Citations

Delayed contact with the medical system may lead to worse patient outcomes in acute myocardial infarction (AMI), particularly ST-elevation myocardial infarction (STEMI). We examined the effect of previously unstudied aspects of patients’ characteristics on delays to presentation, including health status, depressive symptoms, and socioeconomic status. Within the Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health status (TRIUMPH) study, we examined predictors of delays to hospital presentation in 1,476 patients with AMI from 26 sites using multivariable hierarchical ordinal models. Time from symptom onset to hospital presentation was categorized as ≤2 hours, >2 to 6 hours, and >6 hours. Time to hospital presentation was ≤2 hours in 540 (36.6%) patients, between 2– 6 hours in 354 (24.0%) patients, and >6 hours in 582 (39.4%) patients. Factors associated with longer delays to presentation included frequent angina (compared to no angina: daily angina, Odds Ratio [OR] of 3.48 [95% CI: 1.53–7.88]; weekly angina, 2.46 [1.64 –3.67]; and monthly angina, 1.26 [0.96 –1.64]; p for trend<.001), presentation during weekday work hours (8am to 5pm) (compared to weekend: weekday, 1.40 [1.06, 1.85]; weeknight, 1.15 [0.85,1.54]; p for trend = 0.05), cost barriers (1.39 [1.05 to 1.85]; p=0.02), and no healthcare insurance (1.56 [1.15–2.12]; p=0.005). In contrast, patients with STEMI (0.55 [0.43– 0.70]; p<.001), prior coronary revascularization (0.67 [0.48 – 0.92]; p=0.01) and prior AMI (0.68 [0.48 – 0.97]; p=0.03) were more likely to present earlier. No relationship was found for depression, educational level, social support, or marital status. More frequent angina, cost barriers, no healthcare insurance, and time of day are associated with longer delays to hospital presentation, while those with prior AMIs and coronary revascularization were more likely to present earlier. Efforts to reduce delays should address patient issues related to health status (like angina), cost burden, and healthcare access.

Introduction : Obesity is a common risk factor in cardiac rehabilitation (CR), yet many CR patients do not realize significant weight loss, despite engaging in regular exercise training while in CR. Hypothesis : We hypothesized that standard CR would demonstrate favorable body composition (BC) changes even in the absence of weight loss and sought to measure the performance characteristics of weight loss to predict BC changes. Methods : We included consecutive patients enrolled in early outpatient CR who underwent air displacement plethysmography with measurements of height, weight, and waist circumference at initiation and completion of CR. We calculated the accuracy of weight loss to identify significant improvements in BC. Results : Data from 112 patients were available for analysis; mean age 60±12 yr., 76% male, mean body mass index (BMI) 30.2±5.3 kg/m 2 . The indication for CR was myocardial infarction (n=33), percutaneous coronary intervention (n=29), coronary artery bypass or valve surgery (n=45), and heart transplant (n=5). Repeat testing occurred after a median of 81 days and 21 phase II CR sessions. There was no change in BMI (-0.53±1.3 kg/m 2 , p=0.43) and weight (-1.6±4.0 kg, p=0.51). Fat mass showed a borderline significant decrease of 2.9±3.9 kg (p=0.08). However, BC improved significantly as measured by body fat % (-2.5±3.2%, p=0.03) and waist circumference (-4.6±5.2 cm; p=0.01). There was a correlation between weight loss and fat mass loss (r=0.85, p=0.0001, positive predictive value=0.94), and % fat change (r=0.67, p=0.0001, positive predictive value=0.91). See table 1. However, the negative predictive value to detect no fat change for patients who did not lose weight was low (0.49, when assessed by % body fat loss, and 0.57, when assessed by fat mass loss). Among patients who did not lose weight, 29 (51%) had a greater than 1% body fat loss. Conclusions : The diagnostic performance of weight change to predict favorable BC changes is poor and highlights the potential utility of BC measurements in the CR setting. Table. Diagnostic Characteristics of Weight Loss as a Predictor of Improvements in Body Composition Weight Loss (kg) Body Fat % Loss ≤ 1% Fat Mass Loss (kg) > 1kg > 1% ≤ 1kg > 1kg 49 5 51 3 ≤ 1kg or gain 29 28 25 33 Sensitivity 0.63 0.67 Specificity 0.85 0.92 PPV * 0.91 0.94 NPV ** 0.49 0.57 * PPV = Positive Predictive Valve, ** NPV = Negative Predictive Value

Abstract Colorectal cancer (CRC) is a heterogenous disease that develops through somatic mutations in driver genes, leading to activation of diverse neoplastic pathways. To systematically examine if somatically mutated genes and pathways impact survival, we sequenced tumor and normal DNA samples for 4,512 CRC cases using a targeted panel. We performed Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations of disease-specific (DS)-survival with somatically mutated genes and pathways, adjusting for age and sex, and stratifying baseline hazards by study population. We assessed statistical significance using Bonferroni p-value thresholds to account for multiple testing of 214 genes (2.34x10-4) and 6 key CRC pathways (8.3x10-3). We limited analyses to non-silent mutations. We observed that DS-survival was significantly more favorable among individuals with hypermutated (HM) tumors, primarily consisting of microsatellite unstable and POLE-mutated tumors, as compared to those with non-hypermutated (NHM) tumors (HR=0.4, 95% CI: 0.3-0.5, p=1.2x10-17). BRAF V600E mutations were associated with poorer survival (HR=2.0, 95% CI: 1.6-2.5, p=1.6x10-10). This association was more pronounced among NHM tumors (HR=2.3, 95% CI: 1.8-2.9, p=4.3x10-12). We identified suggestive associations (p-values &lt; 5.0x10-3 in overall or stratified analyses) between DS-survival and mutations in B2M, TP53, and SMAD4. Mutations in B2M may provide more favorable prognosis for survival (HR=0.5, 95% CI: 0.3-0.8, p=4.4x10-3), with similar effect sizes in HM and NHM tumors. Poorer survival may be associated with mutations in TP53 (HR=1.2, 95% CI:1.2-1.4, p=9.3x10-4) and SMAD4 (HR=1.3, 95% CI:1.1-1.6, p=3.2x10-3) in NHM tumors. We further observed statistically significant associations between survival and three mutated pathways: TP53/ATM (HR=1.2, 95% CI:1.1-1.4, p=9.0x10-4), receptor tyrosine kinases (RTK) and RAS (HR=1.3, 95% CI:1.1-1.5, p=4.5x10-5), and TGF-beta (HR=1.3, 95% CI:1.1-1.5, p=2.9x10-4). Findings for TP53/ATM and RTK/RAS were primarily due to mutations in one gene within each pathway (TP53 and BRAF, respectively). However, the TGF-beta pathway finding, which was more pronounced in NHM tumors, included two genes with p-values less than 0.05 (SMAD4 p=3.2x10-3 and TGFBR2 p=0.01). Despite our large sample size, relatively few somatically mutated genes were significantly associated with DS-survival. It may be that pathway-level testing affords more power for analyses and that larger sample sizes are needed. It is of interest that non-silent mutations in B2M, whose product is a component of the class I major histocompatibility complex, was associated with improved DS-survival, though our finding was not statistically significant after multiple testing correction so further exploration and replication is needed. Citation Format: Tabitha A. Harrison, Syed H. Zaidi, Conghui Qu, Amanda I. Phipps, Robert S. Steinfelder, Quang M. Trinh, Sonja I. Berndt, Daniel D. Buchanan, Peter T. Campbell, Andrew T. Chan, Kim F. Doheny, David A. Drew, Jane C. Figueiredo, Steven J. Gallinger, Marios Giannakis, Andrea Gsur, Marc J. Gunter, Michael Hoffmeister, Wen-Yi Huang, Paul J. Limburg, Victor Moreno, Polly A. Newcomb, Shuji Ogino, Ross L. Prentice, Tameka Shelford, Wei Sun, Stephen N. Thibodeau, Li Hsu, Ulrike Peters. Associations of somatically mutated genes and pathways with colorectal cancer specific survival in 4,500 colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB090.

Abstract There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P &lt; .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P &lt; .001). Long-term relapse was lower with FM (HR = 0.65, P &lt; .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Personalized treatment of genetically stratified subgroups has the potential to improve outcomes in many malignant tumors. This study distills clinically meaningful prognostic/predictive genomic marker for cervical adenocarcinoma using signature genomic aberrations and single-point nonsynonymous mutation-specific droplet digital PCR (ddPCR). Mutations in PIK3CA E542K, E545K, or H1047R were detected in 41.7% of tumors. PIK3CA mutation detected in the patient’s circulating DNA collected before treatment or during follow-up was significantly associated with decreased progression-free survival or overall survival. PIK3CA mutation in the circulating DNA during follow-up after treatment predicted recurrence with 100% sensitivity and 64.29% specificity. It is the first indication of the predictive power of PIK3CA mutations in cervical adenocarcinoma. The work contributes to the development of liquid biopsies for follow up surveillance and a possibility of tailoring management of this particular women’s cancer.

Background: We performed a multicenter prospective clinical registry across 11 centers to study the association between histopathological characteristics of retrieved clots and imaging, stroke etiology and clinical outcomes. Materials and Methods: Following IRB approval at the 11 centers, patients were enrolled in the STRIP registry. All retrieved emboli were sent for histopathological analysis with H&E and MSB staining. Demographic variables, comorbidities, stroke etiology, imaging findings and procedural details were collected for each case. We studied the association between clot histopathology and imaging findings, stroke etiology and and revascularization outcomes. Student’s t-test was used for continuous variables and chi-squared testing for categorical variables. Results: To date, 1022 patients have been included. There was a significant correlation between platelet rich clots and the absence of hyperdensity on non-contrast CT [p=0.321, p=0.003) and a significant inverse correlation between the percentage of platelets and mean HU on NCCT (p=-0.243, p=0.025). The proportion of platelet-rich clots (55.0% versus 21.2%, p=0.005) and the percentage of platelet content (22.1% versus 13.9%, p=0.03) was significantly higher in patient with large artery atherosclerosis compared to those with a cardioembolic etiology. There was no correlation between RBC density, WBC density, fibrin density or platelet density and revascularization outcomes with stent-retrievers. However, we have found that with aspiration alone, patients with platelet rich clots are less likely to be fully revascularized (i.e. TICI 2c/3) than non-platelet rich clots (OR=0.36, 95%CI=0.12-0.81, P<.0001). Meanwhile, patients with RBC rich clots are more likely to be completely revascularized with aspiration alone than those with RBC poor clots (OR=2.71, 95%CI=1.25-3.24, P=0.02). Conclusions: Interim analysis of the STRIP registry suggests that the platelet content of a clot may be the most revealing factor in determining a clot’s etiology, imaging features and revascularization outcome. Platelet rich clots are less dense on NCCT, are associated with a large artery atherosclerosis source and are less likely to be completely revascularized with aspiration alone.

Introduction: Patient understanding of available therapies for atrial fibrillation (AF) is foundational to shared medical decision making and long term medication adherence. Yet, there is a paucity of data regarding the extent to which patients newly diagnosed with AF in routine community practice understand their options. Hypotheses: 1) Understanding of warfarin, novel oral anticoagulants (NOAC), rhythm control therapy, cardioversion and radio frequency ablation changes little from baseline to 6 months and 2) treatment rates at 6 months are associated with patient understanding of therapies at baseline. Methods: We analyzed survey data from SATELLITE, a substudy of new-onset AF patients enrolled at 56 US sites participating in the ORBIT-AF registry. Patients were surveyed at the baseline and 6 month follow up clinic visit using Likert scales. Agreement between time points was assessed with the McNemar test, and the relationship between understanding and treatment was assessed only for the subset not on treatment at baseline. Results: Of 1000 patients enrolled in SATELLITE, 506 had 6-month survey data (data collection is continuing). Among these, the median age was 69.0 years (IQR 63.0 - 76.0) and 93.7% (474 of 506) were white. There was evidence of improvement in the self-reported understanding of warfarin and NOACs from baseline to 6 months, but not for rhythm control, ablation or cardioversion. The proportion reporting high understanding improved significantly for warfarin (p<.0001) and NOACs (p<.0001) from 47% (223 of 474) and 51% (245 of 481) at baseline to 60% (284 of 474) and 69% (332 of 481) at 6 months respectively (Figure 1). Patients with high understanding of the benefits of ablation (p=0.0005) and options for ablation (p=0.0093) at baseline were more likely to have this therapy at the 6 month follow up (N=590), but improved understanding was not associated with increased use of warfarin/NOACs (N=83) or rhythm control (N=444). Conclusions: Patients with new-onset AF had improved self-reported understanding of some treatment options over the first 6-months from diagnosis; however, factors other than patient understanding may influence AF treatments received at 6 months. Patient understanding of AF treatments remains suboptimal at 6 months, and our results suggest a need for ongoing patient education.

Protein synthesis (translation) is accomplished by ribosomes in all living cells. Ribosomes decode genetic information encoded in messenger RNA and catalyze peptide‐bond formation. We study the mechanisms of translation translation regulation, using structural and biochemical methods. Here, we will present new structural insights into regulation of translation on the ribosome under cellular stress and/or disease.

INTRODUCTION Intestinal enterochromaffin (EC) cells are the specialized epithelial mechanosensors of the gastrointestinal (GI) epithelium and are functionally and developmentally like Merkel cells in the skin. EC cells release serotonin (5‐HT) in response to mechanical stimuli. Recently, we discovered that like Merkel cells, human and mouse EC cells express the mechanosensitive (MS) ion channel Piezo2. However, little is known about the functional properties of this channel in primary EC cells. AIM To determine the role of Piezo2 in primary EC cells. METHODS The enteroendocrine cell transcription factor NeuroD1 was used to mark the late stage of EC cell development and generate NeuroD1‐cre::GCaMP5/tdTomato mouse to identify EC cells and examine their Ca 2+ dynamics. We examined colocalization of tdTomato with 5‐HT and Piezo2 by immunohistochemistry. We established and used primary colon epithelium cultures for whole‐cell patch clamp and Ca 2+ imaging experiments and mechanically stimulated by membrane displacement with a piezoelectrically driven glass probe or shear flow. RESULTS Immunostaining showed no tdTomato labeling outside of the GI epithelium, and epithelial tdTomato cells were 5‐HT+ and Piezo2+. Mechanical stimulation of primary EC cells by membrane displacement produced inward MS currents (20.8±4.9 pA/pF, C m =3.5 pF, n=6) with fast activation and inactivation kinetics (τ inact 11.1±2.8 ms), steep mechanosensitivity (Boltzmann function fit with a mid‐point of 3.46±0.80 μm and slope 0.79±0.27 μm) and a linear current‐voltage relationship (slope 0.61±0.17 pA/mV, x‐intercept −4.26±1.34 mV, n=5). Shear flow (20 s) transiently increased intracellular calcium ((Ca 2+ ) i ) (2.15±0.5 ΔF/F0, upstroke 3–5 s, return to baseline in 60 s, n=12). MS currents were inhibited by the MS ion channel blocker Gd 3+ (20.8±4.9 pA/pF versus 5.3±1.9 pA/pF), Piezo channel blocker GsMTx‐4 (20.8±4.9 pA/pF versus 2.5±0.9 pA/pF) and Piezo2 siRNA (20.8±4.9 pA/pF versus 1.1±0.3 pA/pF), but not non‐targeted (NT) siRNA (20.8±4.9 pA/pF versus 16.0±5.2 pA/pF and) (n=4–6 for each condition, p <0.05 for all except NT siRNA). Similarly, the (Ca 2+ ) i responses to force were inhibited by Gd 3+ (2.28±0.7 ΔF/F0 to 0.09±0.05 ΔF/F0), GsMTx‐4 (2.0±0.6 ΔF/F0 to 0.3±0.1 ΔF/F0), Piezo2 siRNA (2.15±0.5 ΔF/F0 to 0.08±0.05 ΔF/F0), but not NT siRNA (2.15±0.5 ΔF/F0 to 2.7±0.3 ΔF/F0) (n=4–6, p <0.05 for all except NT siRNA). CONCLUSIONS In the mouse epithelium, Piezo2+ EC cells were specifically marked by NeuroD1. Primary colonic NeuroD1+ cells had inward and non‐rectifying MS currents that could be blocked by Gd 3+ , GsMTx‐4 and Piezo2 siRNA. Similarly, shear flow evoked changes in (Ca 2+ ) i that were also blocked by Piezo2 inhibitors and dependent on extracellular Ca 2+ . These results suggest that the MS ion channel Piezo2 acts as the primary EC cell mechanosensor, whose activation by force leads to MS ionic current and (Ca 2+ ) i increase that may mediate mechanically‐induced 5‐HT release. Support or Funding Information This work was supported by NIH K08 DK106456, AGA Research Scholar Award, Mayo Clinic Center for Biomedical Discovery, Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567) and DK52766. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Transcriptional control of Runx2 gene expression through two alternative promoters (P1 and P2) is critical for the execution of its function as an osteogenic cell fate determining factor. Using genomic DNaseI footprinting and in vivo DNA binding assays, we identified a helix‐loop‐helix (HLH) motif that overlaps with a Runx motif in the P1 promoter. The HLH mutation decreases P1 transcription 10‐fold in mesenchymal cells, while mutation of the Runx site enhances transcription 2 fold. Although the HLH element is not cell‐type specific, its function may depend on promoter context. Promoter deletion analysis shows that a GA‐rich region (−200 to −128) positively regulates Runx2 P1 transcription and synergizes with the HLH motif. Examination of the −200/−128 region reveals two tandemly repeated GA‐rich elements (GAY motifs) that each contain recognition motifs for purine‐rich DNA binding factors (i.e., SP1 and KLF10/TGFâ Inducible Factor [TIEG]). Forced expression of SP1 or TIEG modulates Runx2 P1 promoter activity through the GAY motifs. Taken together, our data suggest that the Runx2 gene transcription is regulated by synergistic interactions at multiple conserved composite promoter elements to control Runx2 expression and skeletal development.