Citations

AbstractPeripheral nerve injury‐induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T‐cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2‐mediated DNA demethylation. Global or microglia‐specific deletion of Nfat1 attenuates SNL‐induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia‐related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il‐1b, and c‐Myc in the spinal cord. Microglia‐specific overexpression of c‐MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c‐MYC by intrathecal injection of inhibitor or siRNA alleviates SNL‐induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c‐MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.

AbstractIntroductionCardiac sarcoidosis (CS) is a nonischemic cardiomyopathy (NICM) characterized by infiltration of noncaseating granulomas involving the heart with highly variable clinical manifestations that can include conduction abnormalities and systolic heart failure. Cardiac resynchronization therapy (CRT) has shown significant promise in NICM, though little is known about its efficacy in patients with CS.ObjectiveTo determine if CRT improved cardiac remodeling in patients with CS.MethodsWe retrospectively reviewed all patients with a clinical or histological diagnosis of CS who underwent CRT implantation at the Mayo Clinic enterprise from 2000 to 2021. Baseline characteristics, imaging parameters, heart failure hospitalizations and need for advanced therapies, and major adverse cardiac events (MACE) were assessed.ResultsOur cohort was comprised of 55 patients with 61.8% male and a mean age of 58.7 ± 10.9 years. Eighteen (32.7%) patients had definite CS, 21 (38.2%) had probable CS, while 16 (29.1%) had presumed CS, and 26 (47.3%) with extracardiac sarcoidosis. The majority underwent CRT‐D implantation (n = 52, 94.5%) and 3 (5.5%) underwent CRT‐P implantation with 67.3% of implanted devices being upgrades from prior pacemakers or implantable cardioverter defibrillators. At 6 months postimplantation there was no significant improvement in ejection fraction (34.8 ± 10.9% vs. 37.7 ± 14.2%, p = .331) or left ventricular end‐diastolic diameter (58.5 ± 10.2 vs. 57.5 ± 8.1 mm, p = .236), though mild improvement in left ventricular end systolic diameter (49.1 ± 9.9 vs. 45.7± 9.9 mm, p < .0001). Within the first 6 months postimplantation, 5 (9.1%) patients sustained a heart failure hospitalization. At a mean follow‐up of 4.1± 3.7 years, 14 (25.5%) patients experienced a heart failure hospitalization, 11 (20.0%) underwent cardiac transplantation, 1 (1.8%) underwent left ventricular assist device implantation and 7 (12.7%) patients died.ConclusionsOur findings suggest variable response to CRT in patients with CS with no overall improvement in ventricular function within 6 months and a substantial proportion of patients progressing to advanced heart failure therapies.

A 70-year-old man with severe valvular cardiomyopathy, permanent atrial fibrillation (AF) with a slow ventricular response, and transient atrioventricular (AV) block, was admitted to our center for severe heart failure and recurrent presyncope. While hospitalized, the coronary computed tomography angiography (CTA) showed huge atriums. We tried His bundle pacing (HBP). HB potential was observed at site A, and the His-ventricular (HV) interval was 68 ms. The duration from the stimulus signal to the onset of paced QRS (S-QRSonset) at site A was 232 ms when pacing at 60 beats per minute (BPM) with the pacing threshold of 2.0 V/0.5 ms. The S-QRSonset was longer than the HV interval and had a notable and progressive prolongation from 252 ms to 456 ms during the pacing at 90 BPM. Then, we pushed another lead a little forward, and the S-QRSonset shortened back to 68 ms, and the paced QRS morphology was the same as the intrinsic QRS morphology with the pacing threshold of 1.5 V/0.5 ms. The progressively prolonged S-QRSonset demonstrated a Wenckebach phenomenon (WP), a well-known electrophysiological characteristic of the AV node (AVN). It is the first time to report an intraoperative AVN-pacing related-WP in a patient with persistent AF. The enlarged atrium might be convenient for capturing the AVN. There are some other potential explanations for this phenomenon. The diameters of atriums decreased significantly, and the symptoms improved after the procedure. This is the first reported case in which we might achieve AVN capture in a patient with persistent AF. Although we ultimately chose HBP for better long-term pacing thresholds, the result of this case suggested that AVN pacing may be possible.

Abstract Introduction: Individuals with cancer may be at higher risk of atrial fibrillation (AF). However, sufficient data are lacking in AF risk among breast cancer survivors, especially for the mid-to long-term risk of AF and the impact of cancer treatment on this association. We aimed to investigate the risk of incident AF in women diagnosed with breast cancer and evaluate the association by length of follow-up and breast cancer treatment. Methods: Using the Korean Health Insurance Service database, we studied 96,476 women who were diagnosed with breast cancer (aged≥20 years) without prior history of AF and breast cancer and underwent breast cancer surgery between January 2007 and December 2013. They were matched 1:3 to a cancer-free population (n=289,428) based on birth year and sex and were followed to the end of 2018. Using ICD-10 codes (I48.0 to I48.4, I.48.9), AF was defined when it was a discharge diagnosis or was verified more than twice in an outpatient clinic. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of AF associated with breast cancer relative to the cancer-free population, adjusting for age, income, and comorbidities including diabetes, hypertension and hyperlipidemia. Results: During a median follow-up of 6.8 years, AF developed in 2,105 women with breast cancer (3.2 per 1,000 person-years). Mean age at baseline among participants was 49.6 years. Having breast cancer was associated with increased risk of AF (HR, 2.04; 95% CI, 1.93-2.15). This association was stronger for women aged &lt;50 years (HR, 3.98; 95% CI, 3.59-4.40). When we repeated analyses with lag periods of two years to explore the possibility of reverse causation and mid-to long-term risk of AF (n=91,370), the association was largely attenuated but remained significant (HR, 1.18; 95% CI, 1.09-1.28 for total women and HR, 1.60; 95% CI, 1.38-1.86 for women aged &lt;50 years). However, no increased risk of AF was observed in women with breast cancer aged &gt;65 years. Compared with no use of anthracyclines and taxanes, respectively, ever use of anthracyclines and taxanes was associated with increased risk of AF after further adjusting for other cancer treatment modalities including use of trastuzumab, radiotherapy, and endocrine treatment (HR, 1.25; 95% CI, 1.12-1.40 and HR, 1.37; 95% CI, 1.23-1.53, respectively). This association persisted only among women with breast cancer ever treated with anthracyclines when analysis was limited to those with two year-lag periods (HR, 1.23; 95% CI, 1.04-1.45). Conclusions: In this large-scale nationwide cohort study in South Korea, women with breast cancer had an elevated risk of incident AF, especially for women with breast cancer younger than 50 years, regardless of the length of follow-up. Our findings also suggest that cardiotoxic side effects of cancer treatment such as use of anthracyclines might increase both short-term and mid-to long-term risk of AF among women with breast cancer. Citation Format: Yong-Moon ("Mark") Park, Wonyoung Jung, Yohwan Yeo, Sang Hyun Park, Ronda Henry-Tillman, Hong Seok Lee, Tasneem Z. Naqvi, Kyungdo Han, Dong Wook Shin. Risk of atrial fibrillation among women diagnosed with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3214.

Abstract Background: Large scale genetic perturbations screens have been instrumental for many key discoveries. In the last decade sequence specific genetic perturbations created RNAi and CRISPR (PMID: 25446316). Recently, specific genome targeting approaches using single guide RNAs (sgRNAs) for the CRISPR-Cas9 system have been repurposed to induce sequence-specific repression or activation of gene expression at a genome-wide scale. Different perturbation approaches have different effects and encompass a trade-off between specificity and duration in establishing a measurable perturbation which can result in different biological readouts. However, bench-side strategies are time consuming and expensive. The method described here aims to build a systems-based computational platform to assess pharmacological and biological perturbations at genome-wide network level.Methods: Our network tool NetDecoder (Nucleic Acids Res. 2016; 44(10):e100) that models genome-wide information flow will be used to build context specific protein-protein interaction networks. These networks will be subsequently subjected to in silico perturbations and their impacts on network properties will be assessed. AVANA and Demeter datasets will be used during method validation procedures. Results: Using publicly available expression datasets we generated context specific Breast Cancer networks and individually manipulated nodes and edges of context-specific networks associated with pharmacological FDA approved targets. Our perturbation networks captured cellular rewiring by engulfing new gene players, alterations of the network size and its connectivity. Conclusions: Our in-silico genome wide perturbation platform provides a flexible approach to fine-tune single and tandem manipulations, allowing for inexpensively monitoring a range of pharmacological interventions using large omics data. Citation Format: Cristina Correia, Choong Yong Ung, Cheng Zhang, Scott H. Kaufmann, Hu Li. A genome wide pharmacological perturbation platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1226.

Abstract Current understandings of individual disease etiology and therapeutics are limited despite great need. To fill the gap, we propose a novel computational pipeline which collects potent disease gene cooperative pathways to envision individualized disease etiology and therapies. Our algorithm constructs individualized disease modules de novo which enable us to elucidate the importance of mutated genes in specific patients and to understand the synthetic penetrance of these genes across patients. We reveal that importance of notorious cancer drivers TP53 and PIK3CA fluctuate widely across breast cancers and peak in tumors with distinct numbers of mutations, and that rarely mutated genes such as XPO1 and PLEKHA1 have high disease module importance in specific individuals. Furthermore, individualized module disruption enables us to devise customized singular and combinatorial target therapies which were highly varied across patients demonstrating the need for precision therapeutics pipelines. As the first analysis of de novo individualized disease modules, we illustrate the power of individualized disease modules for precision medicine by providing deep novel insights on the activity of diseased genes in individuals. Citation Format: Taylor Weiskittel, Cristina Correia, Choong Ung, Cheng Zhang, Hu Li. De novo individualized disease modules reveal the synthetic penetrance of genes and inform personalized treatment regimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 490.

Objective The aim of this study was to evaluate the clinical impact of a higher spatial resolution, full field-of-view investigational photon-counting detector computed tomography (PCD-CT) on radiologist confidence in imaging findings and diagnosis of usual interstitial pneumonia (UIP) compared with conventional energy-integrating detector CT (EID-CT). Materials and Methods Patients suspected of interstitial lung disease were scanned on a PCD-CT system after informed consent and a clinically indicated EID-CT. In 2 sessions, 3 thoracic radiologists blinded to clinical history and scanner type evaluated CT images of the right and left lungs separately on EID- or PCD-CT, reviewing each lung once/session, rating confidence in imaging findings of reticulation, traction bronchiectasis, honeycombing, ground-glass opacities (GGOs), mosaic pattern, and lower lobe predominance (100-point scale: 0–33, likely absent; 34–66, indeterminate; 67–100, likely present). Radiologists also rated confidence for the probability of UIP (0–20, normal; 21–40, inconsistent with UIP; 41–60, indeterminate UIP; 61–81; probable UIP; 81–100, definite UIP) and graded image quality. Because a confidence scale of 50 represented completely equivocal findings, magnitude score (the absolute value of confidence scores from 50) was used for analysis (higher scores were more confident). Image noise was measured for each modality. The magnitude score was compared using linear mixed effects regression. The consistency of findings and diagnosis between 2 scanners were evaluated using McNemar test and weighted κ statistics, respectively. Results A total of 30 patients (mean age, 68.8 ± 11.0 years; M:F = 18:12) underwent conventional EID-CT (median CTDIvol, 7.88 mGy) and research PCD-CT (median CTDIvol, 6.49 mGy). The magnitude scores in PCD-CT were significantly higher than EID-CT for imaging findings of reticulation (40.7 vs 38.3; P = 0.023), GGO (34.4 vs 31.7; P = 0.019), and mosaic pattern (38.6 vs 35.9; P = 0.013), but not for other imaging findings (P ≥ 0.130) or confidence in UIP (34.1 vs 22.2; P < 0.059). Magnitude score of probability of UIP in PCD-CT was significantly higher than EID-CT in one reader (26.0 vs 21.5; P = 0.009). Photon-counting detector CT demonstrated a decreased number of indeterminate GGO (17 vs 26), an increased number of unlikely GGO (74 vs 50), and an increased number of likely reticulations (140 vs 130) relative to EID-CT. Interobserver agreements among 3 readers for imaging findings and probability of UIP were similar between PCD-CT and EID-CT (intraclass coefficient: 0.507–0.818 vs 0.601–0.848). Photon-counting detector CT had higher scores in overall image quality (4.84 ± 0.38) than those in EID-CT (4.02 ± 0.40; P < 0.001) despite increased image noise (mean 85.5 vs 36.1 HU). Conclusions Photon-counting detector CT provided better image quality and improved the reader confidence for presence or absence of imaging findings of reticulation, GGO, and mosaic pattern with idiosyncratic improvement in confidence in UIP presence.