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Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D., Fumiaki Imamura and colleagues investigate the association between concentrations of fatty acid involved in de-novo lipogensis and incidence of Type 2 diabetes., Author summary Why was this study done? De novo lipogenesis (DNL) is a metabolic pathway involved in the endogenous synthesis of specific fatty acids, such as 16:0, 16:1n7, 18:0, and 18:1n9, and it is linked to the pathophysiology of cardiometabolic diseases, including type 2 diabetes (T2D). Circulating or tissue concentrations of these fatty acids have been investigated for the associations with T2D incidence in epidemiological research. However, published studies reported inconsistent associations inconsistently and were subject to publication bias. Summary evidence is not available to date for the associations between these fatty acids and T2D incidence. An integration of available cohort studies would increase statistical power and allow assessment of generalizability, standardization of analytical strategies, and evidence synthesis with the potential publication bias minimized. What did the researchers do and find? As a part of the Fatty Acids and Outcomes Research Consortium (FORCE), we conducted new individual-participant data analyses of 17 cohort studies of a total of 65,225 adults free of T2D at baseline, among whom 15,383 developed incident T2D over up to 20 years of follow-up. The cohort studies analyzed the associations between fatty acids (16:0, 16:1n7, 18:0, and 18:1n9) and the risk of developing T2D with standardized analytic strategy. In pooled analyses, each of the fatty acids was positively associated with a higher risk of developing T2D. The associations were independent of major risk factors for T2D, such as age, sex, race/ethnicity, socioeconomic characteristics, smoking status, physical activity, and obesity. What do these findings mean? The findings provide the first summary evidence to date for the positive relationships of concentrations of the DNL-related fatty acids with a risk of T2D, indicating the strong relevance of DNL and its determinants to the development of T2D. These fatty acids potentially reflect the status of DNL activity, which may be stimulated or suppressed by a combination of carbohydrate intake, alcohol intake, polyunsaturated fatty acid intake, and other lifestyle and clinical factors. Therefore, the current findings indicate the need for investigation into determinants and consequences of elevated concentrations of these fatty acids. Despite several advantages of our individual-level data analysis in this pooling project, the results cannot establish whether elevated concentrations of these fatty acids caused the development of T2D or whether underlying peripheral or hepatic insulin resistance, for example, may elevate both the fatty acid concentrations and the risk of T2D independently.

Background Few studies have assessed the associations of ceramides and sphingomyelins (SMs) with diabetes in humans. Objective We assessed associations of 15 circulating ceramides and SM species with incident diabetes in 2 studies. Methods The analysis included 435 American-Indian participants from the Strong Heart Study (nested case-control design for analyses; mean age: 57 y; 34% male; median time until diabetes 4.3 y for cases) and 1902 participants from the Strong Heart Family Study (prospective design for analyses; mean age: 37 y; 39% male; median 12.5 y of follow-up). Sphingolipid species were measured using stored plasma samples by sequential LC and MS. Using logistic regression and parametric survival models within studies, and an inverse-variance-weighted meta-analysis across studies, we examined associations of 15 ceramides and SM species with incident diabetes. Results There were 446 cases of incident diabetes across the studies. Higher circulating concentrations of ceramides containing stearic acid (Cer-18), arachidic acid (Cer-20), and behenic acid (Cer-22) were each associated with a higher risk of diabetes. The RRs for incident diabetes per 1 SD of each log ceramide species (μM) were 1.22 (95% CI: 1.09, 1.37) for Cer-18, 1.18 (95% CI: 1.06, 1.31) for Cer-20, and 1.20 (95% CI: 1.08, 1.32) for Cer-22. Although the magnitude of the risk estimates for the association of ceramides containing lignoceric acid (Cer-24) with diabetes was similar to those for Cer-18, Cer-20, and Cer-22 (RR = 1.13; 95% CI: 1.01, 1.26), the association was not statistically significant after correction for multiple testing (P = 0.007). Ceramides carrying palmitic acid (Cer-16), SMs, glucosyl-ceramides, or a lactosyl-ceramide were not associated with diabetes risk. Conclusions Higher concentrations of circulating Cer-18, Cer-20, and Cer-22 were associated with a higher risk of developing diabetes in 2 studies of American-Indian adults. This trial was registered at clinicaltrials.gov as NCT00005134.

The voltage source inverter used droop control has the characteristics of no communication, plug and play and high flexibility. Since the impedance in the line cannot be accurately measured, if multiple inverters are connected in parallel, the reactive power in parallel system cannot be accurately distributed in proportion. Therefore, a reactive power distributing control strategy of multi-inverter under weak communication conditions is proposed. First, the reactive power generated by each inverter is calculated. Then the impedance between the AC bus and each inverter is adaptively matched according to reactive power deviation. The matching algorithm will stop, when the reactive power is less than the specified threshold. Finally, the virtual impedance parameter of each inverter is adjusted to a fixed value. The proportional distribution of reactive power will no longer rely on communication. Therefore, the proportional distribution of the reactive power of multiple inverters is realized in the weak communication scenario.

With the rapid development of DC microgrid, the speed and reliability of circuit breaker protection in DC distribution networks have become more and more important. The power electronic switching devices used in solid-state circuit breakers(SSCB) has low overvoltage and overcurrent margins. Therefore, suppressing the overvoltage of the power electronic switching device in the case of a short-circuit fault, and quickly consuming the energy in the faulty circuit has become an important content of snubber circuit design. This article analyzes the operating mechanism of traditional circuit breakers. Then, an improved design scheme of solid-state circuit breaker snubber circuit is proposed, and the design method of related parameters is given. Finally, the correctness and effectiveness of the proposed snubber circuit are verified by simulation and experiment result.

Background Animal studies suggest sphingolipids as an early marker of impaired glucose metabolism; however, research in humans is limited. We evaluated whether individual sphingolipid species were associated with fasting plasma glucose and incident impaired fasting glucose in a longitudinal cohort study. Methods We measured 15 sphingolipid species from blood samples collected in 2001–2003 from 2145 participants without prevalent diabetes in the Strong Heart Family Study. Fasting plasma glucose was measured in blood samples collected at baseline and follow-up (mean 5.5 years after baseline). Findings The average age of study participants was 38 years; 41% were men. Ceramide, sphingomyelin, and glucosylceramide species levels were higher in older participants; lactosyl-ceramide levels were higher in participants with lower BMIs. In adjusted analyses, greater concentrations of most ceramide species and lower lactosyl-ceramide with palmitic acid (LC-16) were associated with higher glucose levels at baseline. We did not observe associations of sphingomyelin species or glucosyl-ceramide species with glucose levels. Associations of sphingolipid levels with fasting glucose levels at follow-up were similar but had greater uncertainty than associations with baseline glucose. Although no statistically significant associations of sphingolipids with incident impaired fasting glucose were present, results were similar to glucose analyses. Interpretation We identified several ceramide species associated with higher fasting glucose levels and one sphingolipid, LC-16, that was associated with lower fasting glucose levels. These findings compliment previous research, which linked these sphingolipids with fasting insulin levels, and suggest that higher levels of these ceramides and lower LC-16 may be an early marker of impaired glucose metabolism. Fund US National Institutes Health.

In traditional power electronic power generation devices, there is no rotor inertia like a synchronous machine. Load changes will cause sudden changes in the frequency of the microgrid system, which can easily trigger the protection device of the system and have a negative impact on the stable operation of the microgrid system. At the same time, if there is a large inertia in control loop, it will reduce the response speed of the system and easily cause oscillation. In this article, an adaptive inertia control technology based on power feedback is proposed. By adding power feedback control in the inertia link, the rate of change of frequency can be suppressed and the transient response of the system can be improved at the same time. Finally, the effectiveness of the proposed method is validated by the simulation results.

As the capacity of the wind farm is being increasing, the grid-connected stability problems caused by reactive power and voltage fluctuation cannot be ignored, one effective solution is to adopt the automatic voltage control system (AVCS) in the wind farm. This paper briefly describes the structure and control strategy of AVCS, and introduces an operation scheme for AVCS including the voltage control and reactive power regulation principles. Especially, communication modes of AVCS are introduced. The proposed operation scheme can regulate the voltage of the bus within the scope of dispatching requirements in the wind farm. Also, it can flexibly coordinate the output reactive power of every wind turbine generator and reactive power compensation device in the wind farm. Finally, this paper evaluates the control effect and dynamic response characteristic of the AVCS by the field test, the effectiveness of the proposed operation scheme is verified.

Experimental studies suggest ceramides may play a role in insulin resistance. However, the relationships of circulating ceramides and related sphingolipids with plasma insulin have been underexplored in humans. We measured 15 ceramide and sphingomyelin species in fasting baseline samples from the Strong Heart Family Study (SHFS), a prospective cohort of American Indians. We examined sphingolipid associations with both baseline and follow-up measures of plasma insulin, HOMA of insulin resistance (HOMA-IR), and HOMA of β-cell function (HOMA-B) after adjustment for risk factors. Among the 2,086 participants without diabetes, higher levels of plasma ceramides carrying the fatty acids 16:0 (16 carbons, 0 double bond), 18:0, 20:0, or 22:0 were associated with higher plasma insulin and higher HOMA-IR at baseline and at follow-up an average of 5.4 years later. For example, a twofold higher baseline concentration of ceramide 16:0 was associated with 14% higher baseline insulin (P < 0.0001). Associations between sphingomyelin species carrying 18:0, 20:0, 22:0, or 24:0 and insulin were modified by BMI (P < 0.003): higher levels were associated with lower fasting insulin, HOMA-IR, and HOMA-B among those with normal BMI. Our study suggests lowering circulating ceramides might be a target in prediabetes and targeting circulating sphingomyelins should take into account BMI.

Summary The Genomic Data Storage (GDS) format provides efficient storage and retrieval of genotypes measured by microarrays and sequencing. We developed GENESIS to perform various single- and aggregate-variant association tests using genotype data stored in GDS format. GENESIS implements highly flexible mixed models, allowing for different link functions, multiple variance components and phenotypic heteroskedasticity. GENESIS integrates cohesively with other R/Bioconductor packages to build a complete genomic analysis workflow entirely within the R environment. Availability and implementation https://bioconductor.org/packages/GENESIS; vignettes included. Supplementary information Supplementary data are available at Bioinformatics online.

International audience; BACKGROUND:Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.OBJECTIVE:We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.METHODS:Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.RESULTS:There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.CONCLUSIONS:Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.

High levels of fasting plasma insulin, reflecting insulin resistance, are an early event in the progression to type 2 diabetes. Experimental studies implicate ceramides in insulin resistance; however, whether circulating ceramides and related sphingolipids are associated with plasma insulin in humans is uncertain. We measured 15 ceramide and sphingomyelin species with different saturated fatty acids in baseline fasting plasma samples from the Strong Heart Family Study, a prospective cohort of American Indians. We examined associations of sphingolipids with plasma insulin, HOMA-IR and HOMA-B at baseline and follow-up (median 5 years later) using linear mixed models adjusted for family structure. Among 2086 participants without diabetes, higher levels of plasma ceramides carrying the fatty acids 16:0, 18:0, 20:0 or 22:0 were associated with higher plasma insulin and higher HOMA-IR at baseline and follow-up (Table). BMI modified associations of sphingomyelin species carrying 18:0, 20:0, 22:0 or 24:0 with insulin (p Table. Plasma Ceramides, Insulin and HOMAIR.SpeciesFold change in geometric mean with 2 fold higher ceramide (95% CI), p-valueBaseline insulinFollow-up insulinBaseline HOMAIRFollow-up HOMAIRCer-16:01.13 (1.07-1.20) 1.9x10-51.10 (1.01-1.21) 0.031.15 (1.08-1.22) 4.7x10-61.11 (1.01-1.22) 0.03Cer-18:01.11 (1.06-1.15) 1.0x10-61.12 (1.06-1.19) 1.0x10-51.12 (1.08-1.17) 6.3x10-81.13 (1.06-1.20) 2.0x10-4Cer-20:01.12 (1.07-1.17) 1.5x10-71.10 (1.03-1.18) 0.0031.13 (1.08-1.18) 1.3x10-71.11 (1.04-1.19) 0.002Cer-22:01.13 (1.08-1.19) 3.9x10-71.12 (1.04-1.20) 0.0041.15 (1.09-1.21) 1.0x10-71.13 (1.04-1.22) 0.004Cer-24:01.(0.99-1.11) 0.081.09 (1.01-1.19) 0.041.(1.00-1.13) 0.041.11 (1.01-1.21) 0.03Covariates: age, sex, site, education, smoking, log(BMI), waist, physical activity. Disclosure R.N. Lemaitre: None. C. Yu: None. A. Hoofnagle: Research Support; Self; Waters Corporation. H. Nair: None. P.N. Jensen: None. A.M. Fretts: None. J.G. Umans: None. C. Sitlani: None. D. Siscovick: None. I. King: None. N. Sotoodehnia: None. B. McKnight: None.

In multiple testing scenarios, typically the sign of a parameter is inferred when its estimate exceeds some significance threshold in absolute value. Typically, the significance threshold is chosen to control the experimentwise type I error rate, family-wise type I error rate or the false discovery rate. However, controlling these error rates does not explicitly control the sign error rate. In this paper, we propose two procedures for adaptively selecting an experimentwise significance threshold in order to control the sign error rate. The first controls the sign error rate conservatively, without any distributional assumptions on the parameters of interest. The second is an empirical Bayes procedure, and achieves optimal performance asymptotically when a model for the distribution of the parameters is correctly specified. We also discuss an adaptive procedure to minimize the sign error rate when the experimentwise type I error rate is held fixed., Comment: 19 pages, 4 figures

Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73–0.87); of 17:0, 0.65 (0.59–0.72); of t16:1n7, 0.82 (0.70–0.96); and of their sum, 0.71 (0.63–0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. Conclusions In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D., Fumiaki Imamura and colleagues reveal a correlation between higher levels of circulating and adipose odd-chain fatty and trans-palmitoleic acids and lower risk of developing diabetes., Author summary Why was this study done? Effects of dairy fat on type 2 diabetes (T2D) are not well established. While dairy fat contains palmitic acid that could increase risk of T2D, it also contains several other types of fatty acids and further reflects specific foods, such as cheese or yogurt, that could reduce risk. Most prior studies of dairy foods and T2D have relied on self-reported dietary questionnaires, which may have errors or bias in memory as well as challenges in assessing less apparent sources of dairy fat such as in creams, sauces, cheeses, and cooking fats in mixed meals and prepared foods. Circulating and tissue biomarker concentrations of odd-chain saturated fats (15:0, 17:0) and natural ruminant trans-fats (trans-16:1n7) at least partly reflect dairy fat consumption, help capture multiple dietary sources without relying on memory or subjective reporting, and reflect a complementary approach to investigate associations with T2D. A consortium strategy combining all available studies maximises statistical power and generalizability, allows standardised analytical approaches and methods including of key population subgroups, and minimises potential for publication bias. What did the researchers do and find? We conducted a consortium project to pool new participant-level analyses of 16 cohort studies as part of the Fatty Acids and Outcomes Research Consortium (FORCE), including a total of 63,682 adults free of T2D at baseline, among whom 15,158 developed incident T2D over up to 20 years of follow-up. Participating studies conducted standardised analysis of the prospective associations between fatty acid biomarkers (15:0, 17:0, trans-16:1n7, and their sum) and the risk of developing T2D. Pooling all studies, each of the biomarkers and their sum were associated with lower risk of developing T2D, independently of major risk factors for T2D, including age, sex, race/ethnicity, socioeconomic status, physical activity, and obesity. For example, for the sum of these biomarkers, participants with higher levels experienced 29% (95% CI 21% to 37%) lower risk of T2D than adults with lower levels, comparing between the midpoints of the top fifth and the bottom fifth of concentrations. What do these findings mean? Higher circulating and tissue concentrations of odd-chain saturated fats and a natural ruminant trans-fat are associated with lower risk of T2D. While these biomarkers are known to reflect dairy fat consumption, their levels could also be influenced by other unknown factors. The findings support the need for investigation of determinants of levels of these fatty acids as well as health effects of dairy fat in interventional studies. Despite the several advantages of evaluating fatty acid biomarkers, the results cannot distinguish between different types of dairy foods (e.g., milk, cheese, yogurt, others), which could have differential effects. The findings provide the strongest evidence to date for relationships of these fatty acid biomarkers with T2D, informing the potential health effects and corresponding dietary recommendations for consumption of selected dairy products.

Background: Circulating saturated fatty acids are biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. Unlike palmitic acid (16:0), which has been extensively studied, little is known of the relationship of very long-chain saturated fatty acids (VLSFAs), with 20 carbons or more, to diabetes risk. Objective: To investigate the associations of circulating levels of VLSFA with incident diabetes. Methods: A meta-analysis was conducted within a consortium of prospective (cohort or nested case-control) studies having circulating measures of one or more VLSFAs, including arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0). Standardized analysis was conducted in each study using pre-specified models, exposures, outcomes, and covariates. Study-specific estimates were pooled using fixed effects meta-analysis. Results: Current findings were based on 9 participating studies, including 46,549 total participants and 13,750 incident diabetes. In multivariable-adjusted analyses, higher levels of all 3 VLSFAs were associated with lower risk of incident diabetes. Pooled RRs (95% CI) per interquintile range were 0.80 (0.71-0.90) for 20:0; 0.83 (0.76-0.91) for 22:0; and 0.70 (0.63-0.79) for 24:0, after adjustment for demographics, lifestyle factors and clinical conditions. Additional adjustments for circulating palmitic acid and triglyceride levels moved the RRs toward the null (illustrated for 24:0, in model 3 of the Figure ). Conclusions: Based on meta-analysis of results from several studies around the world, biomarker levels of VLSFA are associated with lower risk of incident diabetes, potentially mediated by effects on circulating triglycerides and 16:0.

Confidence intervals for the means of multiple normal populations are often based on a hierarchical normal model. While commonly used interval procedures based on such a model have the nominal coverage rate on average across a population of groups, their actual coverage rate for a given group will be above or below the nominal rate, depending on the value of the group mean. Alternatively, a coverage rate that is constant as a function of a group's mean can be simply achieved by using a standard $t$-interval, based on data only from that group. The standard $t$-interval, however, fails to share information across the groups and is therefore not adaptive to easily obtained information about the distribution of group-specific means. In this article we construct confidence intervals that have a constant frequentist coverage rate and that make use of information about across-group heterogeneity, resulting in constant-coverage intervals that are narrower than standard $t$-intervals on average across groups. Such intervals are constructed by inverting biased tests for the mean of a normal population. Given a prior distribution on the mean, Bayes-optimal biased tests can be inverted to form Bayes-optimal confidence intervals with frequentist coverage that is constant as a function of the mean. In the context of multiple groups, the prior distribution is replaced by a model of across-group heterogeneity. The parameters for this model can be estimated using data from all of the groups, and used to obtain confidence intervals with constant group-specific coverage that adapt to information about the distribution of group means.

Background Although indolent non-Hodgkin lymphomas (iNHLs) are responsive to initial therapy, patients have a relapsing and progressive disease course and most remain incurable with current treatments. Lenalidomide is an immunomodulatory agent that enhances rituximab-mediated antibody-dependent cellular cytotoxicity. In lymphoma cell lines, animal models, and in several phase II trials, combining lenalidomide and rituximab (R2) resulted in improved antitumor activity relative to either agent alone. However, the immunological mechanisms remain unclear. Here we provide updated results from a phase II trial investigating the clinical activity of R2 in previously untreated and relapsed/refractory (R/R) patients with iNHL. We also present an analysis of immunologic correlative data that may provide insight into the therapy's mechanism-of-action and may also predict response. Aims Study aims were to assess: the clinical activity of the R2 regimen in previously untreated and R/R iNHL patients and, assess the potential of serum cytokine levels to predict response. Methods Patients had previously untreated (n=15) or R/R (n=30) iNHL with measurable disease, and ECOG Performance Status ² 2. Lenalidomide (20 mg/day) was administered on days 1–21 of a 28-day cycle and continued until disease progression, rituximab 375 mg/m2 IV was administered on day 15 of cycle 1 and repeated weekly for a total of 4 doses. The primary clinical endpoint was overall response rate (ORR). Secondary endpoints included response duration (DR), overall survival, progression-free survival (PFS), and safety. The correlative serum cytokine samples were obtained from patients at baseline, D15 (prior to treatment with rituximab), D30 and D60. IL-1, 2, 6, 8, 10, 12, GM-CSF, IFN-γ, TNF-α , CXCL-10/IP-10 levels were measured at each time point using a Meso Scale Discovery multi-plex cytokine assay. The cytokine levels at each time point were then correlated with response using a two-sided T test. Results Of the 30 R/R patients, 22 had follicular lymphoma (FL), the median age was 60 years, median number of prior therapies was 3 (range 1–11), and 50% were refractory to rituximab. Of the 15 previously untreated patients, 12 had FL and the median age was 58. For the 27 evaluable R/R patients, the ORR was 74%, including 12 patients (44%) with a CR. At a median follow-up of 34 months, median PFS was 12.4 months, the median DR and time to next therapy (TTNT) were 15.4 and 37.4 months respectively with 7 remissions that are ongoing including three that have lasted more than 48 months. Of the 15 previously untreated patients 13 are evaluable for response; the ORR was 92% with 6 of 13 (42%) having a CR. At a median follow-up of 18 months the median PFS is 14.5 months; the median DR has not been reached. The correlative analyses showed that there was a significant increase in IFN-γ, GM-CSF, CXCL-10 and IL-2 at Day 15 with a 652, 494, 737, and 242% increase respectively above baseline which correlated with patients who had a CR (p < 0.05), Table. IL-1, 6, 8, 10, 12, and TNF-α were also measured, but did not predict CR at any time point. Phenotypic and functional analyses are ongoing. There was no significant difference in the percent increase in cytokine levels in previously untreated versus R/R patients. Conclusion The R2 regimen has considerable activity in patients with both untreated or R/R iNHL, particularly those with FL. A significant increase in the serum levels of IFN-γ, GM-CSF, IL-2 and CXCL-10/IP-10 after 2 weeks of lenalidomide alone correlates with achievement of CR. Disclosures: Off Label Use: The use of lenalidomide for the treatment of indolent NHL will be discussed which is not an FDA approved indication. Tuscano:Celgene: Honoraria, Research Funding.