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Background:It has been well documented that each additional line of treatment is associated with lower rates of deeper responses, shorter duration of treatment, and increased rates of toxicities/comorbidities in patients with multiple myeloma (MM; Yong K, et al. Br J Haematol 2016. 175[2]:252–264). These factors contribute to treatment discontinuation and impact the proportion of patients reaching subsequent lines of therapy.Aims:To characterize the rate of therapy attrition at relapse for patients with newly diagnosed MM (NDMM) who are transplant eligible in the United States.Methods:Patients with NDMM were identified from 3 US patient‐level data sources: the OPTUM™ Commercial Claims database (period: January 2000–March 2017), the OPTUM™ Electronic Medical Records (EMR) database (period: January 2007–March 2016), and the Surveillance, Epidemiology, and End Results (SEER)‐Medicare Linked database (period: January 2007–December 2014). Patients had 1) an index MM diagnosis on or after 1 January 2007, 2) medical prescription coverage in place at diagnosis, 3) no prior malignancies in the one‐year period prior to index diagnosis, 4) a one‐year look‐back period prior to index diagnosis, and 5) received ≥1 lines of therapy. Patients were considered transplant eligible if they received stem cell transplantation anytime during the follow‐up period. Baseline characteristics including comorbidities, index age, frontline treatment regimens and attrition rates at each subsequent line of therapy were characterized. Attrition was defined as the percentage of patients who did not have any recorded subsequent MM treatments as a result of death or lost to follow‐up in the database for any reason, including end of the database.Results:A total of 1,599 patients were included in this analysis. Baseline patient characteristics and pre‐existing comorbidities are summarized in Table 1. The induction regimens used as frontline treatments included bortezomib/dexamethasone (22%), lenalidomide/dexamethasone (13%), bortezomib/lenalidomide/dexamethasone (25%), all other bortezomib combinations (20%), and other (20%). The proportions of patients observed to progress to each subsequent line of therapy are summarized in Table 2. In total, 77% of patients received a second line of therapy, and only 55% received a third line treatment. The proportion of patients not receiving a subsequent line of therapy due to death is also summarized by lines of therapy in Table 2.Summary/Conclusion:A substantial number of patients with NDMM who are transplant eligible did not receive subsequent lines of therapy, with attrition by lines of therapy ranging from 23–40%. The increase in attrition rates with each additional line of therapy underscores the need to utilize upfront therapy associated with optimal progression‐free survival. Further studies evaluating the etiologic basis for this unexpectedly high attrition rate are warranted.image

Diet-induced insulin resistance (IR) adversely affects human health and life span. We show that muscle-specific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high-fat diet (HFD)–induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented the muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher β-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC1α and PPARβ, and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities.

Abstract Background: Despite a paucity of data on the benign breast transcriptome, reduction mammoplasty tissue is commonly used as a control for RNA biomarker discovery in breast cancer (BC). We evaluated the transcriptome of benign breast to characterize pre-menopausal and post-menopausal coding and non-coding RNA profiles. These profiles will provide insight into the metabolic landscape of benign breast and inform transcriptomic studies of BC and peri-tumoral microenvironments. Methods: With institutional approval, cryobanked fresh breast tissues from reduction mammoplasties (age 15-62y; follow-up: 4-10 y with no cancer events), with histologically-confirmed benign tissues with similar epithelial: stromal tissues were grouped into 4 age sets (< 30y, N=10; 30-39y, N=11; 40-49y, N=10; ≥50y (clinically post-menopausal), N=10). Following RNA extraction, library preparation (Illumina TruSeq Stranded mRNA kit), and sequencing (Illumina HiSeq 4000), reads were processed (MAP-RSeq v3.0.0) and aligned (STAR aligner; hg38). Differential expression (DE) analysis (edgeR 2.6.2) identified DE genes from normalized RPKM reads (absolute log2 fold change (FC) > 1 and false discovery rate (FDR) < 0.10), corrected for intra-group biases using medians (absolute FC cut-off of >1.5). Over-representation analysis [Ingenuity pathway analysis (IPA), Ingenuity® Systems] and gene set enrichment analysis [(GSEA), GeneTrail 2.0] identified significantly-enriched pathways. Results: Across the 4 age sets, 561 DE genes were identified. Compared to the post-menopausal (PM) set, the number of DE genes was highest in <30 y set (N= 372) and decreased with increasing age (N= 170, age 30-39 set and N=20, age 40-49 set), generating up-regulated (PMup) and down-regulated (PMdown) PM transcriptomic profiles. The top PMdown DE genes included RANKL, WNT4, MKI67, extracellular matrix, and lactation-related genes (lactoferrin ,MUC4, MUC16, p < 0.01). Top PMdown canonical pathways were cell cycle-related (CDK1, CCNA2, CCNB2, ESPL1, TOP2A)(p< 0.001). Top PMup genes included those involved in adipogenesis, NPY1R, NPY2R, unsaturated fatty acid synthesis and eicosanoid signaling (P< 0.001). Top PMup canonical pathways included acyl co-A hydrolysis, stearate biosynthesis, acute phase response and RXR signaling (P < 0.001). GSEA of the entire gene set (N=15,466; ranked in order of 561 DE genes) identified 16 significant pathways, functionally grouped as mitochondrial energy metabolism, proteasome, and unsaturated fatty acid biosynthesis and signaling (PPAR pathway). While coding RNAs comprised 85% of DE transcripts, lncRNA comprised ˜5%. Top DE lncRNAs and precursor miRNAs included MEG3, a tumor suppressor, LIN00092, miR22 and miR1182 (p < 0.0001). Conclusions: Pre and post-menopausal benign breast tissues have distinctive transcriptomic profiles. PM benign breast has down-regulated proliferation/cell-cycle-related pathways, and up-regulated genes in mitochondrial energy pathways, lipogenesis and inflammatory pathways. Notably, many of the top DE coding and non-coding RNAs in PM benign breast have been implicated in BC progression, highlighting their value in better understanding breast carcinogenesis and the need to characterize their functional roles in normal aging and menopause. Citation Format: Carter JM, Nair AA, Davila JI, Heinzen EP, Hoskin TL, Winham SJ, Radisky DC, Degnim AC, Visscher DW. Distinctive coding and non-coding RNA profiles of pre-menopausal and post-menopausal benign breast [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-06-01.

Abstract Background: Differences in ER+ and ER- breast cancer tumor biology are well-documented, but little is known about the field of background benign breast in which those cancers arise. We evaluated the transcriptome of benign breast tissues from women with concurrent ipsilateral ER+ and ER- breast cancers (BC) to characterize coding and non-coding RNA profiles. This pilot study provides insight into the transcriptomic landscapes of benign breast tissues in patients with BC, and the microenvironment of the at-risk benign tissue. Methods: With institutional approval, cryobanked breast tissues from patients with concurrent ipsilateral ER+ BC (benign ER+BC, N=14) or ER- BC (benign ER-BC, N=10), were selected for benign tissues with similar epithelial:stromal ratios and grouped into pre (preM) and post-menopausal (PM) groups. Following RNA sequencing (Illumina TruSeq Stranded mRNA kit & Illumina HiSeq 4000), reads were processed (MAP-RSeq v3.0.0) and aligned (STAR aligner; hg38). Differential expression (DE) analysis (edgeR 2.6.2) identified DE genes from normalized RPKM reads (absolute log2 fold change (FC) > 1 and false discovery rate (FDR) < 0.10), corrected for intra-group biases. Over-representation analysis [Ingenuity pathway analysis (IPA), Ingenuity® Systems] and gene set enrichment analysis [(GSEA), GeneTrail 2.0] identified significantly-enriched pathways. Results: In the PM group, there were 144 DE transcripts between benign ER+BC and benign ER-BC, including coding RNAs (40%), antisense RNAs (35%) and lncRNAs (7%). In contrast, the preM group had no significantly DE genes between benign ER+BC and benign ER-BC. In the PM DE coding gene set, the top DE transcripts in benign ER+BC included many genes implicated in BC development# or ER+ BC progression (*) (e.g. up-regulated: KAAG1*, DNAJB7/HSP40*, TMEM151B, ZBTB32# p < 0.001 ; down-regulated: CPB1*, FOS, TPPP3#, CLEC3B#p < 0.001). Top canonical pathways altered in benign ER+BC included MAPK, PI3K, and acute phase response pathways (p<0.05). GSEA of the entire gene set (N=15,223; ranked in order of 144 DE genes) identified 72 altered pathways (P < 0.005); those with the highest normalization enrichment scores (NES) (> 0.4) functionally grouped as immune function-related (T cell function and antigen presentation). Depleted pathways with NES > 0.4, (N=6) functionally grouped into proteasome-related, fatty acid biosynthesis and mitochondrial energy metabolism. Among the non-coding DE gene set, notably, the entire DE antisense RNA gene set (N=51 transcripts) was up-regulated in benign ER+ BC compared to benign ER-BC (P< 0.001) with a subset (N=11) showing marked up-regulation (> 4 log2FC). Among the DE antisense RNAs, 70% have reported roles in carcinogenesis or BC progression (e.g. KRT7-AS, NAV2-AS2, CCDC144NL-AS1, RP11-66B24.4, HSA-MIR4454). Conclusion: The benign breast transcriptome differs between postmenopausal women with ER+ vs ER- BC, with distinctive coding and non-coding RNA signatures. In postmenopausal women with ER+ BC, benign breast expresses a unique antisense RNA set and is enriched in genes implicated in BC development or progression. These data provide insight into at-risk benign breast and facilitate identification of potential biomarkers of carcinogenesis. Citation Format: Carter JM, Nair AA, Davila JI, Heinzen EP, Hoskin TL, Winham SJ, Radisky DC, Visscher DW, Degnim AC. A unique coding and non-coding benign breast transcriptome in post-menopausal ER+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-10.

AbstractObjectivesThe aim of this study was to determine the prevalence of peripheral artery disease (PAD) and its association with in‐hospital outcomes after endovascular transcatheter aortic valve replacement (EV‐TAVR).BackgroundTAVR is an established treatment for patients at prohibitive, high, or intermediate surgical risk. PAD is a significant comorbidity in the determination of surgical risk. However, data on association of PAD with outcomes after EV‐TAVR are limited.MethodsPatients in the National Inpatient Sample who underwent EV‐TAVR between January 1, 2012 and September 30, 2015 were evaluated. The primary outcome was in‐hospital mortality.ResultsA total of 51,685 patients underwent EV‐TAVR during the study period. Of these, 12,740 (24.6%) had a coexisting diagnosis of PAD. The adjusted odds for in‐hospital mortality [OR 1.08 (95% CI 0.83–1.41)], permanent pacemaker implantation [OR 0.98 (0.85–1.14)], conversion to open aortic valve replacement [OR 1.05 (0.49–2.26)], or acute myocardial infarction [OR 1.31(0.99–1.71)] were not different in patients with versus without PAD. However, patients with PAD had greater adjusted odds of vascular complications [OR 1.80 (1.50–2.16)], major bleeding [OR 1.20 (1.09–1.34)], acute kidney injury (AKI) [OR 1.19 (1.05–1.36)], cardiac complications [aOR 1.21 (1.01–1.44)], and stroke [OR 1.39(1.10–1.75)] compared with patients without PAD. Length of stay (LOS) was significantly longer for patients with PAD [7.23 (0.14) days vs. 7.11 (0.1) days, p < 0.001].ConclusionOf patients undergoing EV‐TAVR, ~25% have coexisting PAD. PAD was not associated with increased risk of in‐hospital mortality but was associated with higher risk of vascular complications, major bleeding, AKI, stroke, cardiac complications, and longer LOS.

The objective of this study is to determine whether AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), or peroxisome proliferator-activated receptor β (PPARβ) can independently mediate the increase of glucose transporter type 4 (GLUT4) expression that occurs in response to exercise training. We found that PPARβ can regulate GLUT4 expression without PGC-1α. We also found AMPK and PPARβ are important for maintaining normal physiological levels of GLUT4 protein in the sedentary condition as well following exercise training. However, AMPK and PPARβ are not essential for the increase in GLUT4 protein expression that occurs in response to exercise training. We discovered that AMPK activation increases PPARβ via myocyte enhancer factor 2A (MEF2A), which acted as a transcription factor for PPARβ. Furthermore, exercise training increases the cooperation of AMPK and PPARβ to regulate glucose uptake. In conclusion, cooperation between AMPK and PPARβ via NRF-1/MEF2A pathway enhances the exercise training mediated adaptive increase in GLUT4 expression and subsequent glucose uptake in skeletal muscle.