tbuckley/cabot-search huggingface dataset:
Abstract P133: Role of Akt and p38 in Oxidant Stress Injury and Hypothermic Protection in Murine Cardiomyocytes
Authors: Kimberly R Wojcik, Zuo-Hui Shao, Chang-Qing Li, Kimm J Hamann, Terry L Vanden Hoek
Journal: Circulation (2008)

Cardiac arrest is an ischemia/reperfusion (I/R) disease characterized by oxidant generation, inflammation, and cell death; and hypothermia (HT) has been shown to improve post-cardiac arrest reperfusion injury. We developed a neonatal mouse cardiomyocyte model of I/R (90 min I + 3 hr R) that demonstrates cell injury associated with increased reactive oxygen species (ROS) generation at reperfusion (as measured by DCFH). Mild HT (32°C) protects mouse cardiomyocytes from I/R injury, and we hypothesize that this protection may be related to the activation of the survival kinase Akt. The Akt inhibitor API-2 (10 ìM) reversed HT protection [32.4 ± 7.1% vs 65.7 ± 6.3% with API-2, p&lt; .01(as measured by PI)] to cell death levels commensurate with normothermic I/R injury (60.7 ± 6.0%). Phospho-Akt (pAkt) levels declined during ischemia, and while both Ser473 and Thr308 were phosphorylated in normothermia and HT within 15 min reperfusion, HT showed an augmented level of pAkt at Thr308. Furthermore, this increase was sustained for the first 30 min of reperfusion. To further study this relationship, murine cardiomyocytes were exposed to exogenous H2O2 to mimic the oxidant stress associated with I/R. Mouse cardiomyocytes demonstrated a dose- and time-dependent activation of Akt to H2O2 that showed maximal activation of both the Ser473 and Thr308 sites within 30 min with 200 ìM H2O2. As in I/R-stimulated cells, the Thr308 site declined to near baseline levels within 1 hr while Ser473 remained elevated. Based on recent findings linking Akt and ROS with p38, we examined the effect of I/R and H2O2 on p38. Mouse cardiomyocytes demonstrated a rapid activation of p-p38 (Thr10/Tyr182) in the context of both stresses. Further, we studied the effect of the Akt inhibitor, API-2, as well as the p38 inhibitor, SB 203580, in H2O2-stimulated cells. As in I/R, API-2 blocked H2O2-induced pAkt, but this inhibitor did not have any effect on p-p38. However, when p38 activation was blocked using SB 203580, pAkt levels decreased by 2 hr. These data suggest that HT is, in part, mediated through Akt and that p38 lies upstream of Akt in the context of oxidant stress. These kinases may act as triggers for the initiation of survival pathways in cardiomyocytes to combat potential damage induced by ROS generation.
Comprehensive analysis of metastatic seminoma germ cell tumors shows divergent expression of immune-related pathways.
Authors: Tim Nestler, Friederike Haidl, Maike Wittersheim, Priya Dalvi, Pia Paffenholz, Svenja Wagener-Ryczek, David J. K. P. Pfister, Martin Hellmich, Reinhard Büttner, Margarete Odenthal, Axel Heidenreich
Journal: Journal of Clinical Oncology (2019)

506 Background: Not much is known about the molecular mechanisms resulting in tumor progression and finally leading to metastasis in testicular germ cell tumor (TGCT). Only a few studies in some other tumor types have identified a limited set of genes, related to invasion, progression or metastases to be distinctly upregulated at the invasive tumor front in metastasized patients. However, systematic investigations are missing. Therefore, regional differences in the TGCT subtype seminomas were investigated to achieve a better understanding of the mechanisms involved in the metastatic process. Methods: Formalin-fixed paraffin embedded (FFPE) tissue samples of patients with clinical stage I disease, no adjuvant therapy and a relapse-free survival of at 2 years (n = 21), and patients showing metastasis (n = 14) were selected for the study. The tumor front (TF) and tumor center (TC) regions of each patient were determined and separately collected using laser capture microdissection. RNA was extracted and a multiplex gene expression analysis was performed on all TF and TC samples using nCounter technology of Nanostring. A panel of 770 transcripts was analyzed using the PanCancer Progression panel. Different bioinformatics tools were employed for analyzing the expression data. Results: Differential gene expression patterns were observed in the metastatic and non-metastatic patients, with respect to both the tumor front and tumor center regions. Ingenuity pathway analysis on the differentially expressed genes showed enrichment of tumor functions like migration, invasion, and angiogenesis at the TF as compared to the TC. Remarkably, prominent inflammatory and cancer related pathways such as IL-6 signaling, acute phase response signaling, NF-κB signaling and, dendritic cell maturation were significantly upregulated in the metastatic versus non-metastatic tumors (z-score &gt; ± 2 and p-value &lt; 0.05). Conclusions: This is the first study showing tumor heterogeneity in TGCTs. Evidently, IL-6 signalling was the most significantly upregulated pathway in the metastatic versus the non-metastatic patients, that could serve as a therapeutic target for personalized therapy.
Phase II trial enzalutamide and androgen deprivation therapy (ADT) with salvage radiation in men with high-risk PSA recurrent prostate cancer (PC): The STREAM trial.
Authors: Andrew J. Armstrong, Rhonda L. Bitting, Patrick Healy, Daniel J. George, Sung Kim, Tina M. Mayer, Carolyn Winters, Colleen Riggan, Julia Rasmussen, Rhonda Wilder, Monika Anand, Mark N. Stein, Bart Frizzell, Michael Roger Harrison, Tian Zhang, W. Robert Lee, Yuan Wu, Bridget F. Koontz
Journal: Journal of Clinical Oncology (2019)

29 Background: Salvage external beam radiotherapy (RT) and hormonal therapy improves survival over RT alone in men with non-metastatic hormone naïve PC and PSA recurrence after radical prostatectomy (RP). We investigated the safety/efficacy of enzalutamide with salvage RT and ADT in this setting. Methods: This was a 3 center prospective phase 2 single arm clinical trial in the Dept of Defense Prostate Cancer Clinical Trials Consortium. Eligibility: Gleason 7-10 PC and PSA recurrence within 4 years (yrs) of RP, PSA 0.2-4.0, no prior hormonal therapy, and no metastases on CT/Bone Scan imaging. Men received 6 months (mos) of ADT with 160 mg/d enzalutamide and 66 Gy RT to the prostate bed. Primary endpoint was 2 yr PFS with testosterone (T) recovery to &gt;100 ng/dl. Secondary objectives included PSA nadir, 3 yr PFS, safety and patient reported quality-of-life over time. This trial was designed with 84% power to detect a 20% improvement in 2 yr PFS vs historic data and a 1-sided alpha of 0.05. Results: We enrolled 38 men (90% white, 8% black, 2% Asian); 37 (97%) completed therapy and were evaluable with T recovery at 2 yrs. Median age was 64 yrs; 47% Gleason 8-10, 79% T3/T4 disease, 21% had resected N+ PC; median PSA was 0.4 (0.19-4.19). Median follow-up is 29.5 mo. Treatment was well tolerated with 11 patients (29%) experiencing G3 toxicities (including 4 HTN, 2 urinary retention, 2 CV events); no G4-5 or unexpected toxicities were observed. T recovery occurred in 35 (95%) at 12 mos. The primary endpoint of 2 yr PFS was 65% (95% CI: 47%-78% vs. historic controls with 51% 2 yr PFS rate) among the 37 patients with T recovery. PSA remained at undetectable levels in 69% at 2 yrs. The 3 yr PFS was 53% (95% CI: 36%, 68%). QOL data over time suggest short term reductions in urinary and sexual function with recovery by 12-24 mo in most men. Conclusions: Salvage enzalutamide and ADT for 6 months with RT following RP for men with PSA recurrent high risk PC is safe, and demonstrates encouraging efficacy at 2 and 3 years. Most men have testosterone recovery at 1 year. These data warrant prospective controlled phase 3 trials to assess the impact of potent AR inhibition in this curative intent setting. Clinical trial information: NCT02057939.
Abstract P390: Comparison of the Acute Autonomic Effects of Mainstream Cigarette Smoke to Oral Nicotine Spray
Authors: Affan B Irfan, George Koromia, Waiel Abusnina, Mark Studney, Aruni Bhatnagar, Alex Carll
Journal: Circulation (2019)

Background: Smoking and exposure to environmental tobacco smoke are associated with sympathetic nervous system activation, a leading putative mechanism of adverse cardiovascular events. However, the role of nicotine in cigarette smoke’s sympathomimetic effects remains unknown. Methods: Healthy young smokers were recruited and fasted from food and nicotine/tobacco products for ≥8 hours before each of two visits. On each visit, participants underwent a 12-lead resting electrocardiogram (ECG) for 5 minutes indoors (pre-exposure), 20 minutes outdoors (mid-exposure), and 5 minutes indoors (post-exposure). On the first day, participants smoked cigarette of their preferred brand, and on second day used 4 mg of oral nicotine spray instead. We present preliminary heart rate variability results from 10 smokers who completed two visits (mean age 28 years, 7 males, 0.8 -1.2 mg nicotine per cigarette). Results: Heart rate (HR) increased from 65 ± 20 beats/min (BPM) at pre-exposure to 80 ± 25 BPM during cigarette use (23% increase), and to 78 ± 37 BPM during use of nicotine alone (20% increase) (p&lt;0.05 vs pre-exposure). There was no significant difference in average HR between pre and post exposure. SDRR did not change significantly between phases and exposures (Pre, mid and post exposure (ms) for cigarette; 59 ± 20, 68 ± 25, 57 ± 20 and for nicotine; 70 ± 26, 79 ± 37 and 62 ± 22, respectively.) However, RMSSD decreased with cigarette use by 25% (p&lt;0.01), and also with nicotine but was not significant. Conversely, LF/HF increased during cigarette and nicotine-only exposures relative to pre- (&gt;150%) and post-exposure (&gt;15%) (p&lt;0.05). Conclusion: Our findings suggest smoking may acutely induce relative sympathetic dominance through nicotine, with potential additive effects of other aerosol constituents within tobacco smoke (e.g., aldehydes and particulates).
Fertility counseling in cancer patients: A study of patients and physicians.
Authors: Anem Waheed, Natalie Sophia Grover, Michael G. Douvas
Journal: Journal of Clinical Oncology (2015)

e17721 Background: In 2008, over 130,000 people in the US under age 45 were diagnosed with cancer. Due to increased survival rates, treatment-related infertility is a growing concern among patients. ASCO issued guidelines in 2013 that recommend health care providers address fertility with patients. Methods: We conducted a single center, cross-sectional study at UVa designed to evaluate physicians’ and patients’ perceptions of chemotherapy's effects on fertility. The physician survey focused on perception of fertility risk of many chemotherapy regimens as well as barriers to referring patients to a fertility specialist. The patient survey focused on their experience with counseling, fertility preservation, and perception of treatment effect on future pregnancies and children. Patient eligibility criteria included men and women between ages 18-40 with cancer diagnoses who underwent chemotherapy with curative intent within 1 year. 42 patients and 20 physicians participated. Results: 1/3 of patients reported they were not counseled regarding effects of chemotherapy on fertility. ¾ of patients reported not being offered reproductive counseling. 27% of patients felt their risk of having a child with birth defects was either “much higher” or “almost definite” after treatment completion. 50% of physicians felt conception would be “much less likely” and thought the risk of health problems such as birth defects was much higher after treatment with the low risk regimen R-CHOP. The majority of physicians stated the reasons they do not refer patients to a fertility specialist are patients declining services and insufficient time between diagnosis and treatment. Conclusions: The study results reveal notable deficiencies in physician knowledge about effects of treatment on fertility. Physicians express wide variation in knowledge of effects of chemotherapy regimens on future fertility and birth defects. Not surprisingly, patients have similar misperceptions and many are not counseled adequately and some not at all. Fertility counseling and referral to a fertility preservation specialist should become a routine part of practice. Training for providers and education materials need to be further developed and used in fertility risk counseling.
Abstract 030: Dietary Inflammatory Potential is Associated with Cardiovascular Disease Risk in Two Large Prospective Cohort Studies of US Men and Women
Authors: Jun Li, Donghoon Lee, Yanping Li, Fred Tabung, Shilpa Bhupathiraju, Edward L Giovannucci, JoAnn E Manson, Eric B Rimm, Walter C Willett, Kathryn M Rexrode, Frank Hu
Journal: Circulation (2019)

Introduction: Chronic inflammation plays a pathogenic role in cardiovascular disease (CVD) development. Dietary factors have been implicated in CVD etiology and may have an impact on chronic inflammation. Hypothesis: Proinflammatory diets are associated with higher CVD risk. Methods: We include74,544 women in the Nurses’ Health Study (from 1984 through 2012) and 43,904 men in the Health Professionals Follow-up Study (from 1986 through 2012), who were free of heart disease, stroke, and cancer at baseline. Dietary inflammatory potentials were assessed using an empirical dietary inflammatory pattern (EDIP) score that has been pre-defined by 18 food components based on their associations with circulating levels of systemic inflammation markers C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2. Adjusted hazard ratios (HRs) and 95% confidence internals (CIs) for CVD were calculated using Cox regressions. Results: During 2,831,128 person-years of follow-up, we documented 13,249 incident CVD cases, including 8,178 coronary heart disease cases and 5,182 stroke cases. After adjusting for established risk factors and potential confounders including body-mass index and aspirin or other nonsteroidal anti-inflammatory medication use, a higher EDIP score was associated with an increased risk of CVD (in pooled analyses, HR [95% CI] comparing the highest to the lowest quintiles were 1.29 [1.22 to 1.37]; P trend &lt;0.001), CHD (HR = 1.32[1.23 to 1.42]; P trend &lt;0.001), and stroke (HR = 1.25 [1.14 to 1.37]; P trend &lt;0.001). Associations were similar among subgroups of participants, including by age, sex, family history, BMI, physical activity, and alcohol intake; but were stronger among non/past-smoking than current smoking women ( P interaction &lt;0.002). Conclusions: Findings from two large US prospective cohort studies suggest that inflammation may be a potential mechanism linking dietary patterns to CVD progression. Reducing the proinflammatory potentials of the diet may assist CVD prevention.
Cardiac Magnetic Resonance Imaging-Based Right Ventricular Strain Analysis for Assessment of Coupling and Diastolic Function in Pulmonary Hypertension
Authors: Khodr Tello, Antonia Dalmer, Rebecca Vanderpool, Hossein A. Ghofrani, Robert Naeije, Fritz Roller, Werner Seeger, Jochen Wilhelm, Henning Gall, Manuel J. Richter
Journal: JACC. Cardiovascular imaging (2019)
Current and Future Challenges for Children Across the World
Authors: Zulfiqar A. Bhutta, Robert E. Black
Journal: JAMA (2019)

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Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA/2J glaucoma
Authors: Pete A. Williams, Catherine E. Braine, Krishnakumar Kizhatil, Nicole E. Foxworth, Nicholas G. Tolman, Jeffrey M. Harder, Rebecca A. Scott, Gregory L. Sousa, Alyssa Panitch, Gareth R. Howell, Simon W. M. John
Journal: Molecular Neurodegeneration (2019)

Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. Recent work in animal models suggests that a critical neuroinflammatory event damages retinal ganglion cell axons in the optic nerve head during ocular hypertensive injury. We previously demonstrated that monocyte-like cells enter the optic nerve head in an ocular hypertensive mouse model of glaucoma (DBA/2 J), but their roles, if any, in mediating axon damage remain unclear. To understand the function of these infiltrating monocyte-like cells, we used RNA-sequencing to profile their transcriptomes. Based on their pro-inflammatory molecular signatures, we hypothesized and confirmed that monocyte-platelet interactions occur in glaucomatous tissue. Furthermore, to test monocyte function we used two approaches to inhibit their entry into the optic nerve head: (1) treatment with DS-SILY, a peptidoglycan that acts as a barrier to platelet adhesion to the vessel wall and to monocytes, and (2) genetic targeting of Itgam (CD11b, an immune cell receptor that enables immune cell extravasation). Monocyte specific RNA-sequencing identified novel neuroinflammatory pathways early in glaucoma pathogenesis. Targeting these processes pharmacologically (DS-SILY) or genetically (Itgam / CD11b knockout) reduced monocyte entry and provided neuroprotection in DBA/2 J eyes. These data demonstrate a key role of monocyte-like cell extravasation in glaucoma and demonstrate that modulating neuroinflammatory processes can significantly lessen optic nerve injury.
Whole blood FOLH1 mRNA expression and treatment response in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Edmond Michael Kwan, Sarah Q To, Heidi C Fettke, Maria M Docanto, Patricia Bukczynska, Andrew Michael Mant, David William Pook, Nicole Ng, Lisa-Jane K Graham, Eva Segelov, Kate Mahon, Ian D. Davis, Phillip Parente, Carmel Jo Pezaro, Lisa Horvath, Arun Azad
Journal: Journal of Clinical Oncology (2019)

188 Background: Identifying predictive biomarkers for mCRPC patients receiving androgen receptor signalling inhibitors (ARSI) or chemotherapy remains an unmet clinical need. FOLH1 encodes for Prostate-Specific Membrane Antigen (PSMA), a type II glycoprotein highly expressed on prostate cancer cells. We designed a whole blood assay to detect FOLH1 mRNA, and correlated expression with clinical outcomes in patients commencing ARSI (abiraterone or enzalutamide) or chemotherapy (docetaxel or cabazitaxel). Methods: mCRPC patients commencing ARSI or chemotherapy were prospectively recruited at three Australian centres from June 2016 to July 2018. A quantitative reverse transcription polymerase chain reaction assay was used to detect FOLH1 transcript from whole blood samples collected in PAXgene® RNA tubes. Pre-treatment FOLH1 expression was correlated with PSA response rate (Fisher’s exact test) and PSA progression-free survival (PSA-PFS) (log-rank test). Results: Median follow-up was 13.6 months (IQR 9.7–19.3). In total, 88 pre-treatment samples were analysed, of which 75 (85%) were FOLH1-positive. In patients receiving ARSI, outcomes favoured FOLH1-positive patients compared to FOLH1-negative patients, with higher PSA response rates (39/60, 65% vs. 2/7, 29%; p = 0.1) and longer PSA-PFS (median 9.0 months [95% CI, 7.2-10.8] vs. 2.8 months [95% CI, 2.3-3.3]; p = 0.03). Conversely, in chemotherapy-treated patients, inferior outcomes were observed in FOLH1-positive patients compared to FOLH1-negative patients, with lower PSA response rates (4/15, 27% vs. 5/6, 83%, p = 0.05) and shorter PSA-PFS (median 2.9 months [95% CI, 2.8-3.0] vs. 4.1 months [95% CI, 3.7-4.5]; p = 0.32). Conclusions: Pre-treatment FOLH1 expression may differentiate between outcomes on ARSI vs. chemotherapy in mCRPC patients. The utility of FOLH1 as a predictive biomarker in mCRPC warrants further evaluation in larger, independent cohorts. [Table: see text]
Abstract P012: Cardiovascular Risk Scores Predict Fatigability Among Older Adults
Authors: Yujia Qiao, Pablo Martinez-Amezcua, Jacek K Urbanek, Eleanor M Simonsick, Jennifer A Schrack
Journal: Circulation (2019)

Introduction: Efforts to prevent CVD and its associated health outcomes are paramount to preserving health and functional status in a rapidly aging population. Fatigue is a common side-effect of CVD, but is difficult to measure due to its subjectivity and situational dependence. Fatigability anchors fatigue perception to a standardized walking task, and has been associated with poor functional outcomes with aging. Given the modifiable properties of most CVD risk factors, efforts to prevent the onset and progression of fatigability with aging may benefit from evaluation of -and interventions to treat- components of cardiovascular risk. Hypothesis: Older adults with greater CVD risk have higher fatigability, which is primarily contributed by hypertension. Methods: From 2007-2015, 623 participants of the Baltimore Longitudinal Study of Aging (BLSA) underwent ≥ 2 perceived fatigability and health history assessments. The mean follow-up time is 4.5 years. At baseline, the sex-specific predicted 10-year CVD risk scores were calculated using the Framingham CVD risk score (Framingham) and the Pooled Cohort Equation (ASCVD). At the most recent visit, perceived fatigability was assessed immediately following a slow-paced 5-minute treadmill walk (1.5 mph; 0.67 m/s; 0% grade) using the Borg rating of perceived exertion (RPE; range 6-20). Linear model was used to conduct a cross-sectional analysis. Results: At baseline, participants ranged in age from 32-95 years (mean 68.1±12.0, 56.8% women, 27.6% black), with average CVD risk scores of 17.5±10.5 (Framingham) and 16.8±12.8 (ASCVD), and average fatigability RPE of 8.7±2.4. In crude continuous models, a 5% increase in CVD risk score corresponded to a 0.43 higher RPE (Framingham (p&lt;0.001)) and 0.40 higher RPE (ASCVD (p&lt;0.001)). After adjusting for age, sex, BMI, number of chronic diseases and alcohol intake, the association with the ASCVD score remained essentially unchanged (β=0.16, p=0.010), but the association with the Framingham score was attenuated (β=0.08, p=0.198). Among the primary CVD risk predictors, older age was the largest contributor to higher perceived fatigability (β=0.47, p&lt;0.001), followed by female sex (β=0.12, p=0.001), and hypertension (β=0.10, p=0.005), with diabetes showing a trend (β=0.06, p=0.11). Stratified analyses suggested this association was stronger among those aged ≤70 years (p&lt;0.008) and those with obesity (p&lt;0.002). Conclusions: Perceived fatigability was higher among participants with greater 10-year CVD risk as measured using the Framingham and the ASCVD risk scores. The strong associations with hypertension and obesity suggest interventions to reduce CVD risk may also lower fatigability, particularly among those aged ≤70 years or living with obesity.