Personalized circulating tumor DNA for monitoring disease status in head and neck squamous cell carcinoma.

BACKGROUND: Many patients with locoregionally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) relapse. Circulating tumor (ct)DNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood. METHODS: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera™, Natera) during clinical care of patients treated for predominantly newly diagnosed HPV-negative HNSCC. Signatera™ utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes post-treatment with disease outcomes. RESULTS: Testing was successful in 100/116 (86%) patients (median age: 65, 68% male, 65% smokers); testing failed in 16 (14%) due to insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III-IV disease (82, 71%) while 17 (15%) had distant metastases. Pre-treatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 MTM/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At median follow-up of 5.1 months (range: 0.2-15.1), 55 (55%) had >1 test result (range: 1-7; 194 samples). Of 55, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive vs. negative post-treatment (HR 7.33, 95%CI 3.12-17.2, p<0.001); 1-year overall survival was 89.1% vs. 100%, respectively (HR 7.46, 95%CI 0.46-119.5; p=0.155). CONCLUSIONS: Tumor-informed ctDNA testing is feasible in non-viral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC.

NLRP3 Inflammasome Priming in the Retina of Diabetic Mice Requires REDD1-Dependent Activation of GSK3ß.

Purpose: Inflammasome activation has been implicated in the development of retinal complications caused by diabetes. This study was designed to identify signaling events that promote retinal NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in response to diabetes. Methods: Diabetes was induced in mice by streptozotocin administration. Retinas were examined after 16 weeks of diabetes. Human MIO-M1 Müller cells were exposed to hyperglycemic culture conditions. Genetic and pharmacological interventions were used to interrogate signaling pathways. Visual function was assessed in mice using a virtual optomotor system. Results: In the retina of diabetic mice and in Müller cell cultures, NLRP3 and interleukin-1ß (IL-1ß) were increased in response to hyperglycemic conditions and the stress response protein Regulated in Development and DNA damage 1 (REDD1) was required for the effect. REDD1 deletion prevented caspase-1 activation in Müller cells exposed to hyperglycemic conditions and reduced IL-1ß release. REDD1 promoted nuclear factor κB signaling in cells exposed to hyperglycemic conditions, which was necessary for an increase in NLRP3. Expression of a constitutively active GSK3ß variant restored NLRP3 expression in REDD1-deficient cells exposed to hyperglycemic conditions. GSK3 activity was necessary for increased NLRP3 expression in the retina of diabetic mice and in cells exposed to hyperglycemic conditions. Müller glia-specific REDD1 deletion prevented increased retinal NLRP3 levels and deficits in contrast sensitivity in diabetic mice. Conclusions: The data support a role for REDD1-dependent activation of GSK3ß in NLRP3 inflammasome transcriptional priming and in the production of IL-1ß by Müller glia in response to diabetes.

Germline DNA damage response gene mutations as predictive biomarkers of immune checkpoint inhibitor efficacy.

Background: Impaired DNA damage response (DDR) can affect immune checkpoint inhibitors (ICI) efficacy and lead to heightened immune activation. We assessed the impact of pathogenic or likely pathogenic (P/LP) germline DDR mutations on ICI response and toxicity. Materials and methods: A retrospective analysis of 131 cancer patients with germline DNA testing and ICI treatment was performed. Results: Ninety-two patients were DDR-negative (DDR-), and 39 had ≥1 DDR mutation (DDR+). DDR+ patients showed higher objective response rates (ORRs) compared to DDR- in univariate and multivariable analyses, adjusting for age and metastatic disease (62% vs. 23%, unadjusted OR = 5.41; 95% CI, 2.41-12.14; adjusted OR 5.94; 95% CI, 2.35-15.06). Similar results were seen in mismatch repair (MMR), DDR pathways with intact MMR (DDR+MMRi), and homologous recombination (HR) subgroups versus DDR- (adjusted OR MMR = 24.52; 95% CI 2.72-221.38, DDR+MMRi = 4.26; 95% CI, 1.57-11.59, HR = 4.74; 95% CI, 1.49-15.11). DDR+ patients also had higher ORRs with concurrent chemotherapy (82% vs. 39% DDR-, p=0.03) or concurrent tyrosine kinase inhibitors (50% vs. 5% DDR-, p=0.03). No significant differences in immune-related adverse events were observed between DDR+ and DDR- cohorts. Conclusion: P/LP germline DDR mutations may enhance ICI response without significant additional toxicity.

Revisiting TNM staging for EBV-related nasopharyngeal carcinoma.

Advances in imaging and novel treatment approaches might have outpaced the prognostic capabilities of the current AJCC/UICC TNM 8th edition for staging nasopharyngeal carcinoma (NPC). In this issue of Cancer Cell, Du et al. propose a new TNM-9 classification that incorporates these updates.

SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer.

INTRODUCTION: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. METHODS: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity. RESULTS: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). CONCLUSIONS: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. CLINICAL TRIAL REGISTRATION: NCT02834013 (ClincialTrials.gov). PLAIN LANGUAGE SUMMARY: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609 Cohort 47) in Patients with Gestational Trophoblastic Neoplasia.

PURPOSE: The efficacy of immune checkpoint blockade in gestational trophoblastic neoplasia (GTN) remains uncertain. We report the results of the GTN cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). PATIENTS AND METHODS: This prospective, open-label phase II trial evaluated ipilimumab plus nivolumab across multiple rare tumor cohorts, including GTN. Eligible patients received nivolumab 240 mg, i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks. The primary endpoint was overall response rate [ORR; complete response (CR) + partial response (PR)] by quantitative serum beta human chorionic gonadotropin (ß-hCG); secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Four patients with refractory GTN enrolled and received therapy. At 11 months of ongoing follow-up, 3 of 4 patients responded [ORR = 75% (CR, 25%, n = 1, tumor mutation burden = 1 mutation/megabase; PD-L1 tumor proportion score = 50%); PR, 50%, n = 2)]. Responders included malignant gestational trophoblastic neoplasm (n = 1, CR, PFS 11+ months) and choriocarcinoma (n = 2, both PRs, PFS 10+ and 6+ months). One patient with epithelioid trophoblastic tumor experienced disease progression. The 6-month PFS was 75% [95% confidence interval (CI), 43%-100%], and the median PFS was not reached (range, 35-339+ days); all 4 patients were alive at last follow-up. Two patients experienced grade 3 immune-related toxicity (arthralgia and colitis); there were no grade ≥4 events. CONCLUSIONS: Ipilimumab plus nivolumab demonstrated efficacy in chemotherapy-refractory GTN, an ultra-rare cancer affecting young women. Three of 4 patients achieved ongoing objective responses with a reasonable safety profile at 6-11+ months.

Evaluating e-Connect: Mitigating Race by Gender Disparities in Behavioral Health Referral Among Youths on Probation, Northeast United States, 2019.

Addressing the behavioral health needs of youths involved in the justice system is key to reducing recidivism risk and preventing long-term system involvement. However, rates of treatment referral and initiation remain low, especially among minoritized youths and boys. The e-Connect System, a digital, clinical decision support system, addresses this problem by increasing rates of behavioral health treatment referral and initiation rates among youths on probation. In this study, we examine whether e-Connect helps improve equity in referral and treatment initiation outcomes. (Am J Public Health. 2023;113(12):1267-1270. https://doi.org/10.2105/AJPH.2023.307417).

A randomized controlled trial of recovery management checkups for primary care patients: Twelve-month results.

BACKGROUND: Primary care settings like federally qualified health centers (FQHC) are optimal locations to identify individuals with substance use disorders (SUD) and link them to SUD treatment, yet successful linkage has proven difficult. Recovery management checkups for primary care (RMC-PC) is a promising method for increasing linkage to care, engagement in treatment, and reducing substance use. METHODS: Participants (n = 266) who received screening, brief intervention, and referral to treatment (SBIRT) at four FQHC sites and needed SUD treatment were randomized to receive SBIRT only or SBIRT+RMC-PC. All participants received SBIRT prior to randomization as part of usual care while those in the experimental group also received quarterly checkups. All participants completed research interviews at enrollment and 3, 6, 9, and 12 months post-enrollment. The primary outcome was whether participants received any days of SUD treatment. Key secondary outcomes were days of SUD treatment (total and by SUD level of care), days of alcohol or drug abstinence, and a reduction in days of specific substance use, all based on self-report. RESULTS: Relative to participants receiving SBIRT only, participants assigned to SBIRT+RMC-PC were significantly more likely to have received any SUD treatment over 12 months (adjusted odds ratio [AOR] = 3.85) and more days of SUD treatment over 12 months (Cohen's effect size d = +0.41). The SBIRT+RMC-PC group also reported significantly more days of abstinence over 12 months (d = +0.30), fewer days of alcohol use (d = -0.20) and cannabis use (d = -0.20), and lower combined substance use frequency (d = -0.25). Days of treatment were found to positively mediate the direct effect of SBIRT+RMC-PC on days of abstinence. CONCLUSION: This study provides further evidence of the effectiveness of the "referral to treatment" component of SBIRT when combined with RMC for patients in primary care settings, including those with drug use problems. Moreover, results demonstrate the value of repeated checkups on longer-term treatment and substance use outcomes.

REDD1-dependent GSK3ß dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice.

Increasing evidence supports a role for inflammation in the early development and progression of retinal complications caused by diabetes. We recently demonstrated that the stress response protein regulated in development and DNA damage response 1 (REDD1) promotes diabetes-induced retinal inflammation by sustaining canonical activation of nuclear transcription factor, NF-κB. The studies here were designed to identify signaling events whereby REDD1 promotes NF-κB activation in the retina of diabetic mice. We observed increased REDD1 expression in the retina of mice after 16 weeks of streptozotocin (STZ)-induced diabetes and found that REDD1 was essential for diabetes to suppress inhibitory phosphorylation of glycogen synthase kinase 3ß (GSK3ß) at S9. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented dephosphorylation of GSK3ß and increased NF-κB activation in response to hyperglycemic conditions. Expression of a constitutively active GSK3ß variant restored NF-κB activation in cells deficient for REDD1. In cells exposed to hyperglycemic conditions, GSK3ß knockdown inhibited NF-κB activation and proinflammatory cytokine expression by preventing inhibitor of κB kinase complex autophosphorylation and inhibitor of κB degradation. In both the retina of STZ-diabetic mice and in Müller cells exposed to hyperglycemic conditions, GSK3 inhibition reduced NF-κB activity and prevented an increase in proinflammatory cytokine expression. In contrast with STZ-diabetic mice receiving a vehicle control, macrophage infiltration was not observed in the retina of STZ-diabetic mice treated with GSK3 inhibitor. Collectively, the findings support a model wherein diabetes enhances REDD1-dependent activation of GSK3ß to promote canonical NF-κB signaling and the development of retinal inflammation.

Results of a national survey of substance use treatment services for youth under community supervision.

BACKGROUND: Despite the heightened risk for substance use (SU) among youth in the juvenile justice system, many do not receive the treatment that they need. OBJECTIVES: The purpose of this study is to examine the extent to which youth under community supervision by juvenile justice agencies receive community-based SU services and the factors associated with access to such services. METHODS: Data are from a nationally representative sample of Community Supervision (CS) agencies and their primary behavioral health (BH) partners. Surveys were completed by 192 CS and 271 BH agencies. RESULTS: SU services are more often available through BH than CS for all treatment modalities. EBPs are more likely to be used by BH than by CS. Co-location of services occurs most often in communities with fewer treatment options and is associated with higher interagency collaboration. Youth are more likely to receive services in communities with higher EBP use, which mediates the relationship between the availability of SU treatment modalities and the proportion of youth served. CONCLUSION: Findings identify opportunities to strengthen community systems and improve linkage to care.

Time-varying effect modeling with intensive longitudinal data: Examining dynamic links among craving, affect, self-efficacy and substance use during addiction recovery.

Time-varying effect modeling (TVEM), a statistical technique for modeling dynamic patterns of change, presents new opportunities to study biobehavioral health processes. TVEM is particularly useful when applied to intensive longitudinal data (ILD) because it permits highly flexible modeling of outcomes over continuous time, as well as of associations between variables and moderation effects. TVEM coupled with ILD is ideal for the study of addiction. This article provides a general overview of using TVEM, particularly when applied to ILD, to better enable addiction scientists to conduct novel analyses that are important to realizing the dynamics of addiction-related processes. It presents an empirical example using ecological momentary assessment data from participants throughout their first 90 days of addiction recovery to estimate the (1) associations between morning craving and same-day recovery outcomes, (2) association between morning positive and negative affect and same-day recovery outcomes and (3) time-varying moderation effects of affect on the association between morning craving and recovery outcomes. We provide a didactic overview in implementing and interpreting the aims and results, including equations, computer syntax and reference resources. Our results highlight how affect operates as both a time-varying risk and protective factor on recovery outcomes, particularly when considered in combination with experiences of craving (i.e. dynamic moderation). We conclude by discussing our results, recent innovations and future directions of TVEM for advancing addiction science, including how 'time' can be operationalized to probe new research questions.

E-Connect: Linking probation youth at risk for suicide to behavioral health services.

OBJECTIVE: Youth involved in the justice system (YIJ) have higher rates of suicidal thoughts and behaviors (STB) and associated behavioral health (BH) problems, yet lower levels of service use compared to youth in the general population. This study examined the efficacy of e-Connect, a digital clinical decision support system (CDSS), at improving STB risk identification, referral, and linkage to BH services by probation officers. As the intervention spanned pre- and post-COVID-19 shutdown periods, we also examined the disruption in public agencies' service provision on study outcomes. METHOD: Administrative record data (1,488 youth, ages 10-18 years, 56% male, 56% White) allowed examination of differences between care-as-usual (baseline) and e-Connect in screening, identification of STB and BH problems, referral, and treatment initiation. RESULTS: Compared to care-as-usual, probation officers using e-Connect were over five times as likely to identify YIJ with STB (adjusted odds ratio [aOR] = 5.86; 95% confidence interval, CI [3.24, 11.7]) and over 11 times more likely to refer YIJ in need of BH services to treatment (aOR = 11.04; 95% CI [6.54, 19.43]). In turn, youth referred to treatment via e-Connect were nearly 17 times more likely to initiate (aOR = 16.92; 95% CI [9.17, 32.60]). Results remained unchanged during the pre- and post-COVID-19 shutdown periods. CONCLUSION: e-Connect is one of the first digital STB screening, referral, and linkage-to-service systems that use CDSS technology to successfully assist probation officers in linking youth on their caseload to treatment. Such an approach may support identification of STB and cross-systems linkage in other youth-serving organizations, such as schools, that increasingly manage youth BH problems with minimal clinical support. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Utility of the Global Appraisal of Individual Needs Recommendation and Referral Report for Substance Use Diagnosis, Treatment Planning, and Placement.

OBJECTIVES: This study aims to evaluate the utility of the Global Appraisal of Individual Needs Recommendation and Referral Report (GRRS) as guided by American Psychiatric Association diagnosis criteria and American Society of Addiction Medicine guidelines for treatment planning and placement. METHODS: Global Appraisal of Individual Needs data were gathered between March 2018 and June 2020 from a total of 82 agencies and 245 clinicians as part of a program evaluation of agencies receiving public funding through the Mid-State Health Network under contract with the Michigan Department of Health and Human Services and the Office of Recovery Oriented Systems of Care. Of the 1395 patients 18 years or older, 1027 GRRS reports were produced by clinical staff. κ And ρ analyses were used to measure rates of clinician agreement with the recommendations produced by the GRRS report based on patient interviews. RESULTS: Clinicians agreed with the GRRS preliminary diagnostic recommendations 88% to 100% of the time, with κ scores indicating excellent agreement by ranging from 0.6 to 0.9. For an average patient, 41 of 46 treatment planning statements generated by the GRRS were used by clinicians, with moderate to high correlation indicated by ρ scores ranging from 0.62 to 0.82. The percent agreement for all American Society of Addiction Medicine dimension ratings was greater than 99%, with κ scores of 0.98 and higher. CONCLUSIONS: This study demonstrates the utility and efficiency of the GRRS as a clinical decision support system to support diagnosis, treatment, and placement in routine practice.

Access to Services for Pregnant People With Opioid Use Disorder in Jails in the United States.

The aim of this study was to assess the availability of medications for opioid use disorder (MOUD) and other services for pregnant people in jails in counties heavily impacted by opioid overdose in the United States. Counties were selected based on absolute number and population rate of opioid-overdose fatalities. Structured interviews were completed with representatives from 174 jails that house pregnant women. Descriptive statistics examine MOUD availability and differences in service provision and community-level characteristics based on MOUD availability. Most jails in the study sample (84.5%) had MOUD available for pregnant people; however, less than half of these jails ensured continuity of care. Jails without MOUD available are more likely to provide non-MOUD substance use services. These jails are more often located in smaller, rural counties in the Midwest and have higher rates of White residents and lower rates of Hispanic and African American residents. Gaps in MOUD availability in jails and continuity of care violate medical guidelines for treatment of pregnant patients with opioid use disorder and increase their risk of overdose. In addition, there are disparities across communities in access to MOUD for pregnant people in jails.

Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC.

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

Substance use severity as a predictor for receiving medication for opioid use disorder among adolescents: An analysis of the 2019 TEDS.

BACKGROUND: Medication for opioid use disorder (MOUD) is vastly underutilized in adolescents. Existing treatment guidelines for OUD largely focus on adults, providing limited guidance for pediatric populations. Limited information is known about use of MOUD in adolescents based on substance use severity. METHODS: This secondary data analysis examined how patient-level variables influenced the receipt of MOUD in adolescents aged 12-17 (n = 1866) using the Treatment Episode Data Set (TEDS) 2019 Discharge data set. A crosstabulation and chi-square statistic evaluated the relationship between a proxy for clinical need based on high-risk opioid use (either reporting daily opioid use within the past 30 days and/or history of injection opioid use) for MOUD in states with and without adolescents receiving MOUD (n = 1071). A two-step logistic regression analysis in states with any adolescents receiving MOUD examined the explanatory power of demographic, treatment intake, and substance use characteristics. RESULTS: Completion of 12th grade, a GED, or beyond, decreased the likelihood of receiving MOUD (odds ratio [OR]= 0.38, p = 0.017), as did being female (OR = 0.47, p = .006). None of the remaining clinical criteria were significantly associated with MOUD, although a history of one or more arrests increased the likelihood of MOUD (OR = 6.98, p = 0.06). Only 13% of individuals who met criteria for clinical need received MOUD. CONCLUSIONS: Lower education could serve as a proxy for substance use severity. Guidelines and best practices are needed to ensure the proper distribution of MOUD to adolescents based on clinical need.

Impact of implementation interventions to improve substance use service delivery on recidivism among justice-involved youth.

Substance use disorders (SUD) are prevalent among justice-involved youth (JIY) and are a robust predictor of re-offending. Only a fraction of JIY with substance use problems receive treatment. This paper describes the impacts of system-level efforts to improve identification and referral to treatment on recidivism of JIY. A cluster randomized trial involving 20 county juvenile justice agency sites across 5 states was used to implement an organizational intervention (Core vs Enhanced) to juvenile justice staff and community-based treatment providers, working with 18,698 JIY from March 2014 to August 2017. Recidivism rates over four study time periods were examined. Logistic regression was used to predict recidivism as a function of site, need for SUD services, level of supervision, time, organizational intervention, and time x intervention interaction terms. Results indicated that Enhanced sites showed decreased levels of recidivism compared to Core-only sites, where it increased over time. Additionally, need for SU services, level of supervision, and site were significant predictors of reoffending. Findings suggest the potential value of facilitation of juvenile justice agency efforts to increasing identification of and referral to SUD services of JIY in need of such services for reducing further contact with the legal system.

PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice.

Endoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here, we investigated the role of the stress response protein regulated in development and DNA damage 1 (REDD1) as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 wk, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation. In human AC16 cardiomyocytes exposed to either hyperglycemic conditions or the saturated fatty acid palmitate, REDD1 expression was increased coincident with ER stress and upregulated expression of the proinflammatory cytokines IL-1ß, IL-6, and TNFα. In cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions, pharmacological inhibition of the ER kinase protein kinase RNA-like endoplasmic reticulum kinase (PERK) or knockdown of the transcription factor ATF4 prevented the increase in REDD1 expression. REDD1 deletion reduced proinflammatory cytokine expression in both cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions and in the hearts of obese mice. Overall, the findings support a model wherein HFHS diet contributes to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.NEW & NOTEWORTHY Interplay between endoplasmic reticulum stress and inflammation contributes to cardiovascular disease progression. The studies here identify the stress response protein known as REDD1 as a missing molecular link that connects the development of endoplasmic reticulum stress with increased production of proinflammatory cytokines in the hearts of obese mice.

Quality of life measurement in vitiligo. Position statement of the European Academy of Dermatology and Venereology Task Force on Quality of Life and Patient Oriented Outcomes with external experts.

Members of the European Academy of Dermatology and Venereology (EADV) Task Force on Quality of Life (QoL) and Patient Oriented Outcomes reviewed the instruments available for health-related (HR) QoL assessment in vitiligo and together with external vitiligo experts (including representatives of the EADV Vitiligo Task Force) have made practical recommendations concerning the assessment of QoL in vitiligo patients. The Dermatology Life Quality Index (DLQI) was the most frequently used HRQoL instrument, making comparison of results between different countries possible. Several vitiligo-specific instruments were identified. The vitiligo Impact Scale (VIS) is an extensively validated vitiligo-specific HRQoL instrument with proposed minimal important change and clinical interpretation for VIS-22 scores. VIS-22 was developed for use in India, where there are some specific cultural beliefs concerning vitiligo. The EADV Task Force on QoL and Patient Oriented Outcomes recommends use of the DLQI and the Children's Dermatology Life Quality Index (CDLQI) as dermatology-specific instruments in vitiligo. There is a strong need for a valid (including cross-cultural validation) vitiligo-specific instrument that can be either a new instrument or the improvement of existing instruments. This validation must include the proof of responsiveness.

Loss of 4E-BPs prevents the hindlimb immobilization-induced decrease in protein synthesis in skeletal muscle.

The present study was designed to test the hypothesis that upregulating protein synthesis attenuates the loss of muscle mass in a model of disuse atrophy. The studies compared the effect of unilateral hindlimb immobilization in wild-type (WT) mice and double-knockout (DKO) mice lacking the translational regulators 4E-BP1 and 4E-BP2. Immobilization-induced downregulation of protein synthesis occurred in both groups of mice, but protein synthesis was higher in gastrocnemius muscle from the immobilized hindlimb of fasted DKO compared with WT mice. Surprisingly, although protein synthesis was partially elevated in DKO compared with WT mice, atrophy occurred to the same extent in both groups of animals. This may be partially due to impaired leucine-induced stimulation of protein synthesis in DKO compared with WT mice due to downregulated eukaryotic initiation factor eIF4E expression in muscle of DKO compared with WT mice. Expression of the E3 ubiquitin ligases MAFbx and MuRF-1 mRNAs and total protein ubiquitylation was upregulated in the immobilized compared with the nonimmobilized hindlimb of both WT and DKO mice, with little difference in the magnitude of the upregulation between genotypes. Analysis of newly synthesized proteins revealed downregulation of several glycolytic enzymes in the gastrocnemius of DKO mice compared with WT mice, as well as in the immobilized compared with the nonimmobilized hindlimb. Overall, the results suggest that the elevated rate of protein synthesis during hindlimb immobilization in fasted DKO mice is insufficient to prevent disuse-induced muscle atrophy, probably due to induction of compensatory mechanisms including downregulation of eIF4E expression.NEW & NOTEWORTHY Basal rates of protein synthesis are elevated in skeletal muscle in the immobilized leg of mice lacking the translational repressors, 4E-BP1 and 4E-BP2 (knockout mice), compared with wild-type mice. However, disuse-induced muscle atrophy occurs to the same extent in both wild-type and knockout mice suggesting that compensatory mechanisms are induced that overcome the upregulation of muscle protein synthesis. Proteomic analysis revealed that mRNAs encoding several glycolytic enzymes are differentially translated in wild-type and knockout mice.