tbuckley/cabot-search huggingface dataset:
Optimizing Use of Nonalcoholic Fatty Liver Disease Fibrosis Score, Fibrosis-4 Score, and Liver Stiffness Measurement to Identify Patients With Advanced Fibrosis
Authors: Wah-Kheong Chan, Sombat Treeprasertsuk, George Boon-Bee Goh, Jian-Gao Fan, Myeong Jun Song, Phunchai Charatcharoenwitthaya, Ajay Duseja, Yock-Young Dan, Kento Imajo, Atsushi Nakajima, Khek-Yu Ho, Khean-Lee Goh, Vincent Wai-Sun Wong
Journal: Clinical Gastroenterology and Hepatology (2019)
Effect of IL-6 and related mediators on resistance to abiraterone acetate (abi) and enzalutamide (enza) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Jacob J. Adashek, Haejung Won, Dayson Moreira, Priyanka Duttagupta, Przemyslaw Twardowski, Jeremy Jones, Marcin Kortylewski, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2019)

296 Background: IL-6 is an upstream regulator of various moieties, including STAT3, that are associated with a poor prognosis in mCRPC. The specific association between these moieties and outcomes with enza and abi are as yet undefined. Methods: Pts receiving abi or enza in the course of routine clinical care were consented for blood collection at weeks 0, 4, 8, and 12 of therapy, and at the time of progression (based on PCWG3 criteria). PBMCs were isolated within 4 hours of blood collection and plasma samples were assessed for 30 soluble immune mediators using Luminex analysis. Flow cytometric analysis was used for characterization of CD3, CD4, CD8 and PD-1. CellSearch was used for CTC enumeration. Results: Of 36 patients consented, 21 received abi and 15 received enza. Median age in the cohort was 71 (range, 54-84). Median PSA was 21.9 ng/dL (range, 0-918.3) and mean CTC count was 158 (range, 0-2126). Median duration of therapy (DOT) with abi or enza was 10.5 mos (range, 1-53); pts were divided into two groups around median DOT. Median DOT in Group A and B were 4 mos (range, 1-10) and 49 mos (range, 11-53), respectively. Patients in Group A had higher levels of pre-treatment levels of IL-6, IL-10, GM-CSF, MIG and FGF, and higher expression of PD1 and FoxP3 on CD4+ T cells (P &lt; 0.05 for each). In an exploratory analysis, patients with &gt; 5 CTCs/7.5 mL of blood at baseline had higher levels of IL-6, although this was not statistically significant (P = 0.08). Conclusions: Elevated levels of IL-6 and several other cytokines are seen in patients with relative resistance to abi/enza for mCRPC. Surface expression of PD-1 and FoxP3 on CD4+ T-cells is also higher in the setting of resistance. The dual combination of elevated pro-inflammatory cytokines along with elevated immunosuppressive signals supports ongoing trials assessing checkpoint inhibition with abi/enza, as well as efforts by the current investigators to develop therapies antagonizing STAT3 (Moreira D et al CCR 2018).
Impact of Long-Term Exposure to Wind Turbine Noise on Redemption of Sleep Medication and Antidepressants: A Nationwide Cohort Study
Authors: Aslak Harbo Poulsen, Ole Raaschou-Nielsen, Alfredo Peña, Andrea N. Hahmann, Rikke Baastrup Nordsborg, Matthias Ketzel, Jørgen Brandt, Mette Sørensen
Journal: Environmental Health Perspectives (2019)

Background: Noise from wind turbines (WTs) is associated with annoyance and, potentially, sleep disturbances. Objectives: Our objective was to investigate whether long-term WT noise (WTN) exposure is associated with the redemption of prescriptions for sleep medication and antidepressants. Methods: For all Danish dwellings within a radius of 20-WT heights and for 25% of randomly selected dwellings within a radius of 20-to 40-WT heights, we estimated nighttime outdoor and low-frequency (LF) indoor WTN, using information on WT type and simulated hourly wind. During follow-up from 1996 to 2013, 68,696 adults redeemed sleep medication and 82,373 redeemed antidepressants, from eligible populations of 583,968 and 584,891, respectively. We used Poisson regression with adjustment for individual and area-level covariates. Results: Five-year mean outdoor nighttime WTN of ≥42 dB was associated with a hazard ratio (HR) = 1.14 [95% confidence interval (CI]: 0.98, 1.33) for sleep medication and HR = 1.17 (95% CI: 1.01, 1.35) for antidepressants (compared with exposure to WTN of &lt;24 dB). We found no overall association with indoor nighttime LF WTN. In age-stratified analyses, the association with outdoor nighttime WTN was strongest among persons ≥65y of age, with HRs (95% CIs) for the highest exposure group (≥42 dB) of 1.68 (1.27, 2.21) for sleep medication and 1.23 (0.90, 1.69) for antidepressants. For indoor nighttime LF WTN, the HRs (95% CIs) among persons ≥65y of age exposed to ≥15 dB were 1.37 (0.81, 2.31) for sleep medication and 1.34 (0.80, 2.22) for antidepressants. Conclusions: We observed high levels of outdoor WTN to be associated with redemption of sleep medication and antidepressants among the elderly, suggesting that WTN may potentially be associated with sleep and mental health. https://doi.org/10.1289/EHP3909
Abstract 11985: The Role of Bystanders in Timely CPR and Related Outcomes After Out-of-Hospital Cardiac Arrest
Authors: Gwan Jin Park, Kyoung Jun Song, Young Sun Ro, Tae Han Kim, Yong Joo Park, Jeong Ho Park, Ki Jeong Hong, Kyung Won Lee, Sang Do Shin
Journal: Circulation (2016)

Objective: Without cardiopulmonary resuscitation (CPR), cardiac arrest survival declines 5-10% for every minutes. But, there is a limit to reduce the time from collapse to Emergency medical service (EMS) arrival. This study aimed to examine the association between the time interval from collapse to CPR by EMS providers and related outcomes in patients who received bystander CPR. Methods: A population-based observational study was conducted with out-of-hospital cardiac arrests (OHCA) of cardiac etiology who were witnessed by laypersons in Korea between 2012 and 2014. Exposure variable was the proportion of the time interval from collapse to CPR by EMS providers categorized into quartile groups: group 1 (time &lt; 4 min), group 2 (4 ≤ time &lt; 8), group 3 (8 ≤ time&lt; 15), group 4 (15 ≤ time &lt; 30). Primary endpoint was time interval from collapse to CPR by EMS providers and secondary endpoint were survival to discharge and survival with favorable neurological outcome (Cerebral Performance Category (CPC) 1-2). Multivariable logistic regression analysis was performed. The final model was performed to evaluate interactive effect between bystander CPR and the time interval from collapse to CPR by EMS providers. Results: A total of 15,354 OHCAs were analyzed. Bystander CPR was performed in 8,591 (55.95%). The survival to discharge rate was 10.6% (1632) and favorable neurological outcome was 6.5% (996). In an interaction model of bystander CPR patients, AORs (95% CIs) for survival to discharge rate were 0.89 (0.66-1.20) in group 2, 0.76 (0.57-1.02) in group 3, 0.52 (0.37-0.73) in group 4 compared with group 1. For favorable neurological outcome, AORs were 1.12 (0.77-1.62) in group 2, 0.90 (0.62-1.30) in group 3, 0.59 (0.38-0.91) in group 4. Conclusion: Despite of poor ambulance response time, patients who received bystander CPR would show favorable outcomes. Prompt delivered bystander CPR was strongly associated with increased survival. Keywords: Out-of-hospital cardiac arrest; Cardiopulmonary resuscitation; Emergency medical services
Overexpression of Dlx2 enhances osteogenic differentiation of BMSCs and MC3T3-E1 cells via direct upregulation of Osteocalcin and Alp
Authors: Jianfei Zhang, Wenbin Zhang, Jiewen Dai, Xudong Wang, Steve Guofang Shen
Journal: International Journal of Oral Science (2019)

Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation, and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues. The aim of this study was to investigate the role and the underlying molecular mechanisms of Dlx2 in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells. Initially, we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells. Moreover, Dlx2 overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line. In addition, micro-CT of implanted tissues in nude mice confirmed that Dlx2 overexpression in BMSCs promoted bone formation in vivo. Unexpectedly, Dlx2 overexpression had little impact on the expression level of the pivotal osteogenic transcription factors Runx2, Dlx5, Msx2, and Osterix, but led to upregulation of Alp and Osteocalcin (OCN), both of which play critical roles in promoting osteoblast maturation. Importantly, luciferase analysis showed that Dlx2 overexpression stimulated both OCN and Alp promoter activity. Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis, we provide molecular evidence that Dlx2 transactivates OCN and Alp expression by directly binding to the Dlx2-response cis-acting elements in the promoter of the two genes. Based on these findings, we demonstrate that Dlx2 overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the OCN and Alp gene, suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation. The distal-less homeobox (Dlx) gene family is related to various features of bone development, and the Dlx2 member of that family has been found to play a crucial role in bone formation. A team headed by Steve Guofang Shen at the Shanghai Jiao Tong University School of Medicine in China investigated the function of Dlx2 in osteogenic (bone development) differentiation of mouse bone marrow stromal cells (BMSCs) and MC3T3-E1 cells (precursors of osteoblasts, the major cellular component of bone). The team found that overexpression of Dlx2 promotes osteogenic differentiation in vitro and accelerates bone formation in vivo by enhancing Osteocalcin and Alp genes (both of which play critical roles in promoting osteoblast maturation). The authors conclude that their results suggest a promising future strategy for treating bone defects where BMSCs overexpress Dlx2.
Abstract 17: Environmental Epidemiology of Kawasaki Disease
Authors: Sunita O’Shea, Cedric Manlhiot, Michael Labelle, Heming Bai, Bailey Bernknopf, Nita Chahal, Catherine S Birken, Brian W McCrindle
Journal: Circulation (2015)

Background: The etiology of Kawasaki disease (KD) is commonly described as an exaggerated immune response to an environmental or infectious trigger in developmentally, immunologically and genetically susceptible children. The trigger for KD has not yet been identified. Methods: Patients with newly diagnosed KD (n=73) were enrolled within 6 weeks of KD diagnosis. Control subjects (n=65) were enrolled during pediatric annual visits and from friends of enrolled KD patients. All participants completed an extensive questionnaire about medical history, family and environment. Geographic localisation software characterized the participants’ neighborhoods. A hypothetical scenario was used for control patients to simulate similar recall bias to that of the KD patients. Results: There were no differences in age, gender, allergies, child and family medical history or recent vaccination. Children with KD were more likely to be unwell prior to KD symptom onset than controls, including fever, stomach pain, lethargy, jaundice, loss of appetite and irritability, but not infectious disease symptoms (16% vs. 21%, p=0.49). Infectious symptomatology developed concurrently to classic KD symptoms. Children with KD had less exposure to environmental allergens and were more likely to be exposed to chemical irritants. Conclusions: The presence of symptoms for up to 1 month before onset of KD may suggest that a preceding illness/environmental agents may alter barriers to entry/exposure or prime an immunologic reaction to an etiologic trigger. Children with fewer allergen/infectious exposures and chronic chemical exposure may be immunologically more susceptible.
1-Year Impact on Medical Practice and Clinical Outcomes of FFRCT
Authors: Manesh R. Patel, Bjarne Linde Nørgaard, Timothy A. Fairbairn, Koen Nieman, Takashi Akasaka, Daniel S. Berman, Gilbert L. Raff, Lynne M. Hurwitz Koweek, Gianluca Pontone, Tomohiro Kawasaki, Niels Peter Rønnow Sand, Jesper M. Jensen, Tetsuya Amano, Michael Poon, Kristian A. Øvrehus, Jeroen Sonck, Mark G. Rabbat, Sarah Mullen, Bernard De Bruyne, Campbell Rogers, Hitoshi Matsuo, Jeroen J. Bax, Jonathon Leipsic
Journal: JACC. Cardiovascular imaging (2019)

The 1-year data from the international ADVANCE (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care) Registry of patients undergoing coronary computed tomography angiography (CTA) was used to evaluate the relationship of fractional flow reserve derived from coronary CTA (FFRCT) with downstream care and clinical outcomes.Guidelines for management of chest pain using noninvasive imaging pathways are based on short- to intermediate-term outcomes.Patients (N = 5,083) evaluated for clinically suspected coronary artery disease and in whom atherosclerosis was identified by coronary CTA were prospectively enrolled at 38 international sites from July 15, 2015, to October 20, 2017. Demographics, symptom status, coronary CTA and FFRCT findings and resultant site-based treatment plans, and clinical outcomes through 1 year were recorded and adjudicated by a blinded core laboratory. Major adverse cardiac events (MACE), death, myocardial infarction (MI), and acute coronary syndrome leading to urgent revascularization were captured.At 1 year, 449 patients did not have follow-up data. Revascularization occurred in 1,208 (38.40%) patients with an FFRCT ≤0.80 and in 89 (5.60%) with an FFRCT >0.80 (relative risk [RR]: 6.87; 95% confidence interval [CI]: 5.59 to 8.45; p < 0.001). MACE occurred in 55 patients, 43 events occurred in patients with an FFRCT ≤0.80 and 12 occurred in those with an FFRCT >0.80 (RR: 1.81; 95% CI: 0.96 to 3.43; p = 0.06). Time to first event (all-cause death or MI) occurred in 38 (1.20%) patients with an FFRCT ≤0.80 compared with 10 (0.60%) patients with an FFRCT >0.80 (RR: 1.92; 95% CI: 0.96 to 3.85; p = 0.06). Time to first event (cardiovascular death or MI) occurred cardiovascular death or MI occurred more in patients with an FFRCT ≤0.80 compared with patients with an FFRCT >0.80 (25 [0.80%] vs. 3 [0.20%]; RR: 4.22; 95% CI: 1.28 to 13.95; p = 0.01).The 1-year outcomes from the ADVANCE FFRCT Registry show low rates of events in all patients, with less revascularization and a trend toward lower MACE and significantly lower cardiovascular death or MI in patients with a negative FFRCT compared with patients with abnormal FFRCT values. (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Wave [ADVANCE]; NCT02499679).
A genomic classifier shows improved prediction of oncologic outcomes in African-American men treated with radical prostatectomy.
Authors: Stephen J. Freedland, Marguerite Du Plessis, Jingbin Zhang, Lauren Howard, Amanda de Hoedt, Elai Davicioni
Journal: Journal of Clinical Oncology (2019)

8 Background: Accurate risk stratification after radical prostatectomy (RP) is important to help select men at risk of recurrence who will benefit most from postoperative radiation or multi-modal therapy. Increasingly genomic testing is being used in the clinic for this purpose. However, little is known about how these tests predict outcomes in African-American men (AAM), an underserved at risk population. Here we evaluate Decipher within a large Veteran Affairs cohort and compare its performance to the CAPRA-S clinical model for predicting outcomes in patients. Methods: Decipher genomic classifier (GC) scores were generated for 557 patients, who underwent RP at the VA Medical Center Durham between 1989 and 2016. This was a clinically high-risk cohort which all underwent RP. Cox UVA and MVA proportional hazards models and survival c-index were used to compare the performance of Decipher and CAPRA-S for predicting risk of metastasis and PCa specific mortality (PCSM). Results: Overall, 55% (n = 306) of patients in the cohort were AAM. CAPRA-S classified 10.4% as low risk for recurrence while for GC it was 50.4%. With a median follow-up of 9 years, only 40 patients developed metastases and 18 patients died of PCa. In multivariable analyses, both GC (p = 0.044 HR:1.30 95% CI:1.01-1.69) and CAPRA-S (p = 0.037 HR:1.27 95% CI:1.01-1.58) were significant predictors for metastasis within non-AAM; however, only GC (p &lt; 0.001 HR:1.70 95% CI:1.31-2.20), was significant within AAM. GC but not CAPRA-S was a significant predictor of PCSM for both EAM (p = 0.044 HR:1.54 95% CI:1.01-2.53) and AAM (p = 0.002 HR:1.65 95% CI:1.19-2.42). The survival c-index of GC for predicting metastasis 8 years post RP was 0.84 (95% CI: 0.76-0.90) in AAM and 0.70 (95% CI:0.63-0.80) in non-AAM. For PCSM endpoint, it was 0.82 (0.61-0.93) in AAM and 0.73 (95% CI:0.63-0.84) in non-AAM. Conclusions: Our results among non-AAM confirm many prior studies showing that GC is a powerful predictor of metastasis and PCSM. Among AAM, not only was GC a very strong predictor of poor outcome, there was actually a suggestion that GC may perform better among AAM than EAM, though this requires further validation.
Combining BET and HDAC inhibitors to potentiate their effectiveness against melanoma and to suppress AKT and YAP signaling.
Authors: Peter Hersey, Anja Heinemann, Carleen Cullinane, Stuart Gallagher, Jessamy Tiffen, Nicholas Smithers, Grant A. McArthur
Journal: Journal of Clinical Oncology (2015)

e13557 Background: Increasing evidence suggests that epigenetic changes underlie many of the oncogenic processes in melanoma. In previous studies we have shown that epigenetic regulation of gene expression by histone deacetylases (HDACs) and bromodomain and extra-terminal (BET) readers of acetylated histones play an important role in resistance of melanoma to targeted therapies and have anti-apoptotic and growth promoting activities in melanoma. Methods: We studied the effects of combining the HDAC inhibitor LBH589 (panobinostat) and BET protein inhibitor I-BET151 on apoptosis and cell growth of melanoma and melanocytes as well as changes they induced in signal pathways and proteins using WBs and reverse phase protein arrays (RPPA). SiRNA knockdown was used to confirm involvement of key proteins. Melanoma xenografts in NOD/SCID mice were used to study effects in vivo. Results: The combination of both inhibitors caused growth arrest in G1 or G2-Mphase and induced synergistic increases in apoptosis. The latter proceeded through the mitochondrial pathway, was caspase dependent and involved upregulation of the BH3 pro-apoptotic protein BIM. BIM was confirmed as a major driver of apoptosis, but apoptosis was also dependent on downregulation of anti-apoptotic Bcl-2 family and IAP proteins. Analysis of three melanoma lines resistant to BRAFi revealed that proteins in the AKT and Hippo/YAP signaling pathways were strongly downregulated in the melanoma cells but not in melanocytes. Xenograft studies with a BRAFi-resistant melanoma confirmed the combination of inhibitors was more effective than single drug treatment in inhibiting the xenografts in vivo. Upregulation of BIM and downregulation of XIAP was shown in the xenografts by IHC. Conclusions: Combining these two classes of epigenetic regulators increased their effectiveness against BRAFi resistant and wildtype melanoma by alteration of the balance between pro and anti apoptotic proteins. These changes involved inhibition of the tumor promoting AKT and YAP pathways. These studies place further focus on the potential use of these inhibitors in treatment of melanoma and further studies on scheduling and pharmacokinetics appear warranted.
Abstract 172: Tissue Doppler Imaging as a Predictor of Immunoglobulin Resistance in Kawasaki Disease
Authors: Daniel R Phadke, Sonali S Patel, Samuel R Dominguez, Heather R Heizer, Marsha Anderson, Mary P Glode, Pei-Ni Jone
Journal: Circulation (2015)

Background: Kawasaki disease (KD) causes myocarditis and left ventricular dysfunction during the acute phase of the illness. Despite treatment with intravenous immunoglobulin (IVIG), a significant number of patients are IVIG resistant (fail to defervesce or experience recrudescent fever). We evaluated KD patients in the acute phase using Tissue Doppler Imaging (TDI) to assess if myocardial dysfunction may predict IVIG resistance. Methods: All patients with acute KD presenting to Children’s Hospital Colorado from February, 2007 to March, 2014 were included in this study. All patients underwent echocardiograms with TDI (pulsed wave sample Doppler were placed at the tricuspid, septal, and mitral annuli) upon diagnosis with KD. Patients were divided into two groups: IVIG Responder group and IVIG Resistant group. Group differences were assessed using Wilcoxon-Mann-Whitney and Chi-square testing. Receiver Operating Characteristic (ROC) Curve analysis was utilized to determine threshold values of TDI measurements associated with IVIG resistance. Results: Fifty-one age matched (+/- 6 months) IVIG Responder patients were compared to 51 IVIG Resistant group [33.49 (17.30 - 62.89) months vs 44.57 (20.13 - 77.07) months, p &lt;0.44]. There were 34 males in Responder group versus 33 males in Resistant group (p&lt; 0.83). There were significant differences in the tricuspid, septal, and mitral early diastolic velocities (E’) (p&lt; 0.05, p&lt; 0.001 and p&lt;0.01) respectively. ROC analysis demonstrated that tricuspid E’ &lt; 0.15 cm/s, septal E’ &lt; 0.12 cm/s, and mitral E’ &lt; 0.16 cm/s were good predictors of IVIG unresponsiveness (AUC = 0.66, 0.66, and 0.70 respectively). There were no differences between the systolic velocities (S’) or late diastolic velocities (A’). Conclusions: IVIG resistant KD patients present with significantly greater diastolic dysfunction compared to responders in patients with KD. TDI may be a useful tool to differentiate KD patients who may be IVIG resistant.