Citations

Background: Cardiac tissue possesses high energetic requirements. During development of heart failure there is a shift from fatty acid oxidation to the utilization of other substrates. This transition leads to the decline in NAD/NADH ratio, which increases susceptibility to stress. CD38 is the main NAD + -consuming enzyme responsible for NAD + levels regulation in tissue and therefore represents a possible therapeutic target in such conditions. Objective: To investigate the role of CD38 in cardiovascular performance and its potential use as a therapeutic target in obesity-induced heart failure. Results: When comparing adult Wild-Type (WT) and CD38 Knock-out (KO) mice we observed that the latter had higher exercise performance, increased heart rate variability (HRV) and decreased heart rate (HR). When comparing WT and CD38 catalytically inactive (CI) mice we observed the same results, showing its relation with CD38 catalytic activity. WT mice treated with an antibody which blocks CD38 activity showed improved exercise capacity and HRV. In both genetically modified or antibody treated groups, NAD+ levels were significantly increased in heart. In order to explore the NAD + role in these findings, we compared WT control and CD38KO treated with FK866 (Nampt inhibitor) and observed that NAD+ levels in heart decreased as well as exercise capacity. We then aimed to demonstrate CD38 role as a target for therapeutic intervention in a model of cardiac strain induced by obesity in aged mice. We compared WT and CD38 CI aged mice, placed in normal diet (ND) or high fat diet (HFD). WT animals fed HFD showed decreased exercise capacity and this effect is reversed in CD38 CI fed HFD. Similarly, WT placed in HFD developed diastolic dysfunction seen as a significant increase in E/e’ ratio, and CD38 CI placed in HFD were protect against the development of this dysfunction. Mechanistically, we observed that blockage of CD38 resulted in decreased protein acetylation and increased SERCA expression. Conclusion: CD38 plays a role in cardiovascular performance by regulation of NAD + homeostasis. In a model of obesity-induced diastolic dysfunction NAD+-boosting by blocking CD38 activity led to protection by up-regulating SERCA expression.

Background: Doxorubicin is a chemotherapy medication used to treat several types of cancer. Its major adverse effect is cardiotoxicity, which may limit its use. Doxorubicin-induced cardiotoxicity (DIC), once developed, carries a poor prognosis. Therefore strategies to prevent or treat DIC are of paramount importance but have not yet been fully developed. Being NAD + a critical nucleotide which is involved in oxy-reduction reactions and CD38 the main NAD + -consuming enzyme responsible for NAD levels regulation and homeostasis, we aim to investigate the link of CD38 and NAD + metabolism in DIC and its potential role as a therapeutic target. Methods: We compared Wild-type (WT) control mice with WT mice treated with a single dose injection of 15 mg/kg of doxorubicin who received vehicle or an antibody that blocksCD38 ecto-enzymatic activity. We also compared genetically CD38 catalytic inactive (CI) mice treated or not with the same single dose injection. Results: Doxorubicin caused a decrease in Ejection Fraction (EF) in WT mice. We also observed that CD38 CI mice treated with doxorubicin did not have changes in EF compared to their control. When compared to WT receiving just doxorubicin, WT mice treated also with the antibody had a trend to improve EF. As for exercise performance, our results show a decrease in exercise capacity induced by doxorubicin that was reversed in the antibody group and did not happen in the CD38 CI mice treated with doxorubicin. Doxorubicin caused a decrease in heart rate variability (HRV) which was improved in the antibody treated group. Moreover, our results show a survival rate that is similar to what has been previously shown, with 50% mortality associated with doxorubicin. Blockage of CD38 activity with antibody reduced mortality in this model to approximately 20%. Mechanistically, we did not observe decreases in NAD+ levels induced by Doxorubicin. However, boost of NAD induced by blocking CD38 was related to protection against DIC. Conclusion: Our results indicate that the damage mechanism of DIC may not be related directly with NAD decrease, but NAD boosting induced by CD38 blockage seems to have a positive effect in protection against cardiac dysfunction related to this chemotherapeutic treatment.

Background: Burnout syndrome is very prevalent among healthcare residents. Initiatives addressing workload conditions have had limited impact on burnout. The present study aims to explore the contribution of two emotion regulation strategies, namely emotion suppression and cognitive reevaluation, to residents’ burnout, while accounting for workload factors. Methods: Participants were 105 residents (68.6% women; mean age = 27.5, SD = 3.0). They completed measures of workload, burnout, and emotion regulation. The study was cross-sectional. Results: Emotional suppression was associated with higher burnout (depersonalization scale; β = 0.20, p < 0.05, CI 0.15–2.48) and cognitive revaluation was linked to lower burnout (higher personal accomplishment; β = 0.35, p < 0.01, CI 0.16–2.56), even after controlling for demographic and workload factors. We found interaction effects between workload variables (supervisor support and number of patient hours) and emotion regulation (p < 0.05). Conclusions: The relationship between workload, emotion regulation, and burnout seems to be complex. That is, similar work conditions might generate different levels of burnout depending on the resident’s emotional regulation strategies. This might partly explain why existing initiatives based on workload changes have had a modest impact on burnout. Results also support including emotion regulation training in prevention and treatment programs targeting burnout during residency.

Purpose of review Here we review recent literature on the emerging role of nicotinamide adenine dinucleotide (NAD + ) metabolism and its dysfunction via the enzyme CD38 in the pathogenesis of rheumatologic diseases. We evaluate the potential of targeting CD38 to ameliorate NAD + -related metabolic imbalance and tissue dysfunction in the treatment of systemic sclerosis (SSc), systemic lupus erythematous (SLE), and rheumatoid arthritis (RA). Recent findings In this review, we will discuss emerging basic, preclinical, and human data that point to the novel role of CD38 in dysregulated NAD + -homeostasis in SSc, SLE, and RA. In particular, recent studies implicate increased activity of CD38, one of the main enzymes in NAD + catabolism, in the pathogenesis of persistent systemic fibrosis in SSc, and increased susceptibility of SLE patients to infections. We will also discuss recent studies that demonstrate that a cytotoxic CD38 antibody can promote clearance of plasma cells involved in the generation of RA antibodies. Summary Recent studies identify potential therapeutic approaches for boosting NAD + to treat rheumatologic diseases including SSc, RA, and SLE, with particular attention to inhibition of CD38 enzymatic activity as a target. Key future directions in the field include the determination of the cell-type specificity and role of CD38 enzymatic activity versus CD38 structural roles in human diseases, as well as the indicators and potential side effects of CD38-targeted treatments.

Abstract Background: Familial adenomatous polyposis (FAP) is the most common hereditary polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. If left untreated, nearly all individuals with this syndrome develop colorectal cancer (CRC) by the third decade of life. Prophylactic colectomy is the standard of care, but individuals remain at risk for malignant transformation of duodenal polyps, rectal polyps for those who have undergone rectal-sparing surgeries, and ileal pouch polyps for those with ileal pouch-anal anastomoses. Multiple studies with both nonselective and selective cyclooxygenase inhibitors (such as sulindac or celecoxib) have shown that anti-inflammatory agents may prevent the formation and inhibit the growth of colorectal adenomatous polyps. However, toxicities associated with these agents and their limited efficacy have prevented their further development. Therefore, there is a high unmet need for novel treatment options to reduce polyp burden, delay or eliminate the need for colectomy and recurrent rectal surgery, and intercept the development of adenocarcinomas in individuals with FAP. Polyps from individuals with FAP display inflammatory features associated with the activation of the IL-23/IL-17/JAK/STAT3 pathway. This inflammation is thought to contribute to further carcinogenesis, culminating in tumor development. Specifically, IL-23 is linked to tumor growth and progression in CRC, and adenomas with high-grade dysplasia showed elevated levels of IL-17A and pSTAT3. Guselkumab, a human monoclonal antibody directed against the p19 subunit of IL-23, specifically targets IL-23 and inhibits its interaction with the IL-23 receptor. Pre-clinical models suggest that inhibition of IL-23 signaling will result in less inflammation and reduce tumor development. Methods: This randomized, blind, placebo-controlled study will evaluate the safety and efficacy of guselkumab in adults with FAP (genetic or clinical diagnosis) who have already undergone colectomy. Polyps with a sum of diameters ≥10 mm in the rectum or pouch are required. Subjects will be randomized equally to one of three study arms: 100 mg, 300 mg, or placebo given subcutaneously every 4 weeks for 6 doses. The primary efficacy endpoint is percentage change from baseline in rectal/pouch polyp burden after 24 weeks. Secondary efficacy endpoints include duodenal polyp burden change and changes in InSiGHT and Spigelman staging. Exploratory translational research objectives will explore changes in RNA expression profiles, epigenomic profiles, cytokine levels, and the microbiome. Exclusion criteria include prior IL-23 targeted therapies and any polyps &gt;1 cm that cannot be removed. While participating, subjects are required to stop any other FAP-directed drug therapy except for aspirin. As of January 2019, 18% of the planned 72 subjects have been enrolled. ClinicalTrials.gov Identifier: NCT03649971. Citation Format: Eduardo Vilar-Sanchez, Carol Burke, Marcia R. Cruz Correa, Evelien Dekker, William M. Grady, Philippe Grandval, Bryson W. Katona, Xavier Llor, Douglas L. Riegert-Johnson, Jean-Christophe Saurin, Peter Stanich, Daniel A. Sussman, David Weinberg, Edward F. Attiyeh, Devanand Joseph, Kelly Raybold, Gary V. Borzillo, Thomas J. Prior, Michael Smith, Hong Xie, Kurtis E. Bachman, Jeffrey R. Infante, Niloy Jewel Samadder. A phase 1b, multicenter, randomized, blinded, placebo-controlled study to evaluate the efficacy of guselkumab in subjects with familial adenomatous polyposis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT236.

Abstract Patients diagnosed with germline mutations in MMR genes (Lynch Syndrome, LS) have up to 70-80% lifetime risk of colorectal cancer. Therefore, this high-risk population has the potential to benefit from effective chemopreventive strategies. Naproxen is an NSAID widely used for pain treatment with an excellent safety profile that has demonstrated to be more efficacious preventing colorectal cancer compared to aspirin in vivo using an intestinal tissue-specific mouse model of LS (VC-Msh2-LoxP). The ‘Naproxen trial' was designed to evaluate the modulation of PGE2 levels in colorectal mucosa, evaluate safety and tolerability, and discover novel molecular pathways involved in the chemopreventive activity of naproxen in LS patients. Methods: Participants were randomized to naproxen 440 mg (HD), 220 mg (LD) and placebo by mouth daily for 6 months. Modulation of prostaglandin levels, number of adverse events (AEs) observed in each treatment arm and gene expression profiles by next-generation sequencing (mRNAseq) in normal colorectal mucosa of LS patients after 6 months of intervention were examined. Results: Eighty participants diagnosed with LS were randomized, 25 participants to HD, 27 to LD, and 28 to placebo. From these patients, 54 were considered evaluable per-protocol analysis: 16 in the HD group, 15 in the LD and 23 in placebo. The level of prostaglandin E2 in the colorectal mucosa decreased significantly after treatment with both LD and HD naproxen when compared to placebo (-91.2%±14.1, -93.6%±7.9, and 23.8%±108.4, P-value&lt;0.001, respectively). Moreover, levels of PGE2 urinary metabolite (PGE-M) were significantly changed in both treatment groups when compared to placebo (-47.7%±56.9, -41.1%±40.5, 7.6%±94.3, P-Value&lt;0.018). The intervention was well tolerated, no severe AEs related to treatment were reported, and the total number of AEs was not different across treatment arms. LD and HD naproxen promoted the activity of the immune system by activating different immune cell types without any effect on lymphoid cellularity and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Conclusions: Naproxen is a promising strategy for immune interception in LS that induces immune-modulation coupled with changes in the dynamics of the intestinal crypt. We have also discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. Citation Format: Laura Reyes Uribe, Wenhui Wu, Ozkan Gelincik, Prashant V. Bommi, Alejandro Francisco-Cruz, Luisa M. Solis, Patrick M. Lynch, Ramona Lim, Elena Stoffel, Priyanka Kanth, N. Jewel Samadder, Maureen E. Mork, Melissa W. Taggart, Ginger L. Milne, Lawrence J. Marnett, Lana Vornik, Diane D. Liu, Maria Revuelta, Kyle Chang, Y. Nancy You, Levy Kopelovich, Ignacio I. Wistuba, J. Jack Lee, Shizuko Sei, Robert H. Shoemaker, Eva Szabo, Ellen Richmond, Asad Umar, Marjorie Perloff, Powell H. Brown, Steven M. Lipkin, Eduardo Vilar. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT111.

e15635 Background: Most squamous cell carcinomas of the anal canal (SCC) respond to chemoradiation, but effective therapy for locally-invasive(T4) or recurrent disease that fails standard chemoradiation and/or salvage abdominoperineal resection (APR) has not been clearly delineated. A multimodality approach including chemoradiation, extended pelvic resection and intraoperative radiation therapy (IORT) was assessed for survival impact and treatment morbidity.morbidities. Methods: A prospective registry including 26 patients with locally-invasive or recurrent disease treated between 1993 and 2007 was reviewed. Primary endpoint was overall survival (OS), obtained from prospectively collected patient questionnaires and medical record review, and analyzed by the Kaplan-Meier method. Short (60-day postoperative) and long-term (median followup: 1.6 years; 5.3 years among survivors) complications were assessed. Results: Patients (median age: 51 years) presented with (1) locally-invasive disease that persisted despite initial standard chemoradiation (n=10, 39%), (2) disease that recurred after initial standard chemoradiation (n=10, 39%; median 1.7 years to recurrence), or (3) re-recurrence after a salvage APR (n=6, 23%; median 1.3 years since APR). All patients received chemotherapy and external beam radiation preoperatively, and 19% received additional postoperative chemoradiation. Gross pelvic disease was completely resected in all (R0 in 73%; R1 in 27%). IORT (750–3250cGy) was delivered at single (92%) or two sites (8%). Median overall survival (OS) was 1.7 years. Five-year OS were: 50%, 10%, and 22% for patients with locally-invasive, recurrent, and re-recurrent disease respectively. Short-term complications predominantly related to the perineal wound. Fifteen patients reported long-term complications (>grade3): bowel obstruction in 8 (1 requiring operation), perineal wound fistula/non-healing in 9, leg paresthesia in 5, hydronephrosis in 3. Conclusions: For select patients with locally-persistent or recurrent SCC who fail standard primary treatment, a multimodality approach involving chemoradiation, extended pelvic resection and IORT offers a chance for improved survival. No significant financial relationships to disclose.