Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Effects of slow- v. fast-digested protein supplementation combined with mixed power training on muscle function and functional capacities in older men.

Ageing leads to a progressive loss of muscle function (MF) and quality (MQ: muscle strength (MS)/lean muscle mass (LM)). Power training and protein (PROT) supplementation have been proposed as efficient interventions to improve MF and MQ. Discrepancies between results appear to be mainly related to the type and/or dose of proteins used. The present study aimed at determining whether or not mixed power training (MPT) combined with fast-digested PROT (F-PROT) leads to greater improvements in MF and MQ in elderly men than MPT combined with slow-digested PROT (S-PROT) or MPT alone. Sixty elderly men (age 69 (sd 7) years; BMI 18-30 kg/m2) were randomised into three groups: (1) placebo + MPT (PLA; n 19); (2) F-PROT + MPT (n 21) and (3) S-PROT + MPT (n 20) completed the intervention. LM, handgrip and knee extensor MS and MQ, functional capacity, serum metabolic markers, skeletal muscle characteristics, dietary intake and total energy expenditure were measured. The interventions consisted in 12 weeks of MPT (3 times/week; 1 h/session) combined with a supplement (30 g:10 g per meal) of F-PROT (whey) or S-PROT (casein) or a placebo. No difference was observed among groups for age, BMI, number of steps and dietary intake pre- and post-intervention. All groups improved significantly their LM, lower limb MS/MQ, functional capacity, muscle characteristics and serum parameters following the MPT. Importantly, no difference between groups was observed following the MPT. Altogether, adding 30 g PROT/d to MPT, regardless of the type, does not provide additional benefits to MPT alone in older men ingesting an adequate (i.e. above RDA) amount of protein per d.

Ultra-broadband contactless imaging power meter.

Knowledge of the spatial and temporal distribution of heat flux is of great interest for the quantification of heat sources. In this work, we describe the development of a new ultra-broadband contactless imaging power meter based on electromagnetic to infrared technology. This new sensor and the mathematical processing of images enable the reconstruction of both spatial and amplitude distributions through a wide spectral range of sources. The full modeling of the thermoconverter based on 3D formalism of thermal quadrupoles is presented first before deriving a reduced model more suitable for quick and robust inverse processing. The inverse method makes it possible to simultaneously identify the heat losses and the spatial and temporal source distribution for the first time, to the best of our knowledge. Finally, measurements of multispectral sources are presented and discussed, with an emphasis on the spatial and temporal resolution, accuracy and capabilities of the power meter.

[Characteristics, diseases and mortality of people admitted to nursing homes for dependent seniors during the first quarter of 2013 in France]. / Caractéristiques, pathologies et mortalité des résidents en établissements d'hébergement pour personnes âgées dépendantes (Ehpad) admis au cours du premier trimestre 2013 en France.

BACKGROUND: To describe the state of health, through healthcare consumption and mortality, of people admitted to nursing homes (Ehpad) in France. METHODS: People over the age of 65 years admitted to an Ehpad institution during the first quarter of 2013, beneficiaries of the national health insurance general scheme (69% of the population of this age), were identified from the Resid-Ehpad database and their reimbursed health care was extracted from the SNIIRAM database, identifying 56 disease groups by means of algorithms (long-term disease diagnoses and hospitalisations, medicinal products, specific procedures). Disease prevalences were compared to those of other beneficiaries by age- and sex-standardized morbidity/mortality ratios (SMR). RESULTS: A total of 25,534 people were admitted (mean age: 86 years, 71% women). Before admission, these people presented a marker for cardiovascular or neurovascular disease (48% of cases), dementia (34%), cancer (18%), and psychiatric disorders (14%). Compared to non-residents, new residents more frequently presented dementia (SMR=3-40 according to age and sex), psychiatric disorders (SMR=2.5-12, including psychotic disorders SMR=18-21 in the 65-74 year age-group), neurological disorders (SMR=2-12, including epilepsy SMR=14 in the 65-74 year age-group), and cardiovascular and neurovascular disease (SMR=1.2-3). Overall mortality in 2013 was 22%, with a maximum excess between the ages of 65-74 years (males, SMR=8.8, females, SMR=15.9). CONCLUSION: Medical and administrative data derived from linking the Resid-Ehpad/Sniiram databases reveal a severely impaired state of health, considering healthcare use of institutionalized dependent elderly people, and a high prevalence of diseases responsible for severe dependence and excess mortality, especially among the younger residents.

Classical cadherins control survival through the gp130/Stat3 axis.

Stat3 (Signal Transducer and Activator of Transcription-3) is activated by a number of receptor and nonreceptor tyrosine kinases. We recently demonstrated that engagement of E-cadherin, a calcium-dependent, cell to cell adhesion molecule which is often required for cells to remain tightly associated within the epithelium, also activates Stat3. We now examined the effect of two other classical cadherins, cadherin-11 and N-cadherin, whose expression often correlates with the epithelial to mesenchymal transition occurring in metastasis of carcinoma cells, upon Stat3 phosphorylation and activity. Our results indicate that engagement of these two cadherins also, can trigger a dramatic surge in Stat3 activity. This activation occurs through upregulation of members of the IL6 family of cytokines, and it is necessary for cell survival, proliferation and migration. Interestingly, our results also demonstrate for the first time that, in sharp contrast to Stat3, the activity of Erk (Extracellular Signal Regulated kinase) was unaffected by cadherin-11 engagement. Further examination indicated that, although IL6 was able to activate Erk in sparsely growing cells, IL6 could not induce an increase in Erk activity levels in densely growing cultures. Most importantly, cadherin-11 knock-down did allow Erk activation by IL6 at high densities, indicating that it is indeed cadherin engagement that prevents Erk activation by IL6. The fact that the three classical cadherins tested so far, E-cadherin, N-cadherin and cadherin11, which are present in essentially all tissues, actually activate Stat3 regardless of their role in metastasis, argues for Stat3 as a central survival, rather than invasion factor.

Effects of a pulsed light-induced stress on Enterococcus faecalis.

AIMS: Pulsed light (PL) technology is a surface decontamination process that can be used on food, packaging or water. PL efficiency may be limited by its low degree of penetration or because of a shadow effect. In these cases, surviving bacteria will be able to perceive PL as a stress. Such a stress was mimicked using low transmitted energy conditions, and its effects were investigated on the highly environmental adaptable bacterium Enterococcus faecalis V583. METHODS AND RESULTS: In these laboratory conditions, a complete decontamination of the artificially inoculated medium was performed using energy doses as low as 1.8 J cm(-2) , while a treatment of 0.5, 1 and 1.2 J cm(-2) led to a 2.2, 6 and 7-log(10) CFU ml(-1) reduction in the initial bacterial population, respectively. Application of a 0.5 J cm(-2) pretreatment allowed the bacteria to resist more efficiently a 1.2 J cm(-2) subsequent PL dose. This 0.5 J cm(-2) treatment increased the bacterial mutation frequency and affected the abundance of 19 proteins as revealed by a global proteome analysis. CONCLUSIONS: Enterococcus faecalis is able to adapt to a PL treatment, providing a molecular response to low-energy PL dose, leading to enhanced resistance to a subsequent treatment and increasing the mutation frequency. SIGNIFICANCE AND IMPACT OF THE STUDY: This study gives further insights on Ent. faecalis capacities to adapt and to resist to stress.

Direct cost for initial management of prostate cancer: a systematic review.

BACKGROUND: Prostate cancer (pca) is the most common non-skin cancer among men in Canada and other Western countries. Increased prevalence and higher cost of newer treatments have led to a significant rise in the economic burden of pca. The objectives of the present study were to systematically review the literature on direct costs for the initial management of pca, and to examine the methodologic considerations across studies. METHODS: Bibliographic databases were systematically searched for peer-reviewed articles in English. Studies were reviewed for methodologic considerations and mean direct cost of active surveillance or watchful waiting (as/ww) and initial treatments. Direct cost was standardized to 2011 Canadian dollars. RESULTS: After a review of abstracts and full-text papers, seventeen articles met the eligibility criteria and were included in the review. Studies were published during 1992-2010. The studies reported on health care systems in the United States, France, the United Kingdom, German, Italy, and Spain. Our review identified a lack of methodologic consensus, leading to variation in direct costs between studies. Nevertheless, results indicate a significant direct cost of pca treatments. CONCLUSIONS: The existing literature lacks methodologically rigorous studies on the direct costs of pca treatments specific to publicly funded health care systems. Additional studies are required to appreciate the direct costs of newer treatments and the impact of their adoption on the growing economic burden of pca management.

Infrared thermotransmittance-based temperature field measurements in semitransparent media.

Contactless temperature field measurements in or at the surfaces of semitransparent media are a scientific challenge as classical thermography techniques based on proper material emission cannot be used. In this work, an alternative method using infrared thermotransmittance for contactless temperature imaging is proposed. To overcome the weakness of the measured signal, a lock-in acquisition chain is developed and an imaging demodulation technique is used to retrieve the phase and amplitude of the thermotransmitted signal. These measurements, combined with an analytical model, enable the estimation of the thermal diffusivity and conductivity of an infrared semitransparent insulator (wafer of Borofloat 33 glass) and the monochromatic thermotransmittance coefficient at 3.3 µm. The obtained temperature fields are in good agreement with the model, and a detection limit of ±2 °C is estimated with this method. The results of this work open new opportunities in the development of advanced thermal metrology for semitransparent media.

Early adhesion of human mesenchymal stem cells on TiO(2) surfaces studied by single-cell force spectroscopy measurements.

Understanding the interactions involved in the adhesion of living cells on surfaces is essential in the field of tissue engineering and biomaterials. In this study, we investigate the early adhesion of living human mesenchymal stem cells (hMSCs) on flat titanium dioxide (TiO(2) ) and on nanoporous crystallized TiO(2) surfaces with the use of atomic force microscopy-based single-cell force spectroscopy measurements. The choice of the substrate surfaces was motivated by the fact that implants widely used in orthopaedic and dental surgery are made in Ti and its alloys. Nanoporous TiO(2) surfaces were produced by anodization of Ti surfaces. In a typical force spectroscopy experiment, one living hMSC, immobilized onto a fibronectine-functionalized tipless lever is brought in contact with the surface of interest for 30 s before being detached while recording force-distance curves. Adhesion of hMSCs on nanoporous TiO(2) substrates having inner pore diameter of 45 nm was lower by approximately 25% than on TiO(2) flat surfaces. Force-distance curves exhibited also force steps that can be related to the pulling of membrane tethers from the cell membrane. The mean force step was equal to 35 pN for a given speed independently of the substrate surface probed. The number of tethers observed was substrate dependent. Our results suggest that the strength of the initial adhesion between hMSCs and flat or nanoporous TiO(2) surfaces is driven by the adsorption of proteins deposited from serum in the culture media.

Adaptation of Pseudomonas aeruginosa to a pulsed light-induced stress.

AIMS: Pulsed light (PL) technology is an efficient surface decontamination process. Used in low transmitted energy conditions, PL induces a stress that can be perceived by bacteria. The effect of such a PL stress was investigated on the highly environmental adaptable germ Pseudomonas aeruginosa PAO1. METHODS AND RESULTS: Pulses of transmitted energy (fluence) reaching 1·8Jcm(-2) can kill 10(9) bacteria. Application of a lower sublethal PL dose allowed the bacteria to resist and survive more efficiently to a subsequent dose of PL. This sublethal dose was not increasing the mutation frequency of Ps. aeruginosa, but altered the abundance of 15 proteins as revealed by a global proteome analysis, including stress-induced proteins, phage-related proteins, energy and carbon metabolisms, cell motility, and transcription and translation regulators. CONCLUSIONS: A response to a low-energy PL dose takes place in Ps. aeruginosa, reducing the energy conversion systems, while increasing transcription and translation processes to produce proteins involved in chaperone mechanisms and phage-related proteins, probably to protect the bacterium against a new PL-induced stress. SIGNIFICANCE AND IMPACT OF THE STUDY: Taken together, these results suggest that a low-energy PL dose is sufficient to provoke adaptation of Ps. aeruginosa, leading to enhancing its resistance to a subsequent lethal treatment.

Recognition of radiographers in the workplace: Why it matters.

INTRODUCTION: Recognition of radiographers' work has received limited research attention to date, notably its link with wellbeing at work (i.e., job and career satisfaction) and emotional exhaustion. This research focuses on these links and examines more precisely the mediational psychological mechanism (i.e., professional identification) that could explain these relationships. METHODS: This was a cross-sectional, quantitative study with data obtained through an online survey. The sample comprised 713 radiographers working in France. Structural equation modeling was used to test the mediational model. RESULTS: Results of structural equation analysis suggest that radiographers who perceive more professional recognition from their supervisors, colleagues and patients are those who identify most with their profession and who are most satisfied by their job and their career; they also show lower levels of emotional exhaustion. These results underline the crucial role of recognition in the workplace for these professionals. CONCLUSION: Recognition is one of the basic needs of an individual, and satisfying this need is a crucial issue for organizations. This paper focuses on the importance of recognition for radiographers, notably to protect their psychological health and increase their well-being at work and in their professional career. PRACTICAL IMPLICATIONS: Health organizations and supervisors should be aware of the importance of recognizing radiographers' work in order to improve their psychological health, enhance their perceived quality of life at work, and have a positive perception of their career and their work.

Postprandial hyperaminoacidaemia overcomes insulin resistance of protein anabolism in men with type 2 diabetes.

AIMS/HYPOTHESIS: Although protein is usually ignored when considering insulin resistance, we have shown resistance of protein concurrent with glucose metabolism in men with type 2 diabetes during a hyperinsulinaemic clamp at euglycaemia and fasting aminoacidaemia. We hypothesised that this resistance is even worse during conditions that simulate the postprandial state, when anabolism should be maximal. METHODS: Eight overweight and obese men with type 2 diabetes underwent a hyperinsulinaemic-hyperglycaemic (8 mmol/l) clamp, first with plasma amino acids at postabsorptive (Hyper-2) then at postprandial concentrations (Hyper-3). Whole-body protein kinetics were assessed using L-: [1-(13)C]leucine. Hyper-2 results were compared with those of diabetic men whose plasma glucose was lowered to 5.5 mmol/l and fasting aminoacidaemia maintained during the hyperinsulinaemic clamp (Hyper-1). RESULTS: In Hyper-2 vs Hyper-1 clamps, leucine flux (2.99 ± 0.16 vs 2.62 ± 0.06 µmol kg [fat-free mass (FFM)](-1) min(-1)), rates of synthesis (2.31 ± 0.15 vs 1.98 ± 0.06) and breakdown (2.38 ± 0.16 vs 2.00 ± 0.07) were higher (p < 0.05), but leucine oxidation and net balance did not differ. In Hyper-3 vs Hyper-2 clamps, leucine flux and synthesis and oxidation rates increased markedly as did net balance (0.84 ± 0.09 vs -0.07 ± 0.04 µmol [kg FFM](-1) min(-1), p < 0.0001). CONCLUSIONS/INTERPRETATION: In type 2 diabetic men, insulin resistance of protein metabolism is of the same magnitude at 8 vs 5.5 mmol/l, but turnover rates are higher with hyperglycaemia. Contrary to our hypothesis, sustained postprandial-level hyperaminoacidaemia stimulated positive net protein balance comparable with that previously found in lean non-diabetic men. This was sufficient to overcome the insulin resistance of protein anabolism.

Hyperaminoacidaemia at postprandial levels does not modulate glucose metabolism in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Hyperaminoacidaemia attenuates glucose disposal during hyperinsulinaemic clamps in healthy lean individuals, an effect thought to be mediated by negative feedback on insulin signalling, downstream of the mammalian target of rapamycin (mTOR) signalling pathway. This has been interpreted as amino acids causing insulin resistance in healthy people, and contributing to it in type 2 diabetes. However, the effect of hyperaminoacidaemia on glucose disposal in type 2 diabetic individuals remains to be determined. METHODS: Eight obese men with type 2 diabetes underwent a two-step hyperinsulinaemic-hyperglycaemic (8 mmol/l) clamp, first with amino acids at postabsorptive concentrations, followed by postprandial concentrations. Whole-body glucose turnover was assessed using D: -[3-(3)H]glucose. Vastus lateralis biopsies were obtained at baseline and during each step of the clamp to determine the phosphorylation states of AKT, mTOR, ribosomal protein (rp) S6, and insulin receptor substrate (IRS)-1. RESULTS: Rates of glucose infusion (1.30 ± 0.19 vs 1.15 ± 0.13 mmol/min), endogenous glucose production (0.48 ± 0.06 vs 0.53 ± 0.05 mmol/min) and disposal (1.24 ± 0.17 vs 1.17 ± 0.14 mmol/min) did not differ between postabsorptive and postprandial amino acid concentrations (p > 0.05). Whereas phosphorylation of AKT(Ser473), AKT(Thr308) mTOR(Ser2448) and rpS6(Ser235/236) increased (p < 0.05) with elevated amino acids, that of IRS-1(Ser636/639) and IRS-1(Ser1101) did not change. CONCLUSIONS/INTERPRETATION: Postprandial circulating amino acid concentrations do not worsen the already attenuated glucose disposal in hyperglycaemic type 2 diabetic men, and cell-signalling events are consistent with this. Our results do not support recommendations to restrict dietary protein in type 2 diabetes.

Cell cycle control of replication initiation in eukaryotes.

Studies on the initiation of DNA replication in eukaryotes have progressed recently through different approaches that promise to converge. Proteins interacting with the origin recognition complex form a prereplicative complex early in the cell cycle. The regulation of the binding of MCM/P1 proteins to chromatin plays a key role in the replication licensing system which prevents re-replication in a single cell cycle. Cyclin-dependent kinases provide an overall control of the cell cycle by stimulating S-phase entry and possibly by preventing re-establishment of prereplicative complexes in G2 phase.

3D infrared thermospectroscopic imaging.

This work reports a multispectral tomography technique in transmission mode (called 3DITI for 3D Infrared Thermospectroscopic Imaging) based on a middle wavelength infrared (MWIR) focal plane array. This technique relies on an MWIR camera (1.5 to 5.5 µm) used in combination with a multispectral IR monochromator (400 nm to 20 µm), and a sample mounted on a rotary stage for the measurement of its transmittance at several angular positions. Based on the projections expressed in terms of a sinogram, spatial three-dimensional (3D) cubes (proper emission and absorptivity) are reconstructed using a back-projection method based on inverse Radon transform. As a validation case, IR absorptivity tomography of a reflective metallic screw is performed within a very short time, i.e., shorter than 1 min, to monitor 72 angular positions of the sample. Then, the absorptivity and proper emission tomographies of a butane-propane-air burner flame and microfluidic perfluoroalkoxy (PFA) tubing filled with water and ethanol are obtained. These unique data evidence that 3D thermo-chemical information in complex semi-transparent media can be obtained using the proposed 3DITI method. Moreover, this measurement technique presents new problems in the acquisition, storage and processing of big data. In fact, the quantity of reconstructed data can reach several TB (a tomographic sample cube of 1.5 × 1.5 × 3 cm3 is composed of more than 1 million pixels per wavelength).

Early events in DNA replication require cyclin E and are blocked by p21CIP1.

Using immunodepletion of cyclin E and the inhibitor protein p21WAF/CIP1, we demonstrate that the cyclin E protein, in association with Cdk2, is required for the elongation phase of replication on single-stranded substrates. Although cyclin E/Cdk2 is likely to be the major target by which p21 inhibits the initiation of sperm DNA replication, p21 can inhibit single-stranded replication through a mechanism dependent on PCNA. While the cyclin E/Cdk2 complex appears to have a role in the initiation of DNA replication, another Cdk kinase, possibly cyclin A/Cdk, may be involved in a later step controlling the switch from initiation to elongation. The provision of a large maternal pool of cyclin E protein shows that regulators of replication are constitutively present, which explains the lack of a protein synthesis requirement for replication in the early embryonic cell cycle.

Cell cycle regulation of the replication licensing system: involvement of a Cdk-dependent inhibitor.

The replication licensing factor (RLF) is an essential initiation factor that is involved in preventing re-replication of chromosomal DNA in a single cell cycle. In Xenopus egg extracts, it can be separated into two components: RLF-M, a complex of MCM/P1 polypeptides, and RLF-B, which is currently unpurified. In this paper we investigate variations in RLF activity throughout the cell cycle. Total RLF activity is low in metaphase, due to a lack of RLF-B activity and the presence of an RLF inhibitor. RLF-B is rapidly activated on exit from metaphase, and then declines during interphase. The RLF inhibitor present in metaphase extracts is dependent on the activity of cyclin-dependent kinases (Cdks). Affinity depletion of Cdks from metaphase extracts removed the RLF inhibitor, while Cdc2/cyclin B directly inhibited RLF activity. In metaphase extracts treated with the protein kinase inhibitor 6-dimethylaminopurine (6-DMAP), both cyclin B and the RLF inhibitor were stabilized although the extracts morphologically entered interphase. These results are consistent with studies in other organisms that invoke a key role for Cdks in preventing re-replication of DNA in a single cell cycle.

Antihyperglycaemic medication modifies factors of postprandial satiety in type 2 diabetes.

AIM: Type 2 diabetes is characterized by hyperglycaemia, delayed gastric emptying and a blunted response of gut hormones during feeding that may modulate satiety. We hypothesized that it is associated with more hunger when treated by medication. METHODS: We studied nine type 2 diabetic men (A1C: 6.7+/-0.3%, waist circumference: 104+/-4 cm) after an overnight fast, during 5 h in response to a 2.88 MJ breakfast, twice, in a crossover design, with or without antihyperglycaemic agents. Satiety ratings, thermic effect of meal, gastric emptying, plasma concentrations of gut peptides, leptin, insulin and substrates and intake from a subsequent buffet were determined. RESULTS: With medication, fasting and postprandial plasma glucose levels were lower but area under the curve (AUC) did not vary vs. without medication. Gastric emptying was shortened, branched chain amino acids (BCAA) AUC and thermic effect were lower, and postprandial glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY3-36) were maintained at higher levels beyond 4 h. Correlations were significant between duration of diabetes and fasting ghrelin (r=0.779, p=0.013) and peak insulin (r=-0.769, p=0.016), 5-h postmeal ghrelin and peak glucose (r=0.822, p=0.007), 5-h glucose and GLP-1 (r=-0.788, p=0.012), and 5-h hunger scores and energy intake at buffet (r=0.828, p=0.006). Without medication, fullness scores correlated with BCAA levels. Visual analogue scale scores, ghrelin and leptin levels did not differ between studies. CONCLUSIONS: The decrease in factors associated with postprandial satiety with treatment is counterbalanced by higher GLP-1 and PYY3-36. Medication may normalize the link between perception of hunger and subsequent food intake.

CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex.

Ciliary neurotrophic factor (CNTF) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, CNTFR, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (LIFR). Striking phenotypic differences between CNTF- and CNTFR-deficient mice suggest that CNTFR serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (CLC) and the soluble receptor cytokine-like factor-1 (CLF). CLF expression was required for CLC secretion, and the complex acted only on cells expressing functional CNTF receptors. The CLF/CLC complex activated gp130, LIFR and signal transducer and activator of transcription 3 (STAT3) and supported motor neuron survival. Our results indicate that the CLF/CLC complex is a second ligand for CNTFR with potentially important implications in nervous system development.