REDD1 Deletion Suppresses NF-κB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice.

Activation of the transcription factor NF-κB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-κB controls the expression of an array of pro-inflammatory cytokines and chemokines. We recently discovered that the stress response protein regulated in development and DNA damage response 1 (REDD1) was required for increased pro-inflammatory cytokine expression in the hearts of diabetic mice. The studies herein were designed to extend the prior report by investigating the role of REDD1 in NF-κB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-κB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNFα or hyperglycemic conditions. A similar suppressive effect on NF-κB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3ß. NF-κB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3ß variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3ß at S9 and upregulation of IL-1ß and CCL2. Diabetic REDD1+/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1-/- mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1-/- mice, as compared to diabetic REDD1+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3ß-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.

Personalized ctDNA for Monitoring Disease Status in Head and Neck Squamous Cell Carcinoma.

PURPOSE: Many patients with locoregionally advanced human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood. EXPERIMENTAL DESIGN: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera, Natera) during clinical care of patients treated for predominantly newly diagnosed human papillomavirus-negative HNSCC. Signatera utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes posttreatment with disease outcomes. RESULTS: Testing was successful in 100/116 (86%) patients (median age: 65 years, 68% male, 65% smokers); testing failed in 16 (14%) because of insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III to IV disease (82, 71%), whereas 17 (15%) had distant metastases. Pretreatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 mean tumor molecules/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At a 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 patients, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive versus ctDNA negative posttreatment (HR, 7.33; 95% confidence interval, 3.12-17.2; P < 0.001); 1-year overall survival was 89.1% versus 100%, respectively (HR, 7.46; 95% confidence interval, 0.46-119.5; P = 0.155). CONCLUSIONS: Tumor-informed ctDNA testing is feasible in nonviral 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.

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.

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.

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.

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.

Using recovery management checkups for primary care to improve linkage to alcohol and other drug use treatment: a randomized controlled trial three month findings.

BACKGROUND AND AIMS: Recovery management checkups (RMC) have established efficacy for linking patients to substance use disorder (SUD) treatment. This study tested whether using RMC in combination with screening, brief intervention, and referral to treatment (SBIRT), versus SBIRT alone, can improve linkage of primary care patients referred to SUD treatment. DESIGN: A randomized controlled trial of SBIRT as usual (n = 132) versus SBIRT plus recovery management checkups for primary care (RMC-PC) (n = 134) with follow-up assessments at 3 months post-baseline. SETTING: Four federally qualified health centers in the United States serving low-income populations. PARTICIPANTS: Primary care patients (n = 266, 64% male, 80% Black, mean age, 48.3 [range, 19-53]) who were referred to SUD treatment after SBIRT. INTERVENTIONS: SBIRT alone (control condition) compared with SBIRT + RMC-PC (experimental condition). MEASUREMENT: The primary outcome was any days of SUD treatment in the past 3 months. Key secondary outcomes were days of SUD treatment overall and by level of care, days of alcohol and other drug (AOD) abstinence, and days of using specific substances, all based on self-report. FINDINGS: At 3-month follow-up, those assigned to SBIRT + RMC-PC (n = 134) had higher odds of receiving any SUD treatment (46% vs 20%; adjusted odds ratio = 4.50 [2.49, 8.48]) compared with SBIRT only, including higher rates of entering residential and intensive outpatient treatment. They also reported more days of treatment (14.45, vs 7.13; d = +0.26), more days abstinent (41.3 vs 31.9; d = +0.22), and fewer days of using alcohol (27.14, vs 36.31; d = -0.25) and cannabis (19.49, vs 28.6; d = -0.20). CONCLUSIONS: Recovery management checkups in combination with screening, brief intervention, and referral to treatment are an effective strategy for improving linkage of primary care patients in need to substance use disorder treatment over 3 months.

The impact of substance use on health care utilization, treatment, and outcomes in patients with non-small cell lung cancer.

Background: Mortality from non-small cell lung cancer (NSCLC) has improved with screening and novel treatments. The substance use epidemic has threatened health outcomes in a variety of diseases, but little is known about how it is associated with NSCLC outcomes. Methods: We performed a retrospective cohort study of 211 patients with NSCLC treated at a safety-net hospital. Sociodemographic data and clinical outcomes were extracted via review of electronic medical records. Patients were stratified based on substance use status. Comparative and multivariable analyses were performed to evaluate baseline characteristics and lung cancer outcomes including survival. Results: Among 193 patients (91.5%) with information available on substance use, 24.9% reported substance use; specifically, alcohol, marijuana, and illicit substances. Patients with substance use were more likely to have increased health care utilization and poor social determinants of health, including safe housing, stable employment, and social support. There were no significant differences in treatment adherence. Only 6.3% of patients with substance use did not receive guideline concordant care (GCC) compared to 24.8% of patients without substance use; due to poor performance status, increased comorbidities, or loss to follow up. On univariable analysis, patients with substance use experienced inferior median overall survival (OS) if they had metastatic disease (0.40 vs. 1.03 years, P=0.01). However, in the multivariable analysis, substance use did not predict for survival. Independent predictors of mortality were sex (male HR, 1.67; 95% CI: 1.04-2.68; P=0.04), smoking status (current smoking HR, 2.63; 95% CI: 1.14-6.08; P=0.02), and stage (stage IV HR, 14.96; 95% CI: 6.28-35.63; P=0.008). Conclusions: Substance use is associated with poor social determinants of health and increased health care utilization. On multivariable analysis, substance use was not independently associated with OS once guideline-concordant care was used. Future studies should focus on improving our understanding of these associations, delineating potential mechanisms, and developing evidence-based strategies to reduce health care utilization and overcome challenges related to poor social determinants of health.

Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling.

Inflammation contributes to the progression of retinal pathology caused by diabetes. Here, we investigated a role for the stress response protein regulated in development and DNA damage response 1 (REDD1) in the development of retinal inflammation. Increased REDD1 expression was observed in the retina of mice after 16-weeks of streptozotocin (STZ)-induced diabetes, and REDD1 was essential for diabetes-induced pro-inflammatory cytokine expression. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented increased pro-inflammatory cytokine expression in response to hyperglycemic conditions. REDD1 deletion promoted nuclear factor erythroid-2-related factor 2 (Nrf2) hyperactivation; however, Nrf2 was not required for reduced inflammatory cytokine expression in REDD1-deficient cells. Rather, REDD1 enhanced inflammatory cytokine expression by promoting activation of nuclear transcription factor κB (NF-κB). In WT cells exposed to tumor necrosis factor α (TNFα), inflammatory cytokine expression was increased in coordination with activating transcription factor 4 (ATF4)-dependent REDD1 expression and sustained activation of NF-κB. In both Müller cell cultures exposed to TNFα and in the retina of STZ-diabetic mice, REDD1 deletion promoted inhibitor of κB (IκB) expression and reduced NF-κB DNA-binding activity. We found that REDD1 acted upstream of IκB by enhancing both K63-ubiquitination and auto-phosphorylation of IκB kinase complex. In contrast with STZ-diabetic REDD1+/+ mice, IκB kinase complex autophosphorylation and macrophage infiltration were not observed in the retina of STZ-diabetic REDD1-/- mice. The findings provide new insight into how diabetes promotes retinal inflammation and support a model wherein REDD1 sustains activation of canonical NF-κB signaling.

Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes.

Purpose: Neuroglial dysfunction occurs early in the progression of diabetic retinopathy. In response to diabetes or hypoxia, Müller glia secrete cytokines and growth factors that contribute to disease progression. This study was designed to examine common signaling pathways activated in Müller glia by both type 1 and pre-/type 2 diabetes. Methods: RiboTag (Pdgfra-cre;HA-Rpl22) mice were used to compare the impact of streptozotocin (STZ) and a high-fat, high-sucrose (HFHS) diet on ribosome association of mRNAs in Müller glia by RNA sequencing analysis. Human MIO-M1 Müller cells were exposed to either hyperglycemic or hypoxic culture conditions. Genetic manipulation and pharmacologic inhibition were used to interrogate signaling pathways. Results: Association of mRNAs encoding triggering receptor expressed on myeloid cells 2 (TREM2), DNAX-activating protein 12 kDa (DAP12), and colony stimulating factor 1 receptor (CSF1R) with ribosomes isolated from Müller glia was upregulated in both STZ diabetic mice and mice fed an HFHS diet. The TREM2/DAP12 receptor-adaptor complex signals in coordination with CSF1R to activate spleen tyrosine kinase (SYK). SYK activation was enhanced in the retina of diabetic mice and in human MIO-M1 Müller cell cultures exposed to hyperglycemic or hypoxic culture conditions. DAP12 knockdown reduced SYK autophosphorylation in Müller cells exposed to hyperglycemic or hypoxic conditions. SYK inhibition or DAP12 knockdown suppressed hypoxia-induced expression of the transcription factor hypoxia-inducible factor 1⍺ (HIF1⍺), as well as expression of vascular endothelial growth factor and angiopoietin-like 4. Conclusions: The findings support TREM2/DAP12 receptor-adaptor complex signaling via SYK to promote HIF1α stabilization and increased angiogenic cytokine production by Müller glia.

A phase I study of avelumab, palbociclib, and cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma.

OBJECTIVES: We aimed to test the safety of the CDK4/6 inhibitor palbociclib in combination with the EGFR inhibitor cetuximab and the PD-L1 inhibitor avelumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). MATERIALS AND METHODS: This phase I study enrolled eligible adult patients with R/M HNSCC into three sequential single dose-escalation cohorts of palbociclib (75, 100, and 125 mg) PO daily on days 1 to 21 of a 28-day cycle in combination with avelumab 10 mg/kg IV every 2 weeks and cetuximab 400 mg/m2IV on day 1, then 250 mg/m2weekly thereafter. The study followed a 3 + 3 design with no intra-patient escalation. The primary objective was to identify the recommended phase II dose (RP2D); secondary objectives included overall response rate (ORR), duration of response (DOR), progression free survival (PFS), and overall survival (OS). RESULTS: Palbociclib in combination with avelumab and cetuximab was well tolerated, with rash and fatigue being the most common adverse events. A single dose-limiting toxicity was observed at the 125 mg dose of palbociclib: a grade 3 infusion reaction related to cetuximab. The RP2D of palbociclib is 125 mg, with avelumab and cetuximab at standard doses. The ORR by RECIST v1.1 was 42 %, the median DOR and OS have not been reached. Median PFS was 6.5 months. CONCLUSIONS: The combination of avelumab, cetuximab, and palbociclib was well tolerated and supports further evaluation in patients with R/M HNSCC. CLINICAL TRIAL REGISTRATION NUMBER: NCT03498378.

Unified classification and risk-stratification in Acute Myeloid Leukemia.

Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.

Immune Checkpoint Inhibitor Rechallenge After Prior Immune Toxicity.

OPINION STATEMENT: Immune checkpoint inhibitors (ICIs) have become an essential part of treatment for many cancer types. These monoclonal antibodies remove a critical negative regulatory signal that allows the immune system to recognize and destroy malignant cells that were previously undetectable. Unfortunately, their use has ushered in a whole new form of drug toxicity whereby the immune system attacks normal tissues in the body, referred to hereafter as immune-related adverse events (irAEs). irAEs are common and can result in treatment discontinuation, hospitalization, and death. When alternative modes of treatment are limited, or considered less efficacious, there may be a desire to resume treatment with ICIs after an irAE. Rechallenge with ICIs carries with it a heightened risk of subsequent toxicity, but with careful consideration and appropriate patient selection, this can be considered a reasonable approach.

Identifying individual and environmental predictors of opioid and psychostimulant use among adolescents and young adults following outpatient treatment.

BACKGROUND: The United States (US) continues to grapple with a drug overdose crisis. While opioids remain the main driver of overdose deaths, deaths involving psychostimulants such as methamphetamine are increasing with and without opioid involvement. Recent treatment admission data reflect overdose fatality trends suggesting greater psychostimulant use, both alone and in combination with opioids. Adolescents and young adults are particularly vulnerable with generational trends showing that these populations have particularly high relapse rates following treatment. METHODS: We assessed demographic, psychosocial, psychological comorbidity, and environmental factors (percent below the poverty line, percent unemployed, neighborhood homicide rate, population density) that confer risk for opioid and/or psychostimulant use following substance use disorder treatment using two complementary machine learning approaches-random forest and least absolute shrinkage and selection operator (LASSO) modelling-with latency to opioid and/or psychostimulant as the outcome variable. RESULTS: Individual level predictors varied by substance use disorder severity, with age, tobacco use, criminal justice involvement, race/ethnicity, and mental health diagnoses emerging at top predictors. Environmental variabels including US region, neighborhood poverty, population, and homicide rate around patients' treatment facility emerged as either protective or risk factors for latency to opioid and/or psychostimulant use. CONCLUSIONS: Environmental variables emerged as one of the top predictors of latency to use across all levels of substance use disorder severity. Results highlight the need for tailored treatments based on severity, and implicate environmental variables as important factors influencing treatment outcomes.

Retinal Protein O-GlcNAcylation and the Ocular Renin-angiotensin System: Signaling Cross-roads in Diabetic Retinopathy.

It is well established that diabetes and its associated hyperglycemia negatively impact retinal function, yet we know little about the role played by augmented flux through the Hexosamine Biosynthetic Pathway (HBP). This offshoot of the glycolytic pathway produces UDP-Nacetyl- glucosamine, which serves as the substrate for post-translational O-linked modification of proteins in a process referred to as O-GlcNAcylation. HBP flux and subsequent protein O-GlcNAcylation serve as nutrient sensors, enabling cells to integrate metabolic information to appropriately modulate fundamental cellular processes including gene expression. Here we summarize the impact of diabetes on retinal physiology, highlighting recent studies that explore the role of O-GlcNAcylation- induced variation in mRNA translation in retinal dysfunction and the pathogenesis of Diabetic Retinopathy (DR). Augmented O-GlcNAcylation results in wide variation in the selection of mRNAs for translation, in part, due to O-GlcNAcylation of the translational repressor 4E-BP1. Recent studies demonstrate that 4E-BP1 plays a critical role in regulating O-GlcNAcylation-induced changes in the translation of the mRNAs encoding Vascular Endothelial Growth Factor (VEGF), a number of important mitochondrial proteins, and CD40, a key costimulatory molecule involved in diabetes-induced retinal inflammation. Remarkably, 4E-BP1/2 ablation delays the onset of diabetes- induced visual dysfunction in mice. Thus, pharmacological interventions to prevent the impact of O-GlcNAcylation on 4E-BP1 may represent promising therapeutics to address the development and progression of DR. In this regard, we discuss the potential interplay between retinal O-GlcNAcylation and the ocular renin-angiotensin system as a potential therapeutic target of future interventions.

Variation in brief treatment for substance use disorder: a qualitative investigation of four federally qualified health centers with SBIRT services.

BACKGROUND: Brief treatment (BT) can be an effective, short-term, and low-cost treatment option for many people who misuse alcohol and drugs. However, inconsistent implementation is suggested to result in BT that often looks and potentially costs similar to regular outpatient care. Prior research is also rife with inconsistent operationalizations regarding the measurement of BT received by patients. As such, there is a need to more explicitly identify and document variations in BT practice. METHODS: A qualitative investigation of BT in four Federally Qualified Health Centers (FQHC) was undertaken as a sub study of a larger clinical trial. Researchers interviewed 12 staff (administrators and clinicians) involved in BT oversight, referral, or delivery within the four FQHCs. Data were analyzed following an inductive approach guided by the primary research questions. RESULTS: Findings demonstrate considerable differences in how BT was conceptualized and implemented within the FQHCs. This included a variety of ways in which BT was presented and described to patients that likely impacts how they perceive the BT they receive, including potentially not understanding they received substance use disorder treatment at all. CONCLUSIONS: The findings raise questions regarding the validity of prior research, demonstrating more objective definitions of BT and fidelity checklists are needed to ensure integrity of results. Future work in this area should seek to understand BT as practiced among a larger sample of providers and the direct experiences and perspectives of patients. There is also a need for more consistent implementation, quality assurance guidelines, and standardized stage of change assessments to aid practitioners.

Screening for more with less: Validation of the Global Appraisal of Individual Needs Quick v3 (GAIN-Q3) screeners.

Multi-morbidity is the norm among adolescents and adults with substance use and other mental disorders and warrants a multi-pronged screening approach. However, the time constraints on assessment inherent in clinical practice often temper the desire for a full understanding of multi-morbidity problems. The 15- to 25-minute Global Appraisal of Individual Needs Quick version 3 (GAIN-Q3) includes screeners for 9 common clinical problems that are short (4 to 10 items) and provide dimensional measures of problem severity in each area that are also categorized to guide clinical decision making. The screeners are summed into a total score that represents a 10th screener for multi-morbidity. This paper provides background on the development of the GAIN-Q3 screeners, their psychometric behaviors, efficiency, and predictive power relative to the 1-2 h full GAIN-I. Based on literature showing differential item and scale functioning by age, analyses were conducted separately using data from 10,625 adolescent and 10,167 adult treatment clients. Despite the condensed lengths of the screening measures compared with their longer versions, the reliability estimates are within the good to excellent range (0.7 to 0.9) in terms of internal consistency for 6 of the 10 screeners for adolescents and 7 of the 10 screeners for adults. In addition, the part to whole correlation for all 10 comparisons for both adolescents and adults are excellent (0.82 to 0.96). Moreover, there is strong evidence for the measures' convergent and discriminant validity and efficiency (i.e., maximum information gathered in as few items possible) relative to the full-length scales as well as relative to other scales in the full GAIN-I. Analyses of the interpretive cut-scores provide accurate identification of cases with high sensitivity and specificity, thus supporting the screeners' capacity to triage. PUBLIC SIGNIFICANCE STATEMENT: This study reports on the ability (GAIN-Q3) to efficiently screen for multiple co-occurring substance use, mental health, and associated problems. Multi-problem presentation in the social service sector is the normal expectation, yet time constraints prevent broad assessment of potentially many problematic areas. The GAIN-Q3 showed convergent and discriminant validity relative to the full-length scales as well as other scales assessed in the GAIN-I. The GAIN-Q3 achieves the desired balance between broad coverage and measurement efficiency to provide ample information to identify the best course of action for an individual.

The Missing Link(age): Multilevel Contributors to Service Uptake Failure Among Youths on Community Justice Supervision.

OBJECTIVES: Youths in the juvenile justice system often do not access needed behavioral health services. The behavioral health services cascade model was used to examine rates of substance use screening, identification of substance use treatment needs, and referral to and initiation of treatment among youths undergoing juvenile justice system intake and to identify when treatment access is most challenged. Characteristics associated with identification of behavioral health needs and linkage to community services were also examined. METHODS: Data were drawn from administrative records of 33 community justice agencies in seven states participating in Juvenile Justice-Translational Research on Interventions for Adolescents in the Legal System, funded by the National Institute on Drug Abuse (N=8,307 youths). Contributions of youth, staff, agency, and county characteristics to identification of behavioral health needs and linkage to community services were examined. RESULTS: More than 70% (5,942 of 8,307) of youths were screened for substance use problems, and more than half needed treatment. Among those in need, only about one-fifth were referred to treatment, and among those referred, 67.5% initiated treatment. Overall, <10% of youths with identified needs initiated services. Multivariable multilevel regression analyses revealed several contributors to service-related outcomes, with youths' level of supervision being among the strongest predictors of treatment referral. CONCLUSIONS: Community justice agencies appear to follow an approach that focuses identification and linkage practices on concerns other than youths' behavioral health needs, although such needs contribute to reoffending. Local agencies should coordinate efforts to support interagency communication in the referral and cross-system linkage process.

Artificial Intelligence for Histology-Based Detection of Microsatellite Instability and Prediction of Response to Immunotherapy in Colorectal Cancer.

Microsatellite instability (MSI) is a molecular marker of deficient DNA mismatch repair (dMMR) that is found in approximately 15% of colorectal cancer (CRC) patients. Testing all CRC patients for MSI/dMMR is recommended as screening for Lynch Syndrome and, more recently, to determine eligibility for immune checkpoint inhibitors in advanced disease. However, universal testing for MSI/dMMR has not been uniformly implemented because of cost and resource limitations. Artificial intelligence has been used to predict MSI/dMMR directly from hematoxylin and eosin (H&E) stained tissue slides. We review the emerging data regarding the utility of machine learning for MSI classification, focusing on CRC. We also provide the clinician with an introduction to image analysis with machine learning and convolutional neural networks. Machine learning can predict MSI/dMMR with high accuracy in high quality, curated datasets. Accuracy can be significantly decreased when applied to cohorts with different ethnic and/or clinical characteristics, or different tissue preparation protocols. Research is ongoing to determine the optimal machine learning methods for predicting MSI, which will need to be compared to current clinical practices, including next-generation sequencing. Predicting response to immunotherapy remains an unmet need.