A projected cost-utility analysis of avacopan for the treatment of antineutrophil cytoplasmic antibody-associated vasculitis in Spain.

BACKGROUND: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are rare autoimmune diseases characterized by inflammation of blood vessels. This study aimed to assess the cost-utility of avacopan in combination with rituximab (RTX) or cyclophosphamide (CYC) compared with glucocorticoids (GC) for the treatment of severe, active AAV in Spain. METHODS: A 9-state Markov model was designed to reflect the induction of remission and sustained remission of AAV over a lifetime horizon. Clinical data and utility values were mainly obtained from the ADVOCATE trial, and costs (€ 2022) were sourced from national databases. Quality-adjusted life years (QALYs), and incremental cost-utility ratio (ICUR) were evaluated. An annual discount rate of 3% was applied. Sensitivity analyses were performed to examine the robustness of the results. RESULTS: Avacopan yielded an increase in effectiveness (6.52 vs. 6.17 QALYs) and costs (€16,009) compared to GC, resulting in an ICUR of €45,638 per additional QALY gained. Avacopan was associated with a lower incidence of end-stage renal disease (ESRD), relapse and hospitalization-related adverse events. Sensitivity analyses suggested that the model outputs were robust and that the progression to ESRD was a driver of ICUR. CONCLUSIONS: Avacopan is a cost-effective option for patients with severe, active AAV compared to GC in Spain.

Association between serum 25-hydroxyvitamin D and prostate-specific antigen: a retrospective study in men without prostate pathology.

Objectives: Recently, vitamin D status has been associated with prostate cancer risk. However, some studies argue that there is no association of vitamin D with prostate cancer risk and serum prostate-specific antigen (PSA) concentrations. No clear conclusions can be drawn from the studies found in the literature. Our aim was to assess the relationship between PSA and 25-hydroxyvitamin D [25(OH)D]. Methods: We selected 415 individuals without prostate pathologies and subgroups were generated according to age and 25(OH)D. Statistical analyses were performed using Shapiro-Wilk test, Student's t and ANOVA tests, and Pearson's correlation. Besides, the minimum sample size needed to obtain statistically significant results between groups according to 25(OH)D concentration was calculated and a Student's t-test for paired samples was performed to study individuals with two PSA measurements over time, where 25(OH)D concentration increased or decreased more than 25 %. Results: We observed a slight correlation between age and PSA concentration (r=0.379, p<0.001). However, we found no significant differences when we compared PSA concentrations between groups according to 25(OH)D concentrations (p=0.891): 1.25 ± 1.32 µg/L (group with 25(OH)D<50 nmol/L) and 1.17 ± 0.90 (group with 25(OH)D≥50 nmol/L). Pearson's correlation coefficient was close to 0. The minimum samples size to obtain statistically significant results was 815,346 men, and we observed no differences in PSA concentrations in individuals with two measurements. Conclusions: Our findings show no association in men without prostate pathologies, based on 25(OH)D levels.

Factors Underpinning the Shift to Eveningness during Early Adolescence: Pubertal Development and Family Conflicts.

Biological and psychosocial factors have been related to the shift to eveningness during early adolescence but it is necessary to study them from a longitudinal perspective. This longitudinal study examined the contribution of these factors to the onset of a shift towards eveningness in early adolescence. A sample of 440 (49.9% boys) Spanish adolescents were assessed for pubertal development, family conflicts, and morningness/eveningness. The same measures were taken twice at the age of 12 and one year later (T1: M = 12.47, SD = 0.75 and T2: M = 13.64, SD = 0.78). Pubertal development and family conflicts were considered predictors of morningness/eveningness in a mixed-effects multilevel model. The developmental shift towards eveningness appeared in girls but not in boys. The shift was related to more advanced pubertal development and more conflicts in the family. This study has implications for shaping healthy sleep habits in adolescents and possible interventions focused on family dynamics.

Before-and-After Study of the First Four Years of the Enhanced Recovery after Surgery (ERAS®) Programme in Older Adults Undergoing Elective Colorectal Cancer Surgery.

BACKGROUND: The aim of this study was to determine whether the inclusion of older patients undergoing elective colorectal cancer resection in the Enhanced Recovery After Surgery (ERAS®) programme could improve clinical outcomes during hospital admission. METHODS: A before-and-after study in ≥70-year-old patients electively admitted for colorectal cancer resection was designed. In total, 213 patients were included in the ERAS® group, and 158 were included in the control group. RESULTS: The average age was 77.9 years old (SD 5.31) and 57.14% of them were men, with a Charlson Index score of 3.42 (SD 3.32). The ERAS® group presented a lower transfusion rate of 42 (19.7%), compared to 75 (47.5%) in the control group (p < 0.001). The crude odds ratio (OR) for transfusion was 0.27 (95% CI 0.17-0.43; p < 0.001), and the adjusted odds ratio was 0.26 (95% CI 0.14-0.48; p < 0.001). The ERAS® group had a lower percentage of patients with moderate-severe malnutrition on admission, at 23.4% (37 patients) against 36.2% in the control group (42 patients) (p = 0.023), with an OR of 0.47 (95% CI 0.29-0.75; p < 0.002) and an adjusted OR of 0.48 (95% CI 0.29-0.78; p = 0.003). The number of patients who required admission to the intensive care unit (ICU) was also markedly lower: 54 from the ERAS® group (25.4%) versus 71 from the control group (44.9%) (p < 0.001). CONCLUSIONS: The inclusion of ≥70-year-old adults in the ERAS® programme resulted in a decrease in transfusions, number of erythrocyte concentrates transfused, and number of ICU admissions, along with improved nutritional status.

Adipokines Profile and Inflammation Biomarkers in Prepubertal Population with Obesity and Healthy Metabolic State.

(1) Background and aims: Obesity and high body max index (BMI) have been linked to elevated levels of inflammation serum markers such as C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), adiponectin, and resistin. It has been described that adipose tissue presents a high production and secretion of these diverse pro-inflammatory molecules, which may have local effects on the physiology of the fat cell and also systemic effects on other organs. Our aim was to evaluate the impact that lifestyle modifications, following a Mediterranean Diet (MedDiet) program and physical activity (PA) training, would have on inflammatory biomarkers in a metabolically healthy prepubertal population with obesity (MHOPp) from Malaga (Andalusia, Spain). (2) Methods: 144 MHOPp subjects (aged 5-9 years) were included in this study as they met ≤1 of the following criteria: waist circumference and blood pressure ≥ 90 percentile, triglycerides > 90 mg/dL, high-density lipoprotein cholesterol (HDL-c) < 40 mg/dL, or impaired fasting glucose (≥100 md/dL). Selected subjects followed a personalized intensive lifestyle modification. Anthropometric measurements, inflammation biomarkers, and adipokine profile were analyzed after 12 and 24 months of intervention. (3) Results: 144 MHOPp participants (75 boys-52% and 69 girls-48%; p = 0.62), who were 7.8 ± 1.4 years old and had a BMI 24.6 ± 3.3 kg/m2, were included in the study. After 24 months of MedDiet and daily PA, a significant decrease in body weight (-0.5 ± 0.2 SD units; p < 0.0001) and BMI (-0.7 ± 0.2 SD units; p < 0.0001) was observed in the total population with respect to baseline. Serum inflammatory biomarkers (IL-6, TNF-alpha, and CRP) after 24 months of intervention were significantly reduced. Adipokine profile (adiponectin and resistin) did not improve with the intervention, as adiponectin levels significantly decreased and resistin levels increased in all the population. Inflammatory biomarkers and adipokine profile had a significant correlation with anthropometric parameters, body composition, and physical activity. (4) Conclusions: After 24 months of lifestyle modification, our MHOPp reduced their Z-score of BMI, leading to an improvement of inflammatory biomarkers but inducing deterioration in the adipokine profile, which does not improve with MedDiet and physical activity intervention. An adequate education within the family about healthier habits is necessary to prevent and reduce an excessive increase in obesity in childhood.

Malnutrition and Increased Risk of Adverse Outcomes in Elderly Patients Undergoing Elective Colorectal Cancer Surgery: A Case-Control Study Nested in a Cohort.

BACKGROUND: Malnutrition increases worse outcomes during hospital admission for elective colorectal cancer (CRC) surgery in older adults. METHODS: This work was designed an observational, monocentric, case-control study nested in a cohort of patients undergoing elective surgery for CRC disease at the Hospital Universitario de la Ribera (HULR) (Alzira, Valencia, Spain) between 2011 and 2019. The study considered patients with a CONUT score in the range of moderate to severe malnutrition (>4 points), with control patients with normal nutritional situations or mild malnutrition. RESULTS: Moderate-to-severe malnutrition cases presented a greater length of stay (LOS), a higher incidence of adverse events (both medical and surgical complications), a higher incidence of surgical-wound infection, a greater need for blood transfusion, and a greater amount of transfused packed red blood cells. During hospitalization, the percentage of patients without nutritional risk decreased from 46 to 9%, and an increase in mild, moderate, and severe risk was observed. Patients with severe nutritional risk at hospital admission had significantly increased mortality at 365 days after discharge (HR: 2.96 (95% CI 1.14-7.70, p = 0.002)). After adjusting for sex, age, and Charlson index score, patients with severe nutritional risk at admission maintained a higher mortality risk (HR: 3.08 (95% CI 1.10-8.63, p = 0.032)). CONCLUSION: Malnutrition prevalence is high in older adults undergoing CRC elective surgery. Furthermore, this prevalence increases during hospital admission. Malnutrition is linked to worse outcomes, such as LOS, surgical and clinical complications, and mortality. For this reason, nutritional interventions are very important in the perioperative period.

Lifestyle Modification Improves Insulin Resistance and Carotid Intima-Media Thickness in a Metabolically Healthy Obese Prepubescent Population.

OBJECTIVES: The aim of this study was to analyze effects of a 12-month lifestyle modification that involved a Mediterranean diet (MedDiet) and physical activity (PA) program in a population of metabolically healthy obese children (MHOCh). METHODS: We included a population of MHOCh with ≤1 of the following criteria: waist circumference and blood pressure ≥90 percentile, triglycerides >150 mg/dL, high-density lipoprotein-cholesterol (HDL-c) <40 mg/dL, or impaired fasting glucose. After 12 months of intensive lifestyle modification, anthropometric measurements, glycemic and lipid profiles, adherence to the MedDiet, energy intake, PA, body composition, and carotid intima-media thickness (cIMT) were analyzed. RESULTS: One hundred thirty-one MHOCh (70 boys and 61 girls; P = 0.65, age: 7.9 ±â€Š1.3 years, body mass index [BMI]: 24.7 ±â€Š3.5 kg/m2) were included. After 12 months of intervention, a significant decrease in standard deviation (SD) units of body weight (-0.5 ±â€Š0.1; P < 0.001) and BMI (-0.5 ±â€Š0.1; P < 0.001) were observed in the total population. A significant improvement in adherence to the MedDiet (+2 points) and a significant reduction in protein, fatty acids, total fat, and cholesterol intake in the entire population were observed. All participants did more moderate-vigorous PA, which led to a significant increase in lean and total mass and decrease in total fat. Significant improvements in the glycemic profile (insulin levels [-6.6 µIU/mL, P < 0.001] and HOMA index [-1.2, P < 0.001]) were observed. Participants with pathological cIMT values reduced this cardiovascular predictor to normal values. CONCLUSIONS: A 12-month lifestyle modification intervention involving weight loss with MedDiet and PA in MHOCh yielded improvements in MedDiet adherence, lipid intake, moderate-vigorous PA, body composition, insulin resistance, and cIMT.

Metabolically Healthy Obesity: Presence of Arterial Stiffness in the Prepubescent Population.

AIM: Arteriosclerotic cardiovascular disease, one of the world's leading causes of death, first manifests itself at an early age. The identification of children who may have increased cardiovascular risk in the future could be an important prevention strategy. Our aim was to assess the clinical, analytical, and dietary variables associated with arterial stiffness (AS), measured by carotid-femoral pulse wave velocity (cfPWV) in a prepubescent population with metabolically healthy obesity (MHO). SUBJECTS AND METHODS: A cross-sectional study in prepubescent subjects with obesity who had ≤1 metabolic syndrome criteria (abdominal perimeter and blood pressure ≥90th percentile, triglycerides >150 mg/dL, HDL-cholesterol <40 mg/dL, fasting plasma glucose ≥100 mg/dL) was conducted. Adherence to Mediterranean Diet, blood pressure, BMI, waist/height ratio (WHtR), glycemic status, lipid profile, and cfPWV were analyzed. 75 MHO children (boys: 43; girls: 32; p = 0.20) (age = 10.05 ± 1.29 years; BMI = 25.29 ± 3.5 kg/m2) were included. RESULTS: We found a positive correlation between cfPWV and weight (r = 0.51; p < 0.0001), BMI (r = 0.44; p < 0.0001), WHtR (r = 0.26; p = 0.02), fasting insulin levels (r = 0.28; p = 0.02), and insulin resistance (Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index) (r = 0.25; p = 0.04). Multiple linear regression analysis identified BMI and HOMA-IR as independent parameters associated with cfPWV. CONCLUSIONS: Prepubescent children with obesity who were shown to be metabolically healthy presented with arterial stiffness, which is closely related to BMI and the state of insulin resistance.

Epigenetic approach in obesity: DNA methylation in a prepubertal population which underwent a lifestyle modification.

BACKGROUND: Metabolically healthy obesity (MHO) is a considerably controversial concept as it is considered a transitory condition towards the development of different pathologies (type 2 diabetes, insulin resistance, or cardiovascular disease). MHO is closely related to lifestyle and environmental factors. Epigenetics has become an essential biological tool to analyze the link between obesity and metabolic status. The aim of this study was to determine whether MHO status is conditioned by the DNA methylation (DNAm) of several genes related to lipid metabolism (lipoprotein lipase, retinoid X receptor alpha, liver X receptor, stearoyl-CoA desaturase, sterol regulatory element binding factor 1), and inflammation (LEP) in peripheral blood mononuclear cells (PBMCs) from 131 prepubertal subjects with MHO phenotype after lifestyle modifications with personalized Mediterranean diet (MedDiet) combined with a physical activity (PA) program. RESULTS: The DNAm of all studied genes were significantly modified in the population after 12 months of lifestyle modifications (MedDiet and PA). In addition, associations were found between the DNAm studies and BMI, homeostatic model assessment of insulin resistance, monounsaturated fatty acid and polyunsaturated fatty acid, moderate-vigorous PA, fat mass, and adherence to MedDiet. CONCLUSIONS: It was found that DNAm of genes related to lipid metabolism and inflammation are also present in childhood and that this methylation profile can be modified by interventions based on MedDiet and PA.

Periprocedural Direct Oral Anticoagulant Management: The RA-ACOD Prospective, Multicenter Real-World Registry.

Introduction There is scarce real-world experience regarding direct oral anticoagulants (DOACs) perioperative management. No study before has linked bridging therapy or DOAC-free time (pre-plus postoperative time without DOAC) with outcome. The aim of this study was to investigate real-world management and outcomes. Methods RA-ACOD is a prospective, observational, multicenter registry of adult patients on DOAC treatment requiring surgery. Primary outcomes were thrombotic and hemorrhagic complications. Follow-up was immediate postoperative (24-48 hours) and 30 days. Statistics were performed using a univariate and multivariate analysis. Data are presented as odds ratios (ORs [95% confidence interval]). Results From 26 Spanish hospitals, 901 patients were analyzed (53.5% major surgeries): 322 on apixaban, 304 on rivaroxaban, 267 on dabigatran, 8 on edoxaban. Fourteen (1.6%) patients suffered a thrombotic event, related to preoperative DOAC withdrawal (OR: 1.57 [1.03-2.4]) and DOAC-free time longer than 6 days (OR: 5.42 [1.18-26]). Minor bleeding events were described in 76 (8.4%) patients, with higher incidence for dabigatran (12.7%) versus other DOACs (6.6%). Major bleeding events occurred in 17 (1.9%) patients. Bridging therapy was used in 315 (35%) patients. It was associated with minor (OR: 2.57 [1.3-5.07]) and major (OR: 4.2 [1.4-12.3]) bleeding events, without decreasing thrombotic events. Conclusion This study offers real-world data on perioperative DOAC management and outcomes in a large prospective sample size to date with a high percentage of major surgery. Short-term preprocedural DOAC interruption depending on the drug, hemorrhagic risk, and renal function, without bridging therapy and a reduced DOAC-free time, seems the safest practice.

Circadian preference and relationship satisfaction among three types of couples.

Mate selection is part of a growing interest in the study of processes by which couples are established, consolidated and/or separated. Similarity in psychological traits has been related to the well-being of couples, but given the possible effect of temporal convergence, it is necessary to control for the relationship length and whether or not both members of the couple live together. The aim of this study was to analyse the association between Morningness/Eveningness (M/E) similarity and relationship satisfaction in young-dating-non-cohabiting, young-married-cohabiting and old-married-cohabiting couples. Participants included 357 heterosexual couples (357 women and 357 men) with a mean age of 38.42 years old (SD = 13.11; age range between 19 and 69) who completed M/E (Composite Scale of Morningness) and relationship satisfaction measures (Comprehensive Marital Satisfaction Scale). Similarity in M/E was positively related to greater relationship satisfaction in both young cohabiting and non-cohabiting couples. In women, their own M/E was related to their own relationship satisfaction, whereas the level of relationship satisfaction in men was related to their partner's M/E. This relationship was observed in young-married-cohabiting couples. M/E similarity may operate differently as a function of the relationship stage.

Social jetlag, academic achievement and cognitive performance: Understanding gender/sex differences.

Adolescents in high school suffer from circadian misalignment, undersleeping on weekdays and oversleeping on weekends. Since high schools usually impose early schedules, adolescents suffer from permanent social jetlag (SJL) and thus are a suitable population to study the effects of SJL on both academic and cognitive performance. In this study, 796 adolescents aged 12-16 years reported information about their sleep habits, morningness-eveningness (M-E), cognitive abilities and grade point average (GPA). Time in bed on both weekdays and weekends was not related to cognitive abilities, and only time in bed on weekdays was related to academic achievement. SJL was negatively related to academic achievement, cognitive abilities (except for vocabulary and verbal fluency abilities) and general cognitive ability (g), whereas M-E was slightly positively related to academic achievement and marginally negatively related to inductive reasoning. Results separated by sex/gender indicated that SJL may be more detrimental to girls' performance, as it was negatively related to a greater number of cognitive abilities and GPA.

Chronotype and time-of-day effects on mood during school day.

Existing evidence suggests an association between mood, time-of-day and morningness-eveningness (M-E). Since few studies have been carried out among adolescents, in this study daily mood fluctuations were analyzed in the naturalistic school context during 2 d in order to test how chronotype and time-of-day are related to mood during the school schedule period and check if sleep length is involved in the above relation. A sample of 655 adolescents (12-16 years) reported mood levels (current level of pleasantness) three times during school day (8:10-8:30 h, 10:20-11:40 h, 13:50-14:10 h). They also reported M-E preference and time in bed. Neither age nor sex were related to mood. However, the results indicated that regardless of chronotype mood increased throughout the school day from the lowest morning levels. Moreover, morning types showed better mood compared to other chronotypes, while evening types exhibited the lowest mood. Evening-oriented students slept less than other chronotypes, but time in bed was not involved in the relationship between chronotype and mood. These results suggest that it is not shortened sleep duration responsible for decreased mood in evening-oriented students.

Evening adolescents: the role of family relationships and pubertal development.

Accumulating evidence suggests that evening-type adolescents are exposed to a number of determinants that might have a negative impact on their health condition. Despite the fact that biological and psychosocial factors are interrelated, their impacts on the shift toward eveningness during puberty have been considered only separately. In this study, the effects of frequency of conflicts and functional autonomy on the relationship between pubertal development and Morningness-Eveningness (M-E) were tested together. A sample of 2081 adolescents aged 12-16 completed pubertal development, M-E, family frequency of conflicts and functional autonomy scales. Results indicated that greater functional autonomy and more conflicts in the family were unique predictors of greater eveningness, and they both together were better predictors of M-E than an advanced age and pubertal development. Apart from biological development, family relationship seems an important factor explaining progressive tendency toward eveningness during puberty and adolescence. Some implications to adolescent development were indicated.

Daily fluctuations in attention at school considering starting time and chronotype: an exploratory study.

Interest to investigate daily fluctuations in cognitive tasks, so-called "school-rhythms", lies in exploring the most favourable time-of-day for learning considering the analysis of variations in performance taking into account individual differences. The aim of this study was to describe daily fluctuations in attention at three different times of the school day, two different days, considering chronotype and three different school start times (08:00, 08:15 and 08:30 h). Participants were 669 adolescents aged 12-16. Sleep length and inductive reasoning were considered as covariates. In general, attention increased throughout the school day, boys reached higher attention than girls and, moreover, evening type boys reached higher attention than evening type girls. No differences between chronotypes were observed. When students were familiar with the task, chronotype, sex and time-of-day interactions seem to be important factors to consider.

Circadian preference and thinking styles: implications for school achievement.

Research has shown that thinking styles could have an influence on academic achievement. Previous studies have described that evening types are usually right-thinkers who tend to be creative and intuitive, whereas morning types tend to be left-thinkers who prefer verbal and analytic strategies in processing information. However, these studies have been realized among undergraduates, who have more freedom to choose their time schedules according to their circadian preference than adolescents or adult workers. On other hand, the relationship between thinking styles and circadian preference has not been analyzed considering school achievement. The present study aims (1) to investigate the relationship between circadian preference, that is, behavioral differences in circadian rhythmic expression, and thinking styles, referring to the preference toward information processing typical of the right versus the left cerebral hemisphere; and (2) to test the implications for self-reported school achievement. A sample of 1134 preadolescents and adolescents (581 girls; mean ± SD age: 12.1 ± 1.47, range: 10-14 yrs) completed the Morningness-Eveningness Scale for Children (MESC) as measure of circadian preference (morning, neither, or evening types), the Hemispheric Preference Test (HPT), conceived as a tool to measure thinking styles (right-, balanced-, and left-thinkers), and self-reported school achievement. Results indicated a greater percentage of left-thinkers among morning types and a greater percentage of right-thinkers among evening types. No differences were found among balanced-thinkers and neither types. Morning types and left-thinkers reported the highest subjective level of achievement, followed by evening types and left-thinkers, and morning types and right-thinkers. Evening types and right-thinkers reported the lowest subjective level of achievement. Finally, multivariate regression analysis indicated that age, left hemisphere and morning preferences accounted for 14.2% of total variance on self-reported achievement.

Chemokine CXCL12 uses CXCR4 and a signaling core formed by bifunctional Akt, extracellular signal-regulated kinase (ERK)1/2, and mammalian target of rapamycin complex 1 (mTORC1) proteins to control chemotaxis and survival simultaneously in mature dendritic cells.

Chemokines control several cell functions in addition to chemotaxis. Although much information is available on the involvement of specific signaling molecules in the control of single functions controlled by chemokines, especially chemotaxis, the mechanisms used by these ligands to regulate several cell functions simultaneously are completely unknown. Mature dendritic cells (maDCs) migrate through the afferent lymphatic vessels to the lymph nodes, where they regulate the initiation of the immune response. As maDCs are exposed to chemokine CXCL12 (receptors CXCR4 and CXCR7) during their migration, its functions are amenable to be regulated by this ligand. We have used maDCs as a model system to analyze the mechanisms whereby CXCL12 simultaneously controls chemotaxis and survival in maDCs. We show that CXCL12 uses CXCR4, but not CXCR7, and the components of a signaling core that includes G(i)/Gßγ, PI3K-α/-δ/-γ, Akt, ERK1/2 and mammalian target of rapamycin complex 1 (mTORC1), which organize hierarchically to control both functions. Downstream of Akt, Forkhead box class O (FOXO) regulates CXCL12-dependent survival, but not chemotaxis, suggesting that downstream of the aforementioned signaling core, additional signaling molecules may control more selectively CXCL12-dependent chemotaxis or survival. Finally, the data obtained also show that CXCR4 uses a signaling signature that is different from that used by CCR7 to control similar functions.

mTORC2 targets AGC kinases through Sin1-dependent recruitment.

The protein kinase TOR (target of rapamycin) is a key regulator of cell growth and metabolism with significant clinical relevance. In mammals, TOR signals through two distinct multi-protein complexes, mTORC1 and mTORC2 (mammalian TOR complex 1 and 2 respectively), the subunits of which appear to define the operational pathways. Rapamycin selectively targets mTORC1 function, and the emergence of specific ATP-competitive kinase inhibitors has enabled assessment of dual mTORC1 and mTORC2 blockade. Little is known, however, of the molecular action of mTORC2 components or the relative importance of targeting this pathway. In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC. Inducible expression of Sin1 mutants, lacking the PKC-interaction domain, displaces endogenous Sin1 from mTORC2 and disrupts PKC phosphorylation. PKB (protein kinase B)/Akt phosphorylation is also suppressed by these Sin1 mutants, but not the mTORC1 substrate p70(S6K) (S6 kinase), providing evidence that Sin1 serves as a selectivity adaptor for the recruitment of mTORC2 targets. This inducible selective mTORC2 intervention is used to demonstrate a key role for mTORC2 in cell proliferation in three-dimensional culture.

CD69 modulates sphingosine-1-phosphate-induced migration of skin dendritic cells.

In this study, we have investigated the role of CD69, an early inducible leukocyte activation receptor, in murine dendritic cell (DC) differentiation, maturation, and migration. Skin DCs and DC subsets present in mouse lymphoid organs express CD69 in response to maturation stimuli. Using a contact sensitization model, we show that skin DCs migrated more efficiently to draining lymph nodes (LNs) in the absence of CD69. This was confirmed by subcutaneous transfer of CD69-/- DCs, which presented an increased migration to peripheral LNs. Two-photon microscopy analysis showed that once DCs reached the LNs, CD69 deficiency did not alter DC interstitial motility in the LNs. Chemotaxis to sphingosine-1-phosphate (S1P) was enhanced in CD69-/- DCs compared with wild-type DCs. Accordingly, we detected a higher expression of S1P receptor type-1 (S1P(1)) by CD69-/- DCs, whereas S1P(3) expression levels were similar in wild-type and CD69-/- DCs. Moreover, in vivo treatment with S1P analogs SEW2871 and FTY720 during skin sensitization reduced skin DC migration to peripheral LNs. These results suggest that CD69 regulates S1P-induced skin DC migration by modulating S1P(1) function. Together, our findings increase our knowledge on DC trafficking patterns in the skin, enabling the development of new directed therapies using DCs for antigen (Ag) delivery.