Neural crest cell survival is dependent on Rho kinase and is required for development of the mid face in mouse embryos.

Neural crest cells (NCC) give rise to much of the tissue that forms the vertebrate head and face, including cartilage and bone, cranial ganglia and teeth. In this study we show that conditional expression of a dominant-negative (DN) form of Rho kinase (Rock) in mouse NCC results in severe hypoplasia of the frontonasal processes and first pharyngeal arch, ultimately resulting in reduction of the maxilla and nasal bones and severe craniofacial clefting affecting the nose, palate and lip. These defects resemble frontonasal dysplasia in humans. Disruption of the actin cytoskeleton, which leads to abnormalities in cell-matrix attachment, is seen in the RockDN;Wnt1-cre mutant embryos. This leads to elevated cell death, resulting in NCC deficiency and hypoplastic NCC-derived craniofacial structures. Rock is thus essential for survival of NCC that form the craniofacial region. We propose that reduced NCC numbers in the frontonasal processes and first pharyngeal arch, resulting from exacerbated cell death, may be the common mechanism underlying frontonasal dysplasia.

Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy.

PURPOSE: Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. RESULTS: In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. CONCLUSION: Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.

The impact of highly active antiretroviral therapy on the survival of vertically HIV-infected children and adolescents in Belo Horizonte, Brazil

The use of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)-infected patients has reduced the number of acquired immune deficiency syndrome-related deaths worldwide. This study assessed the impact of HAART on the survival and death rates of vertically HIV-infected children and adolescents in Belo Horizonte, Brazil. Data were obtained from a historic cohort of vertically HIV-infected children and adolescents aged zero-19 years old who were admitted from March 1989-December 2004 and were followed until June 2006. Patients who used HAART were included if they were treated for at least 12 weeks. Of 359 patients, 320 patients met the inclusion criteria. The overall mortality rate was 9.7% [31/320; 95% confidence interval (CI): 6.0-13%]. The median survival for the non-HAART and HAART groups was 31.5 and 55.9 months, respectively (log rank = 22.11, p < 0.0001). In the multivariate analysis, the statistically significant variables were HAART and the weight-for-age Z score < -2, with HAART constituting a protective factor [relative risk (RR): 0.13; CI 95%: 0.05-0.33] and malnutrition constituting a risk factor (RR: 3.44; CI 95%: 1.60-7.40) for death. The incidence of death was 5.1/100 person-years in the non-HAART group and 0.8/100 person-years in the HAART group (p < 0.0001).

Extracellular matrix molecules enhance the neurotrophic effect of schwann cell-like differentiated adipose-derived stem cells and increase cell survival under stress conditions.

Since the first reports of induction of adipose-derived stem cells (ASC) into neuronal and glial cell phenotypes, expectations have increased regarding their use in tissue engineering applications for nerve repair. Cell adhesion to extracellular matrix (ECM) is a basic feature of survival, differentiation, and migration of Schwann cells (SC) during nerve regeneration, and fibronectin and laminin are two key molecules of this process. Interaction between ECM and SC-like differentiated ASC (dASC) could potentially improve the neurotrophic potential of the stem cells. We have investigated the effect of ECM molecules on SC-like dASC in terms of proliferation, adhesion, and cell viability. Fibronectin and laminin did not affect the proliferation of dASC when compared with cell adherent tissue culture plastic, but significantly improved viability and cell attachment when dASC were exposed to apoptotic conditions. To assess the influence of the ECM molecules on dASC neurotrophic activity, dASC were seeded onto ECM-coated culture inserts suspended above dorsal root ganglia (DRG) sensory neurons. Neurite outgrowth of DRG neurons was enhanced when dASC were seeded on fibronectin and laminin when compared with controls. When DRG neurons and dASC were in direct contact on the various surfaces there was significantly enhanced neurite outgrowth and coculture with laminin-conditioned dASC produced the longest neurites. Compared with primary SCs, dASC grown on laminin produced similar levels of neurite outgrowth in the culture insert experiments but neurite length was shorter in the direct contact groups. Anti β1 integrin blocking antibody could inhibit baseline and dASC evoked neurite elongation but had no effect on outgrowth mediated by laminin-conditioned dASC. ECM molecules had no effect on the levels of nerve growth factor and brain-derived neurotrophic factor secretion from dASC. The results of the study suggest that ECM molecules can significantly improve the potential of dASC for nerve regeneration.

Influence of deep sternal wound infection on long-term survival after cardiac surgery.

BACKGROUND: This study aimed to investigate the influence of deep sternal wound infection on long-term survival following cardiac surgery. MATERIAL AND METHODS: In our institutional database we retrospectively evaluated medical records of 4732 adult patients who received open-heart surgery from January 1995 through December 2005. The predictive factors for DSWI were determined using logistic regression analysis. Then, each patient with deep sternal wound infection (DSWI) was matched with 2 controls without DSWI, according to the risk factors identified previously. After checking balance resulting from matching, short-term mortality was compared between groups using a paired test, and long-term survival was compared using Kaplan-Meier analysis and a Cox proportional hazard model. RESULTS: Overall, 4732 records were analyzed. The mean age of the investigated population was 69.3±12.8 years. DSWI occurred in 74 (1.56%) patients. Significant independent predictive factors for deep sternal infections were active smoking (OR 2.19, CI95 1.35-3.53, p=0.001), obesity (OR 1.96, CI95 1.20-3.21, p=0.007), and insulin-dependent diabetes mellitus (OR 2.09, CI95 1.05-10.06, p=0.016). Mean follow-up in the matched set was 125 months, IQR 99-162. After matching, in-hospital mortality was higher in the DSWI group (8.1% vs. 2.7% p=0.03), but DSWI was not an independent predictor of long-term survival (adjusted HR 1.5, CI95 0.7-3.2, p=0.33). CONCLUSIONS: The results presented in this report clearly show that post-sternotomy deep wound infection does not influence long-term survival in an adult general cardio-surgical patient population.

Survival, classifications, and desmosomal plaque genes in non-small cell lung cancer.

Novel biomarkers are required to improve prognostic predictions obtained with lung cancer staging systems. This study of 62 surgically-treated Non-Small Cell Lung Cancer (NSCLC) patients had two objectives: i) to compare the predictive value of T-stage classifications between the 6(th) and 7(th) editions of the Tumor, Node, and Metastasis staging system (TNM); and ii) to examine the association of Pkp1 and/or Krt15 gene expression with survival and outcomes. Multivariate and Kaplan-Meier survival analyses were performed, examining the relationship of survival with T-stage, recurrence, and TNM-stage (by each TNM edition) and with the single/combined expression of Pkp1 and/or Krt15 genes. Five-year survival rates only significantly differed as a function of T-stage in patients without recurrence when estimated using the 6(th) edition of the TNM classification and only in patients in pathologic TNM-stage IA using the 7(th). Overall survival for patients with elevated expression of both genes was 13.5 months in those with adenocarcinoma and 34.6 months in those with squamous cell carcinoma. Overall survival was 30.4 months in patients with Pkp1 gene upregulation and 30.9 months in those with Krt15 gene upregulation. In conclusion, survival estimations as a function of T-staging differed between the 6(th) and 7(th) editions of TNM. Overall survival differed according to the expression of Pkp1 and/or Krt15 genes, although this relationship did not reach statistical significance.

The prognostic value of health-related quality-of-life data in predicting survival in glioblastoma cancer patients: results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study.

This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R(2)-coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R(2)-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.

Colorectal cancer survival in the USA and Europe: a CONCORD high-resolution study.

OBJECTIVES: To assess the extent to which stage at diagnosis and adherence to treatment guidelines may explain the persistent differences in colorectal cancer survival between the USA and Europe. DESIGN: A high-resolution study using detailed clinical data on Dukes' stage, diagnostic procedures, treatment and follow-up, collected directly from medical records by trained abstractors under a single protocol, with standardised quality control and central statistical analysis. SETTING AND PARTICIPANTS: 21 population-based registries in seven US states and nine European countries provided data for random samples comprising 12 523 adults (15-99 years) diagnosed with colorectal cancer during 1996-1998. OUTCOME MEASURES: Logistic regression models were used to compare adherence to 'standard care' in the USA and Europe. Net survival and excess risk of death were estimated with flexible parametric models. RESULTS: The proportion of Dukes' A and B tumours was similar in the USA and Europe, while that of Dukes' C was more frequent in the USA (38% vs 21%) and of Dukes' D more frequent in Europe (22% vs 10%). Resection with curative intent was more frequent in the USA (85% vs 75%). Elderly patients (75-99 years) were 70-90% less likely to receive radiotherapy and chemotherapy. Age-standardised 5-year net survival was similar in the USA (58%) and Northern and Western Europe (54-56%) and lowest in Eastern Europe (42%). The mean excess hazard up to 5 years after diagnosis was highest in Eastern Europe, especially among elderly patients and those with Dukes' D tumours. CONCLUSIONS: The wide differences in colorectal cancer survival between Europe and the USA in the late 1990s are probably attributable to earlier stage and more extensive use of surgery and adjuvant treatment in the USA. Elderly patients with colorectal cancer received surgery, chemotherapy or radiotherapy less often than younger patients, despite evidence that they could also have benefited.

Comparison of drug survival rates for tumor necrosis factor antagonists in rheumatoid arthritis.

BACKGROUND Persistence of anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis (RA) is an overall marker of treatment success. OBJECTIVE To assess the survival of anti-TNF treatment and to define the potential predictors of drug discontinuation in RA, in order to verify the adequacy of current practices. DESIGN An observational, descriptive, longitudinal, retrospective study. SETTING The Hospital Clínico Universitario de Valladolid, Valladolid, Spain. PATIENTS RA patients treated with anti-TNF therapy between January 2011 and January 2012. MEASUREMENTS Demographic information and therapy assessments were gathered from medical and pharmaceutical records. Data is expressed as means (standard deviations) for quantitative variables and frequency distribution for qualitative variables. Kaplan-Meier survival analysis was used to assess persistence, and Cox multivariate regression models were used to assess potential predictors of treatment discontinuation. RESULTS In total, 126 treatment series with infliximab (n = 53), etanercept (n = 51) or adalimumab (n = 22) were administered to 91 patients. Infliximab has mostly been used as a first-line treatment, but it was the drug with the shortest time until a change of treatment. Significant predictors of drug survival were: age; the anti-TNF agent; and the previous response to an anti-TNF drug. LIMITATION The small sample size. CONCLUSION The overall efficacy of anti-TNF drugs diminishes with time, with infliximab having the shortest time until a change of treatment. The management of biologic therapy in patients with RA should be reconsidered in order to achieve disease control with a reduction in costs.

Survival-independent function of NF-kappaB/Rel during late stages of thymocyte differentiation.

Transcription factors of the NF-kappaB/Rel family are important mediators of extracellular signals. Their implication in positive selection of thymocytes is suggested by a defective thymic development in transgenic mice that over-express IkappaB in thymocytes. These mice exhibit an accumulation of an unusually prominent population of TCRhigh/CD4/CD8 double positive cells in the thymus and a dramatic reduction of CD4+ and CD8+ cells in the periphery. The present study addresses the role of NF-kappaB in survival and differentiation processes of maturing thymocytes using IkappaB/bcl-2 and IkappaB/HY double-transgenic mice. Neither the introduction of the anti-apoptosis gene bcl-2 nor the positively selecting background in female HY transgenic mice resulted in a rescue of the maturational defects observed in the thymus of IkappaB transgenic mice. Thus, rather than promoting survival the main role of NF-kappaB/Rel proteins during positive selection of thymocytes appears to be the mediation of differentiation signals.

Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis.

INTRODUCTION Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. METHODS We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003-02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. RESULTS Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. CONCLUSIONS Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes.

Anopheles gambiae eicosanoids modulate Plasmodium berghei survival from oocyst to salivary gland invasion

Eicosanoids affect the immunity of several pathogen/insect models, but their role on the Anopheles gambiae response to Plasmodium is still unknown. Plasmodium berghei-infected mosquitoes were injected with an eicosanoid biosynthesis inhibitor, indomethacin (IN), or a substrate, arachidonic acid (AA), at day 7 or day 12 post-infection (p.i.). Salivary gland invasion was evaluated by sporozoite counts at day 21 p.i. IN promoted infection upon sporozoite release from oocysts, but inhibited infection when sporozoites were still maturing within the oocysts, as observed by a reduction in the number of sporozoites reaching the salivary glands. AA treatment had the opposite effect. We show for the first time that An. gambiae can modulate parasite survival through eicosanoids by exerting an antagonistic or agonistic effect on the parasite, depending on its stage of development.

Estimation of Aedes aegypti (Diptera: Culicidae) population size and adult male survival in an urban area in Panama

Traditional mosquito control strategies rely heavily on the use of chemical insecticides. However, concerns about the efficiency of traditional control methods, environmental impact and emerging pesticide resistance have highlighted the necessity for developing innovative tools for mosquito control. Some novel strategies, including release of insects carrying a dominant lethal gene (RIDL®), rely on the sustained release of modified male mosquitoes and therefore benefit from a thorough understanding of the biology of the male of the species. In this report we present the results of a mark-release-recapture study aimed at: (i) establishing the survival in the field of laboratory-reared, wild-type male Aedes aegypti and (b) estimating the size of the local adult Ae. aegypti population. The study took place in Panama, a country where recent increases in the incidence and severity of dengue cases have prompted health authorities to evaluate alternative strategies for vector control. Results suggest a life expectancy of 2.3 days for released male mosquitoes (confidence interval: 1.78-2.86). Overall, the male mosquito population was estimated at 58 males/ha (range 12-81 males/ha), which can be extrapolated to an average of 0.64 pupae/person for the study area. The practical implications of these results are discussed.

Interferon-γ inhibits group B Streptococcus survival within human endothelial cells

Endothelial dysfunction is a major component of the pathophysiology of septicaemic group B Streptococcus (GBS) infections. Although cytokines have been shown to activate human umbilical vein endothelial cells (HUVECs), the capacity of interferon (IFN)-γ to enhance the microbicidal activity of HUVECs against GBS has not been studied. We report that the viability of intracellular bacteria was reduced in HUVECs activated by IFN-γ. Enhanced fusion of lysosomes with bacteria-containing vacuoles was observed by acid phosphatase and the colocalisation of Rab-5, Rab-7 and lysosomal-associated membrane protein-1 with GBS in IFN-γ-activated HUVECs. IFN-γ resulted in an enhancement of the phagosome maturation process in HUVECs, improving the capacity to control the intracellular survival of GBS.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.

Objective: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma.Methods: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors.Results: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). Conclusions: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.