tbuckley/cabot-search huggingface dataset:
Therapeutic relevance of homologous recombination repair (HRR) pathway variants in metastatic colorectal cancer (mCRC).
Authors: Ravi Kishore Narra, Arun K. Singavi, Paul S. Ritch, James P. Thomas, Abdel Alqwasmi, Aniko Szabo, Ben George
Journal: Journal of Clinical Oncology (2018)

677 Background: Intact HRR pathway genes play a critical role in repairing double-stranded DNA breaks. Genomic alterations (GA) in several HRR pathway genes have been well characterized, demonstrating prognostic and predictive significance. However, there are many variants of unknown significance (VUS) in the HRR pathway genes that need better characterization. Methods: Patients (pts) with mCRC that harbored VUSs in HRR pathway genes (HRR- VUS; BRCA1/2, ATM, ATR, RAD50, RAD51, PALB2, CHEK1, CHEK2) and treated with front line platinum therapy were identified by review of our institutional molecular data base (MDB) and EMR. Time to 2 nd line therapy (TT2L) and Overall Survival (OS) were calculated. DNA was extracted from formalin fixed paraffin embedded clinical specimens and Next Generation Sequencing (NGS) was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of &gt; 600 unique reads utilizing the Foundation Medicine NGS platform. Results: Among the 873 pts in our institutional MDB, 96 (11%) had mCRC, 20 (21%) harbored HRR pathway GAs, 15 (16%) were categorized as VUSs. HRR-VUS pts had a median age of 57 at diagnosis, 5 (33%) were male, 3 (20%) were right-sided. Distribution of HRR-VUSs in this cohort is summarized in table 1. All pts with HRR-VUSs were micro-satellite stable (MSS), median TMB was 4.5 (range 0 – 8.1). Median TT2L and OS in mCRC pts with HRR-VUSs were 8.0 and 43 months (m) respectively. Two pts with HRR-VUSs had TT2L &gt; 24 m and OS &gt; 40 m; one of them had a BRCA1P1464A mutation, while the other had a BRCA2 amplification. Conclusions: BRCA2, ATM and BRCA1 were the HRR genes that harbored VUSs most frequently in pts with mCRC. Majority with HRR-VUSs had left sided primaries, were MSS and had low TMB. BRCA1P1464A mutation in the ATM binding domain needs further characterization on account of prolonged TT2L with platinum based chemotherapy. Patients with HRR-VUSs that are predictive of benefit with platinum based chemotherapies could be considered for maintenance therapy with PARP inhibitors [Table: see text]
P282High throughput screen to identify EMT-inducing compounds in human epicardial cells
Authors: E Dronkers, T Van Herwaarden, M J Goumans, A M Smits
Journal: Cardiovascular Research (2018)

Introduction: -Protein quality is assured at a cellular level by a finely tuned biological machinery called unfolded protein response (UPR) devoted to recognize, unfold, and refold abnormally arranged proteins.A growing set of previously unrelated disorders has been associated to adverse effects deriving from the accumulation of non-functional aggregates of unfolded proteins named oligomers.Those can perturb the homeostasis, and ultimately the survival of the cell itself.As far as the heart is concerned, an elevated oligomer presence was detected within the myocardium of idiopathic dilated cardiomyopathy (iDCM) cases compared to matched controls.Purpose: -A defective UPR system in the myocardium of iDCM could represent a possible biological foundation leading to or a consequence of a toxic proteic buildup.Methods: -Lysates from left ventricle specimens of iDCM (n¼8), and matched control cases (n¼8) were employed for transcript and protein analysis in order to evaluate components of the UPR system.Both groups were subdivided into young and old subjects (n¼4 for each subgroup).Results: -Young and old subgroups mean ages for iDCM subjects were 30 and 58.8 respectively and 29.5 and 56.8 for controls.Men and women were equally represented in every subgroup.Significant differences (P <0.05) and diverse defects along the pathway were detected by comparing same age subjects.Young iDCM patients showed a significant increase in PERK as well as CHOP, Caspase-12 and the spliced form of XBP-1.Consistent with previous findings Proteasome 20S5b was found to be diminished.On the other hand, older iDCM cases expressed significantly lower levels of spliced XBP-1, ATF6 ratio and higher levels of ATF4 and eIF2a.In addition, significant differences with aging were appreciated throughout the pathway in control subjects in contrast with the iDCM cohort.Conclusion: -These findings shed light on the pivotal role of proteotoxcity overwhelming UPR control as an additional etiology of heart failure.The combined alteration of several target proteins of this pathway configures as a condition of misfolded peptides accumulation ultimately exhausting the cell survival capabilities.
Do we need controlled attenuation parameter adjustment for fibrosis estimation in nonalcoholic fatty liver disease patients?
Authors: Thomas Karlas, Sebastian Beer, Jonas Babel, Harald Busse, Alexander Schaudinn, Nicolas Linder, Johannes Wiegand, David Petroff
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Karlas received unrestricted research grants from Echosens. TO THE EDITOR: Reliable noninvasive prediction of fibrosis in obese nonalcoholic fatty liver disease (NAFLD) patients is a growing need and a diagnostic challenge. The recent article by Petta et al.1 could thus be particularly influential, and it is important that it be cautious with claims and clinical recommendations. The researchers conclude that high values of controlled attenuation parameter (CAP), a noninvasive measure of steatosis, are associated with inaccurate liver stiffness measurements (LSMs) and propose a diagnostic algorithm based on CAP. State‐of‐the‐art demands that high body mass index (BMI) and large skin‐to‐liver‐capsule distance (SLD) be taken into account when performing LSM with transient elastography (FibroScan). The researchers of the above article have already recommended using “specifically designed probes” to improve LSM performance and “enable the examination of significantly more patients.”2 It is thus surprising that their recommended diagnostic flow chart disregards the possibility of using the XL‐probe and neglects to mention the failure rate with respect to screened patients. Given the high prevalence of obesity in their heterogeneous cohorts (21%‐50% with body mass index [BMI] > 30 kg/m2), the M‐probe limitations and presumably high SLD values will most certainly have influenced their analysis. We have compiled data from 80 diabetic and cardiovascular patients at high risk for NAFLD (44% female; 67 ± 8 years; 36% BMI > 30 kg/m2). Invalid M‐probe measurements occurred in 6 of 23 (26%) patients with SLD ≥ 25 mm, but in 0 of 23 with the XL probe. For patients with valid results for both probes, LSM was 35% (95% confidence interval, 17‐53; P < 0.001) higher with the M‐probe, but only differed by 1% (P = 0.63) for CAP. Using the recently introduced CAP software for the XL‐probe,4 one finds that distinction of steatosis (here assessed using proton magnetic resonance spectroscopy) is at least as good as with the M‐probe for the total cohort (Fig. 1). These data suggest that it is necessary to take obesity‐associated anthropometrics into account through a probe switch, but that CAP itself may be less relevant.Figure 1: Estimation of hepatic steatosis severity using controlled attenuation parameter (CAP) with transient elastography M‐ and XL‐probes.Use of the XL‐probe and results of a validation study will ultimately determine the value of the CAP‐based diagnostic flow chart in Petta et al.'s article.
TCTAP C-176 Endovascular Hemostasis of Recurrent Bleeding from Mandibular Aneurysmal Bone Cyst After Tooth Extraction
Authors: Sergey Vladimirovich Sokolov, Irina E. Nikolaeva, Vladimir V. Plechev, Igor V. Buzaev, Ilgiz Zagitov, Nail Ayratovich Davletshin, Anatoliy Vladimirovich Timoshenko, Timur Faritovich Akhmetov, Akhmetshin Rustem Zakievich, Aitbay Akhmetovich Gumerov, Nataliya Makusheva
Journal: Journal of the American College of Cardiology (2018)
Molecular characterization of autophagic and apoptotic signaling induced by Sorafenib in liver cancer cells: In vitro and in vivo studies
Authors: M.Á. Rodríguez-Hernández, R. González, Á.J. De la Rosa, P. Gallego, L. Contreras, R. Ordóñez, E. Navarro-Villarán, M. Rodríguez-Arribas, J. González-Gállego, J.M. Álamo-Martínez, L.M.M. Gómez, J.A.D.C. Castillo, J.L. Quiles, J.M. Fuentes, J. De la Cruz, J.L. Mauriz, F.J. Padillo, J. Muntané
Journal: Journal of Hepatology (2018)
Abstract 18744: Time Trends in the Population Attributable Risk for Cardiovascular Disease: Atherosclerosis Risk in Communities Study
Authors: Susan Cheng, Brian Claggett, Andrew Correia, Amil Shah, Deepak Gupta, Hicham Skali, Hanyu Ni, Josef Coresh, Scott Solomon
Journal: Circulation (2013)

BACKGROUND: Traditional cardiovascular disease (CVD) risk factors remain widely prevalent in the community. Whether relative contributions of risk factors to incident CVD may have changed over time, in the population at large or in important subgroups, is unclear. METHODS: We studied 13,541 participants (56% women, 26% black) in the Atherosclerosis Risk in Communities Study who were aged 52-66 years and free of CVD at visits 1 (1987-1989), 2 (1990-1992), 3 (1993-1995), or 4 (1996-1998). In this middle-aged sample at each visit, and in sex- and race-stratified analyses, we estimated multivariable-adjusted population attributable risks (PAR) for the 10-year incidence of new-onset CVD. RESULTS: Overall, the contributions of smoking (PAR 0.15 [95% CI 0.12-0.17] to 0.12 [0.10-0.14], P=0.05) and dyslipidemia (0.18 [0.10-0.24] to 0.09 [0.03-0.16], P=0.085) to CVD risk appeared to decrease from visit 1 to visit 4; the contributions of obesity (P=0.79), hypertension (P=0.70), and diabetes (P=0.28) were unchanged. The contribution of all risk factors combined was higher in women than men at visit 1 (P&lt;0.001) but not by visit 4 (P=0.11) (Figure). The contribution of all risk factors combined appeared higher in blacks than whites at visit 1 (P=0.06) and this difference was more pronounced by visit 4 (P=0.02). Differences by sex (P=0.051) and race (P=0.089) in the contribution of hypertension to CVD risk had decreased and were borderline significant by visit 4. However, the contribution of diabetes remained substantially higher in women than men (P&lt;0.001) and in blacks than whites (P&lt;0.001) by visit 4. CONCLUSION: The contribution to incident CVD of all traditional risk factors combined is greater in blacks than whites, and this difference may be increasing. The CVD risks attributable to hypertension and diabetes have remained especially high, in women as well as blacks, highlighting the need for continued targeted risk factor modification particularly in these subgroups.
Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia
Authors: Md Kamrul Hasan, Jian Yu, George F. Widhopf, Laura Z. Rassenti, Liguang Chen, Zhouxin Shen, Steven P. Briggs, Donna S. Neuberg, Thomas J. Kipps
Journal: Blood (2018)
TCTAP C-109 Guide Wire Fracture with Remnant Filaments in Left Main Coronary Artery During Chronic Total Occlusion Intervention: Wire Intertwining Retrieval Technique
Authors: Akhtar Fajar Muzakkir, Amir Aziz Alkatiri, Doni Firman, Sunarya Soerianata
Journal: Journal of the American College of Cardiology (2018)
Prevalence estimates and risk factors for early childhood wheeze across Europe: the EuroPrevall birth cohort
Authors: Anna Selby, Alasdair Munro, Kate E Grimshaw, Victoria Cornelius, Thomas Keil, Linus Grabenhenrich, Michael Clausen, Ruta Dubakiene, Alessandro Fiocchi, Marek L Kowalski, Nikolaos G Papadopoulos, Marta Reche, Sigurveig T Sigurdardottir, Aline B Sprikkelman, Paraskevi Xepapadaki, E N Clare Mills, Kirsten Beyer, Graham Roberts
Journal: Thorax (2018)

Background Preschool wheeze is an important problem worldwide. No comparative population-based studies covering different countries have previously been undertaken. Objective To assess the prevalence of early childhood wheeze across Europe and evaluate risk factors focusing on food allergy, breast feeding and smoke exposure. Methods Infants from nine countries were recruited into the EuroPrevall birth cohort. At 12 and 24 months, data on wheeze, allergic signs/symptoms, feeding, smoke exposure, infections and day care attendance were collected using questionnaires. Poisson regression was used to assess risk factors for wheeze. Results 12 049 infants were recruited. Data from the second year of life were available in 8805 (73.1%). The prevalence of wheeze in the second year of life ranged from &lt;2% in Lodz (Poland) and Vilnius (Lithuania) to 13.1% (95% CI 10.7% to 15.5%) in Southampton (UK) and 17.2% (95% CI 15.0% 19.5%) in Reykjavik (Iceland). In multivariable analysis, frequent lower respiratory tract infections in the first and second years of life (incidence rate ratio (IRR) 1.9 (95% CI 1.3 to 2.6) and 2.5 (95% CI 1.9 to3.4), respectively), postnatal maternal smoking (IRR 1.6, 95% CI 1.1 to 2.4), day care attendance (IRR 1.6, 95% CI 1.1 to 2.5) and male gender (IRR 1.3, 95% CI 1.0 to 1.7) were associated with wheeze. The strength of their association with wheeze differed between countries. Food allergy and breast feeding were not independently associated with wheeze. Conclusion The prevalence of early childhood wheeze varied considerably across Europe. Lower respiratory tract infections, day care attendance, postnatal smoke exposure and male gender are important risk factors. Further research is needed to identify additional modifiable risk factors that may differ between countries.
Abstract 14900: Association of Endothelial Microparticles and Mediators of Systemic Inflammation With Exposure to Fine Particulate Matter Air Pollution
Authors: Timothy O’Toole, Wesley Abplanalp, Daniel J Conklin, Aruni Bhatnagar, C. A Pope
Journal: Circulation (2016)

Introduction: A growing body of evidence indicates that exposure to fine particulate matter air pollution (PM2.5) contributes to the risk of cardiovascular morbidity and mortality, but the mechanis...
Abstract 300: No Improved Outcome with Vasopressor Drugs or Sodium Nitroprusside in a 10-Minute Untreated VF Cardiac Arrest Model in Swine
Authors: Mathias Zuercher, Sang Hoon Na, Ronald W Hilwig, Gordon A Ewy, Karl B Kern
Journal: Circulation (2012)

Background: The use of epinephrine to treat cardiac arrest is increasingly challenged. However, previous investigations have shown minimal favorable outcome without the use of vasopressors or surprisingly positive outcome using sodium-nitroprusside in a modified resuscitation protocol. Hypothesis: Vasopressor support improves coronary perfusion pressure (CPP) and favorable 24h neurological outcome in prolonged cardiac arrest. Methods: 35 domestic swine (33.5±5.5 kg) had VF electrically induced and left untreated for 10 minutes. Chest compression only (100/min) advanced life support was given for the first 3 of 7 epochs (2 min each) before ventilation with oxygen was started. Defibrillation attempts were made every 2 minutes. Animals were randomly assigned to one of 5 treatment groups: Placebo, epinephrine (0.045mg/kg), norepinephrine (0.025mg/kg), sodium-nitroprusside (0.0165 mg/kg) plus epinephrine (0.045mg/kg) or sodium-nitroprusside (0.0165 mg/kg). If the rhythm analysis at the beginning of epoch 3 to 7 did not show a perfusing rhythm, the assigned study drug was administered and the protocol continued until ROSC or 25 min, after which the animal was considered non-resuscitated. A swine cerebral performance category (CPC) was determined at 24 hours after onset of cardiac arrest. Data are presented as median and quartiles. Results: ROSC was achieved in 22 (63%) animals and 12 (34%) survived for 24 hours with a favorable neurological outcome (CPC 1+2) in 10 (29%). There was no significant difference in between drug groups. Of these 10, seven achieved ROSC within the first two epochs before any study drug was administered. In the remaining three a vasopressor drug was administered. CPP (mmHg) was significantly higher in animals with favorable outcome during the first two epochs (Epoch 1: 29 (20/40) vs. 15 (10/19); Epoch 2: 18 (12/25) vs. 7 (3/13); p &lt; 0.05). Conclusion: Following four minutes of chest compressions and two defibrillation attempts, the administration of epinephrine, norepinephrine, sodium-nitroprusside plus epinephrine or sodium-nitroprusside alone did not influence 24-hour neurological outcome in a swine model of out-of-hospital VF cardiac arrest.
Allergen‐specific immunotherapy induces regulatory T cells in an atopic dermatitis mouse model
Authors: J. U. Shin, S. H. Kim, J. Y. Noh, J. H. Kim, H. R. Kim, K. Y. Jeong, K. H. Park, J. Lee, H. Chu, J.‐H. Lee, T.‐S. Yong, J.‐W. Park, K. H. Lee
Journal: Allergy (2018)

Abstract Background Several studies have demonstrated that allergen‐specific immunotherapy (SIT) can be an effective treatment for atopic dermatitis (AD). However, there is no relevant mouse model to investigate the mechanism and validate the novel modality of SIT in AD. Methods NC/Nga mice with induced AD‐like skin lesions received a subcutaneous injection of SIT (an extract of the house dust mite Dermatophagoides farinae [ DfE ]) or placebo for 5 weeks). Clinical and histological improvements of AD‐like skin lesions were examined. The responses of local and systemic regulatory T (Treg) cells, natural killer (NK) cells, B cells, serum immunoglobulin, and T‐cell cytokine response to DfE were evaluated to determine the underlying mechanism of the observed results. Results Specific immunotherapy significantly improved AD‐like skin lesions. Histologically, SIT decreased epidermal thickness and reduced inflammatory cell infiltration, especially that of eosinophils. Concomitantly, SIT suppressed Th2 responses and induced local infiltration of Treg cells into the skin. Also, SIT induced the immunoglobulin G4 and attenuated allergen‐specific immunoglobulin E. Furthermore, SIT induced local and systemic IL‐10‐producing Treg cells and regulatory NK cells. Conclusion We established a SIT model on AD mice and showed that our model correlates well with previous reports about SIT‐treated patients. Also, we revealed NK cells as another possible resource of IL‐10 in SIT. Based on our results, we suggest our SIT model as a useful tool to investigate mechanism of action of SIT and to validate the efficacy of new SIT modalities for the treatment of AD.
Bidirectional juxtacrine ephrinB2/Ephs signaling promotes angiogenesis of ECs and maintains self-renewal of MSCs
Authors: Cen Cao, Ying Huang, Qingming Tang, Chenguang Zhang, Lei Shi, Jiajia Zhao, Li Hu, Zhewen Hu, Yun Liu, Lili Chen
Journal: Biomaterials (2018)
<i>LPA</i> Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins
Authors: Wei-Qi Wei, Xiaohui Li, Qiping Feng, Michiaki Kubo, Iftikhar J. Kullo, Peggy L. Peissig, Elizabeth W. Karlson, Gail P. Jarvik, Ming Ta Michael Lee, Ning Shang, Eric A. Larson, Todd Edwards, Christian M. Shaffer, Jonathan D. Mosley, Shiro Maeda, Momoko Horikoshi, Marylyn Ritchie, Marc S. Williams, Eric B. Larson, David R. Crosslin, Harris T. Bland, Jennifer A. Pacheco, Laura J. Rasmussen-Torvik, David Cronkite, George Hripcsak, Nancy J. Cox, Russell A. Wilke, C. Michael Stein, Jerome I. Rotter, Yukihide Momozawa, Dan M. Roden, Ronald M. Krauss, Joshua C. Denny
Journal: Circulation (2018)

Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown.
Abstract 18651: Proteomic Discovery of Pulmonary Hypertension Biomarker Hepatoma Derived Growth Factor
Authors: Melanie K Nies, Jun Yang, Zongming Fu, Rachel L Damico, Paul M Hassoun, Frederick K Korley, Allen D Everett
Journal: Circulation (2015)

Introduction: A non-cardiac blood based biomarker could enhance treatment monitoring and prognostication for pulmonary hypertension (PH). We investigated the diagnostic and prognostic value of hepatoma derived growth factor (HDGF), a pulmonary angiogenic factor in PH. Methods: Using a cohort of Johns Hopkins Pulmonary Hypertension Clinic patients (JHPH, n=73; 49% idiopathic PAH, 51% PAH associated with scleroderma), a healthy control group (n=30) and Johns Hopkins Emergency Department (ED) patients with left sided heart failure (N=55) or chronic illnesses (DM, hypertension, hypercholesterolemia, or smoking, N=66), we investigated the association of HDGF and NT-proBNP and the diagnosis of PH, PH survival, left sided heart failure and chronic disease. Results: HDGF concentrations were significantly elevated in PH versus healthy controls (p=0.013), left sided heart failure (p=0.0026) or chronic disease (p=0.0002), but were not significantly different between healthy controls versus left sided heart failure (P=0.70) or chronic disease (P=0.29). Among PH subjects, the area under the receiver operator curve (AUC) for discriminating survival was 0.71 (p=0.001) for HDGF, with no significant difference between the survival AUC for HDGF and NT-proBNP (p=0.66). The hazard ratio of survival for a HDGF concentration of &gt;0.426 ng/mL was 3.7 (95% CI: 1.5-8.7, P=0.02) and when adjusted for NT-proBNP increased to 4.5 (95% CI: 1.0-20.1, P &lt;0.05) (figure 1). HDGF concentrations were significantly associated with decreased six minute walk distance (6MWD; p=0.04) but not mean PA pressure (p=0.8) or PVR (p=0.4). Conclusion: HDGF is a novel non-cardiac PH biomarker equivalent to NT-proBNP, not confounded by left sided heart failure and significantly associated with 6MWD, the single most important clinical functional measure in PH. Thus, HDGF may add additional value in PH risk stratification for clinical trials as well as future PH drug development.
Effect of melatonin on the circadian clock pathway in liver fibrosis and progression to hepatocarcinoma
Authors: B.G. Fernández, D.I.S. Paniagua, I. Crespo, B.S. Miguel de Vega, D.M. Sánchez, F. Jorquera, J. González-Gállego, M.J.T. González
Journal: Journal of Hepatology (2018)
Towards personalised approach in systemic treatment for hepatocellular carcinoma. The value of AGT M235T gene polymorphism
Authors: M. Reig, L. Boix, F. Torres, A. Darnell, A. Diaz-Gonzalez, N. Llarch, E. Belmonte, V. Sapena, M.S. Zamparelli, J. Corominas, A. Forner, C. Ayuso, J. Bruix
Journal: Journal of Hepatology (2018)