the 50 to 69 age interval to 30% for annual exams in the 40 to 74 age interval. When strategies differ in periodicity but not in the age interval of exams, biennial screening achieved almost 80% of the annual screening MR. In contrast to MR, the effect on YLG of extending screening from 69 to 74 years of age was smaller than the effect of extending the screening from 50 to 45 or 40 years. Conclusion: In this study we have obtained a measure of the effect of breast cancer screening in terms of mortality and years of life gained. The Lee and Zelen mathematical models have been very useful for assessing the impact of different modalities of early detection on MR and YLG in Catalonia (Spain).

Survival of wild adults of Ceratitis capitata (Wiedemann) under natural winter conditions in north east Spain

The overwintering of the Mediterranean fruit fly (medfly), Ceratitis capitata (Wiedemann) at the northern limits of its geographic distribution is not yet well known. With the aim of estimating the survival rate of medfly adults in northeast Spain under natural winter conditions, a two-winter-season trial was carried out. A control was carried out in a climatic chamber at 25°C. The results showed that medfly adults were unable to survive the entire winter season in the Girona area. Climatic conditions, including the daily minimum temperature, daily maximum temperature and the high rainfall, appeared to be involved in adult mortality in winter.

Neuronal survival induced by neurotrophins requires calmodulin

It has been reported that phosphoinositide 3-kinase (PI 3-kinase) and its downstream target, protein kinase B (PKB), play a central role in the signaling of cell survival triggered by neurotrophins (NTs). In this report, we have analyzed the involvement of Ca2+ and calmodulin (CaM) in the activation of the PKB induced by NTs. We have found that reduction of intracellular Ca2+ concentration or functional blockade of CaM abolished NGF-induced activation of PKB in PC12 cells. Similar results were obtained in cultures of chicken spinal cord motoneurons treated with brain-derived neurotrophic factor (BDNF). Moreover, CaM inhibition prevented the cell survival triggered by NGF or BDNF. This effect was counteracted by the transient expression of constitutive active forms of the PKB, indicating that CaM regulates NT-induced cell survival through the activation of the PKB. We have investigated the mechanisms whereby CaM regulates the activation of the PKB, and we have found that CaM was necessary for the proper generation and/or accumulation of the products of the PI 3-kinase in intact cells.

Univariate Parametric Survival Analysis using GS-distributions

The GS-distribution is a family of distributions that provide an accurate representation of any unimodal univariate continuous distribution. In this contribution we explore the utility of this family as a general model in survival analysis. We show that the survival function based on the GS-distribution is able to provide a model for univariate survival data and that appropriate estimates can be obtained. We develop some hypotheses tests that can be used for checking the underlying survival model and for comparing the survival of different groups.

GD3 Synthase Overexpression Sensitizes Hepatocarcinoma Cells to Hypoxia and Reduces Tumor Growth by Suppressing the cSrc/NF-κB Survival Pathway

Abstract Background: Hypoxia-mediated HIF-1a stabilization and NF-kB activation play a key role in carcinogenesis by fostering cancer cell survival, angiogenesis and tumor invasion. Gangliosides are integral components of biological membranes with an increasingly recognized role as signaling intermediates. In particular, ganglioside GD3 has been characterized as a proapoptotic lipid effector by promoting cell death signaling and suppression of survival pathways. Thus, our aim was to analyze the role of GD3 in hypoxia susceptibility of hepatocarcinoma cells and in vivo tumor growth. Methodology/Principal Findings: We generated and characterized a human hepatocarcinoma cell line stably expressing GD3 synthase (Hep3B-GD3), which catalyzes the synthesis of GD3 from GM3. Despite increased GD3 levels (2-3 fold), no significant changes in cell morphology or growth were observed in Hep3B-GD3 cells compared to wild type Hep3B cells under normoxia. However, exposure of Hep3B-GD3 cells to hypoxia (2% O2) enhanced reactive oxygen species (ROS) generation, resulting in decreased cell survival, with similar findings observed in Hep3B cells exposed to increasing doses of exogenous GD3. In addition, hypoxia-induced c-Src phosphorylation at tyrosine residues, NF-kB activation and subsequent expression of Mn-SOD were observed in Hep3B cells but not in Hep3B-GD3 cells. Moreover, MnTBAP, an antioxidant with predominant SOD mimetic activity, reduced ROS generation, protecting Hep3B-GD3 cells from hypoxia-induced death. Finally, lower tumor growth, higher cell death and reduced Mn-SOD expression were observed in Hep3B-GD3 compared to Hep3B tumor xenografts. Conclusion: These findings underscore a role for GD3 in hypoxia susceptibility by disabling the c-Src/NF-kB survival pathway resulting in lower Mn-SOD expression, which may be of relevance in hepatocellular carcinoma therapy.

Empirical study of correlated survival times for recurrent events with proportional hazards margins and the effect of correlation and censoring.

Background: In longitudinal studies where subjects experience recurrent incidents over a period of time, such as respiratory infections, fever or diarrhea, statistical methods are required to take into account the within-subject correlation. Methods: For repeated events data with censored failure, the independent increment (AG), marginal (WLW) and conditional (PWP) models are three multiple failure models that generalize Cox"s proportional hazard model. In this paper, we revise the efficiency, accuracy and robustness of all three models under simulated scenarios with varying degrees of within-subject correlation, censoring levels, maximum number of possible recurrences and sample size. We also study the methods performance on a real dataset from a cohort study with bronchial obstruction. Results: We find substantial differences between methods and there is not an optimal method. AG and PWP seem to be preferable to WLW for low correlation levels but the situation reverts for high correlations. Conclusions: All methods are stable in front of censoring, worsen with increasing recurrence levels and share a bias problem which, among other consequences, makes asymptotic normal confidence intervals not fully reliable, although they are well developed theoretically.

Prognostic Importance of the Cuse of Renal Failure in Patients With Cirrhosis

BACKGROUND & AIMS: The prognostic value of the different causes of renal failure in cirrhosis is not well established. This study investigated the predictive value of the cause of renal failure in cirrhosis. METHODS: Five hundred sixty-two consecutive patients with cirrhosis and renal failure (as defined by serum creatinine 1.5 mg/dL on 2 successive determinations within 48 hours) hospitalized over a 6-year period in a single institution were included in a prospective study. The cause of renal failure was classified into 4 groups: renal failure associated with bacterial infections, renal failure associated with volume depletion, hepatorenal syndrome (HRS), and parenchymal nephropathy. The primary end point was survival at 3 months. RESULTS: Four hundred sixty-three patients (82.4%) had renal failure that could be classified in 1 of 4 groups. The most frequent was renal failure associated with infections (213 cases; 46%), followed by hypovolemia-associated renal failure (149; 32%), HRS (60; 13%), and parenchymal nephropathy (41; 9%). The remaining patients had a combination of causes or miscellaneous conditions. Prognosis was markedly different according to cause of renal failure, 3-month probability of survival being 73% for parenchymal nephropathy, 46% for hypovolemia-associated renal failure, 31% for renal failure associated with infections, and 15% for HRS (P .0005). In a multivariate analysis adjusted for potentially confounding variables, cause of renal failure was independently associated with prognosis, together with MELD score, serum sodium, and hepatic encephalopathy at time of diagnosis of renal failure. CONCLUSIONS: A simple classification of patients with cirrhosis according to cause of renal failure is useful in assessment of prognosis and may help in decision making in liver transplantation.

Incidence and survival of chronic myelomonocytic leukemia in Girona (Spain): a populationbased study, 1993-2007

Chronic myelomonocytic leukemia is a very rare blood cancer observed mostly in the elderly. Here we report the incidence trends and survival of patients with chronic myelomonocytic leukemia over a 15-year period (1993-2007). Cases were provided by the population-based Girona Cancer Registry. The crude incidence rate was 0.72/100,000 inhabitants/year. No statistically significant increase in trends was detected over the 15 years. Median overall survival was 28 months although survival markedly decreased with advancing age. The 5-years observed and relative survival were 20% and 29%, respectively. This is the first population-based study that reports the incidence and survival of chronic myelomonocytic leukemia in Spain

Survival of European patients diagnosed with lymphoid neoplasms in 2000-2002: results of the HAEMACARE project

The European Cancer Registry-based project on hematologic malignancies (HAEMACARE), setup to improve the availability and standardization of data on hematologic malignancies in Europe, used the European Cancer Registry-based project on survival and care of cancer patients (EUROCARE-4) database to produce a new grouping of hematologic neoplasma(defined by the International Classification of Diseases for Oncology, Third Edition and the 2001/2008 World Health Organization classifications) for epidemiological and public healthpurposes. We analyzed survival for lymphoid neoplasms in Europe by disease group, comparing survival between different European regions by age and sex. Design and Methods Incident neoplasms recorded between 1995 to 2002 in 48 population-based cancer registries in 20 countries participating in EUROCARE-4 were analyzed. The period approach was used to estimate 5-year relative survival rates for patients diagnosed in 2000-2002, who did not have 5years of follow up. Results: The 5-year relative survival rate was 57% overall but varied markedly between the definedgroups. Variation in survival within the groups was relatively limited across European regions and less than in previous years. Survival differences between men and women were small. The relative survival for patients with all lymphoid neoplasms decreased substantially after the age of 50. The proportion of ‘not otherwise specified’ diagnoses increased with advancing age.Conclusions: This is the first study to analyze survival of patients with lymphoid neoplasms, divided into groups characterized by similar epidemiological and clinical characteristics, providing a benchmarkfor more detailed analyses. This Europe-wide study suggests that previously noted differences in survival between regions have tended to decrease. The survival of patients with all neoplasms decreased markedly with age, while the proportion of ‘not otherwise specified’ diagnoses increased with advancing age. Thus the quality of diagnostic work-up and care decreased with age, suggesting that older patients may not be receiving optimal treatment

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia

Speed of travelling fronts: Two-dimensional and ballistic dispersal probability distributions

The speed of traveling fronts for a two-dimensional model of a delayed reactiondispersal process is derived analytically and from simulations of molecular dynamics. We show that the one-dimensional (1D) and two-dimensional (2D) versions of a given kernel do not yield always the same speed. It is also shown that the speeds of time-delayed fronts may be higher than those predicted by the corresponding non-delayed models. This result is shown for systems with peaked dispersal kernels which lead to ballistic transport

Efecto de la suplementación con ácidos grasos de cadena media sobre la evolución de peso en lechones con poco peso al nacimiento

La evolución de peso en los períodos de lactación y transición de 583 lechones fue estudiada mediante un análisis estadístico, evaluando el efecto de la suplementación con ácidos grasos de cadena media (AGCM) en lechones con poco peso al nacimiento. 188 de los 375 lechones que nacieron con un peso al nacimiento (PN) <1250 g recibieron 3mL de AGCM cada 24 h durante los primeros 3 días de vida; su peso medio al destete (día 28) fue inferior respecto al grupo control (lechones no suplementados) (-114,17 g). No obstante, 106 de los 180 lechones nacidos con un PN <1000 g fueron suplementados, y su peso medio al destete y a finales de transición (día 63) fue superior respecto al grupo control (destete: +315,16 g; día 63: +775,47 g). Finalmente, los lechones suplementados con PN<800 g tuvieron los peores resultados: su diferencia de peso medio al destete fue de -177,58 g respecto al grupo control. Por lo tanto, en esta prueba fueron estudiados los lechones con un PN entre 800 y 999 g porque el grupo suplementado al destete tuvo una diferencia de peso medio considerable respecto al grupo control:+511,58 g. Asimismo, considerando una probabilidad de error inferior a 0,05, no hubieron diferencias significativas en las diferentes categorías de PN analizadas. De todas maneras, es importante destacar el alto grado de significación en la suplementación con AGCM en lechones con PN entre 800 y 999g (P=0,059). Por otra parte, el PN del grupo suplementado con PN<1000 g fue inferior que el del grupo no suplementado con PN<1000 g; esta diferencia de PN fue significativa (P=0,004) y como consecuencia el grado de significación en la suplementación con AGCM en lechones con PN entre 800 y 999 g fue inferior al esperado. Además, en esta prueba se incluyeron algunos resultados generales y también un análisis simple de supervivencia, aunque no era el objetivo principal