tbuckley/cabot-search huggingface dataset:
Abstract #854: Role for FoxO3a in the apoptotic response of ZNF198-FGFR1-expressing leukemia cells to kinase inhibitor therapy
Authors: L. Cristina Gavrilescu, Katherine Lazarides, Richard Van Etten
Journal: Cancer Research (2009)

8p11 myeloproliferative syndrome (EMS) is a stem cell disease characterized by chromosomal translocations producing fusions of the tyrosine kinase FGFR1 with several partner proteins. ZNF198-FGFR1, product of the t(8;13) translocation, is a cytoplasmic, constitutively activated tyrosine kinase. Here, we show that PD173074, a potent and selective FGFR kinase inhibitor, inhibits the proliferation and survival of IL-3-independent Ba/F3 cell lines stably expressing FGFR1 fusion kinases (IC50   99%. Upon PD173074 treatment, there were lower levels of apoptosis in these cells and no induction of Bim. However, because ZNF198-FGFR1 was still inhibited, the cells were eventually sensitive to the drug in vitro. To assess the importance of FoxO3a to the response to kinase inhibitor therapy in vivo, we injected Balb/c mice with ZNF198-FGFR1 Ba/F3 cells expressing either a scrambled shRNA or FoxO3a shRNA, and treated them daily with 20 mg/kg PD173074 by oral gavage. Untreated mice succumbed by 19 days post-transplant, while PD173074 treatment prolonged the survival of mice injected with scrambled shRNA-expressing cells (median survival 50 days) without obvious drug toxicity. By contrast, PD173074 was much less effective in mice injected with FoxO3a shRNA-expressing cells (median survival 39 days, P  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 854.
Neutrophil Extracellular Traps in Tissue and Periphery in Juvenile Dermatomyositis
Authors: Bhargavi Duvvuri, Lauren M. Pachman, Gabrielle Morgan, Amer M. Khojah, Marisa Klein‐Gitelman, Megan L. Curran, Stephen Doty, Christian Lood
Journal: Arthritis & Rheumatology (2019)

Objective Neutrophils are key immune cells participating in host defense through several mechanisms, including the formation of neutrophil extracellular traps ( NET s). This study was undertaken to investigate the role of neutrophils in juvenile dermatomyositis ( JDM ). Methods Electron microscopy was used to identify neutrophils in tissue. NET s were also imaged using fluorescence microscopy and quantified using a myeloperoxidase‐ DNA enzyme‐linked immunosorbent assay ( ELISA ) in plasma obtained from healthy children (n = 20), disease controls (n = 29), JDM patients (n = 66), and JDM patients with history of calcifications (n = 20). Clinical data included disease activity scores and complement C4 levels. Levels of immune complexes ( IC s) and calprotectin were analyzed using ELISA . Results Using electron microscopy, neutrophils were found to infiltrate affected muscle tissue, engulfing deposited calcium crystals. Uptake of the crystals led to neutrophil activation ( P &lt; 0.01) and subsequent phosphatidylinositol 3‐kinase– and NADPH oxidase–dependent but peptidylarginine deiminase 4–independent formation of NETs, which contained mitochondrial DNA ( P &lt; 0.05), as confirmed in vivo ( P &lt; 0.001) and in vitro ( P &lt; 0.01). Peripheral NET levels were associated with calcinosis ( P = 0.01), IC s ( P = 0.008), and interleukin‐8 levels ( P = 0.004). Children with JDM had impaired NET clearance ( P = 0.01), associated with autoantibody profiles including melanoma differentiation–associated protein 5 ( P = 0.005), and depressed complement C4 levels (r = −0.72, P = 0.002). Furthermore, children with JDM showed evidence of neutrophil activation, with elevated levels of peroxidase activity ( P = 0.02) and calprotectin ( P &lt; 0.01), which were associated with disease activity ( P = 0.007), and dyslipidemia (odds ratio 4.7, P &lt; 0.05). Conclusion We found novel mechanisms of both calcium crystal–mediated neutrophil activation and cell death in JDM pathophysiology. Targeting this pathway may reduce the frequency and extent of calcinosis, as well as prevent long‐term development of comorbidities, including atherosclerosis.
A Molecular Analysis of Cereblon-Related Immunomodulatory Drug Resistance in Commpass Multiple Myeloma Patients
Authors: Sheri Skerget, Brooks Benard, Austin Christofferson, Christophe Legendre, Jessica Aldrich, Sara Nasser, Jennifer Yesil, Daniel Auclair, Winnie Liang, Sagar Lonial, Jonathan J. Keats
Journal: Blood (2017)
Metal‐Protein Nanotheranostics: Photo‐Fenton‐like Metal–Protein Self‐Assemblies as Multifunctional Tumor Theranostic Agent (Adv. Healthcare Mater. 15/2019)
Authors: Tianliang Li, Jia Zhou, Lirui Wang, Hanfu Zhang, Cunfeng Song, Jesús M. de la Fuente, Yunxiang Pan, Jie Song, Chunlei Zhang, Daxiang Cui
Journal: Advanced Healthcare Materials (2019)

In article number 1900192 by Chunlei Zhang, Daxiang Cui, and co-workers, Cu2+-protein self-assemblies loaded with photosensitizer (ICG) and an anticancer drug (doxorubicin) are constructed. The combined nanofomulation can catalyze H2O2 generating more amounts of ·OH under light irradiation when Cu2+ is reduced to Cu+ by glutathione, while presenting efficient photo-Fenton-like activity. For the in vivo experiment, effective tumor accumulation capacity observed by fluorescence/photoacoustic/magnetic resonance imaging, and enhanced tumor therapeutic performance, are achieved.
Monolayer Graphene Coating of Intracortical Probes for Long‐Lasting Neural Activity Monitoring
Authors: Antoine Bourrier, Polina Shkorbatova, Marco Bonizzato, Elodie Rey, Quentin Barraud, Gregoire Courtine, Riadh Othmen, Valerie Reita, Vincent Bouchiat, Cécile Delacour
Journal: Advanced Healthcare Materials (2019)

The invasiveness of intracortical interfaces currently used today is responsible for the formation of an intense immunoresponse and inflammatory reaction from neural cells and tissues. This leads to a high concentration of reactive glial cells around the implant site, creating a physical barrier between the neurons and the recording channels. Such a rejection of foreign analog interfaces causes neural signals to fade from recordings which become flooded by background noise after a few weeks. Despite their invasiveness, those devices are required to track single neuron activity and decode fine sensory or motor commands. In particular, such quantitative and long‐lasting recordings of individual neurons are crucial during a long time period (several months) to restore essential functions of the cortex, disrupted after injuries, stroke, or neurodegenerative diseases. To overcome this limitation, graphene and related materials have attracted numerous interests, as they gather in the same material many suitable properties for interfacing living matter, such as an exceptionally high neural affinity, diffusion barrier, and high physical robustness. In this work, the neural affinity of a graphene monolayer with numerous materials commonly used in neuroprostheses is compared, and its impact on the performance and durability of intracortical probes is investigated. For that purpose, an innovative coating method to wrap 3D intracortical probes with a continuous monolayer graphene is developed. Experimental evidence demonstrate the positive impact of graphene on the bioacceptance of conventional intracortical probes, in terms of detection efficiency and tissues responses, allowing real‐time samplings of motor neuron activity during 5 weeks. Since continuous graphene coatings can easily be implemented on a wide range of 3D surfaces, this study further motivates the use of graphene and related materials as it could significantly contribute to reduce the current rejection of neural probes currently used in many research areas, from fundamental neurosciences to medicine and neuroprostheses.
GEMME: A Simple and Fast Global Epistatic Model Predicting Mutational Effects
Authors: Elodie Laine, Yasaman Karami, Alessandra Carbone
Journal: Molecular Biology and Evolution (2019)

The systematic and accurate description of protein mutational landscapes is a question of utmost importance in biology, bioengineering, and medicine. Recent progress has been achieved by leveraging on the increasing wealth of genomic data and by modeling intersite dependencies within biological sequences. However, state-of-the-art methods remain time consuming. Here, we present Global Epistatic Model for predicting Mutational Effects (GEMME) (www.lcqb.upmc.fr/GEMME), an original and fast method that predicts mutational outcomes by explicitly modeling the evolutionary history of natural sequences. This allows accounting for all positions in a sequence when estimating the effect of a given mutation. GEMME uses only a few biologically meaningful and interpretable parameters. Assessed against 50 high- and low-throughput mutational experiments, it overall performs similarly or better than existing methods. It accurately predicts the mutational landscapes of a wide range of protein families, including viral ones and, more generally, of much conserved families. Given an input alignment, it generates the full mutational landscape of a protein in a matter of minutes. It is freely available as a package and a webserver at www.lcqb.upmc.fr/GEMME/.
Cholangioscopic management of proximally migrated biliary stent using a novel through-the-cholangioscope snare
Authors: Sreelakshmi Kotha, Philip Berry, George Webster, Terry Wong
Journal: Endoscopy (2019)

Endoscopic biliary stenting using plastic or metal stents is an established therapy for the management of biliary obstruction due to benign or malignant disease. Stent migration (proximal or distal) has been reported to occur in 5 % – 10 % of cases [1] [2] [3]. Distally migrated stents mostly pass through the intestine without incident, although bowel perforation, fistulas, and gastrointestinal bleeding have been reported. Proximally migrated stents can cause jaundice and cholangitis, and can be tricky to retrieve. Proximal migration is rare with pigtail stents [4]. This video describes the retrieval of a proximally migrated pigtail stent using a novel through-the-cholangioscope snare ([Video 1]).
GSK458 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in T Cell Lymphomas As a Single Agent and in Combination Therapy
Authors: Juan Gu, Lianjuan Yang, Dennis C Gaughan, Ling He, Weina Shen, Cory Mavis, Francisco J. Hernandez-Ilizaliturri
Journal: Blood (2018)
Abstract #972: Underlying causes of the Black-White racial disparity in breast cancer mortality: A population-based analysis
Authors: Idan Menashe, William Anderson, Ismail Jatoi, Rosenberg Philip
Journal: Cancer Research (2009)

Background: In the United States, a Black-to-White disparity in age-standardized breast cancer mortality rates emerged in the 1980\#8217;s and has widened since then. Methods: To explore this racial disparity, Black-to-White breast cancer rate ratios for mortality (MRRBW), incidence (IRRBW), hazard of breast cancer death (HRRBW), and incidence-based mortality (IBM RRBW) were investigated using data from the NCI\#8217;s SEER program (1990- 2004). A statistical model was developed to characterize the IBM RRBW expected if the distribution of cases by estrogen receptor (ER) expression and hazard rates for breast cancer death were equal in Blacks and Whites. Results: During this period, observed mortality rates improved in Blacks and Whites. However, MRRBW was >1.0 and increased over time, while IRRBW was generally  1.0 for both diseases. Equalizing the proportions of ER+ and ER- tumors in Blacks and Whites decreased expected IBM RRBW slightly; however, the racial disparity was essentially eliminated when hazard rates of breast cancer death were matched for ER+ and ER- tumors. Conclusions: Our results suggest that the racial disparity in breast cancer mortality was largely driven by the early excess hazard of breast cancer death among Black women diagnosed with ER+ and ER- tumors. Greater emphasis should be placed on identifying the etiology of these early excess hazards, and developing targeted therapeutic strategies accordingly.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 972.
Guided implant surgery risks and their prevention
Authors: Dimitris N. Tatakis, Hua‐Hong Chien, Andreas O. Parashis
Journal: Periodontology 2000 (2019)

Abstract Ideal implant placement may reduce surgical complications, such as nerve injury and lingual cortical plate perforation, and minimize the likelihood of functional and prosthetic compromises. Guided implant surgery ( GIS ) has been used as the means to achieve ideal implant placement. GIS refers to the process of digital planning, custom‐guide fabrication, and implant placement using the custom guide and an implant system–specific guided surgery kit. GIS includes numerous additional steps beyond the initial prosthetic diagnosis, treatment planning, and fabrication of surgical guide. Substantial errors can occur at each of these individual steps and can accumulate, significantly impacting the final accuracy of the process with potentially disastrous deviations from proper implant placement. Pertinent overall strategies to reduce or eliminate these risks can be summarized as follows: complete understanding of the possible risks is fundamental; knowledge of the systems and tools used is essential; consistent verification of both diagnostic and surgical procedures after each step is crucial; proper training and surgical experience are critical. This review article summarizes information on the accuracy and efficacy of GIS , provides insight on the potential risks and problems associated with each procedural step, and offers clinically relevant recommendations to minimize or eliminate these risks.
Altered recognition of antigen is a novel mechanism of CD8+ T cell tolerance in cancer
Authors: Srinivas Nagaraj, Kapil Gupta, Vladimir Pisarev, Leo Kinarsky, Simon Sherman, Loveleen Kang, Donna Herber, Jonathan Schneck, Dmitry Gabrilovich
Journal: Cancer Research (2007)

1587  Antigen-specific CD8+ T-cell tolerance is one of the major mechanisms of tumor escape. Recent studies have shown that this tolerance was induced by myeloid-derived suppressor cells (MDSC). Using in vivo models we have found that MDSC directly disrupted the binding of the specific peptide-MHC dimers (pMHC) to CD8+ T cells via nitration of tyrosines within TCR/CD8 complex, which resulted in the inability of CD8+ T cells to bind pMHC and respond to the specific peptide. At the same time, these cells retained their ability to respond to non-specific stimulation. Nitration of TCR/CD8 was induced by MDSC via hyperproduction of reactive oxygen species (ROS) and peroxynitrite during direct cell-cell contact. Molecular modeling suggested specific sites of nitration that could affect conformational flexibility of TCR/CD8 and its interaction with pMHC. This data demonstrates novel mechanisms of T-cell tolerance in cancer that also can be pertinent to many pathological conditions associated with accumulation of MDSC.
Efficacy and Safety of Pomalidomide As a Replacement Therapy for Lenalidomide for Relapsed/Refractory Multiple Myeloma Patients Refractory to a Lenalidomide-Containing Combination Regimen
Authors: James R Berenson, Alexa Cohen, Tanya M. Spektor, Ashkan Lashkari, Roy Mackintosh, Alberto Bessudo, Haresh Jhangiani, Nashat Gabrail, Ibrahim Nakhoul, Samir Kubba, Jeffrey D. Neidhart, Maluso Tina, Regina Swift, Robert Vescio
Journal: Blood (2017)
The impact of race/ethnicity concordance between patients and their navigators in time to diagnostic resolution of breast and cervical cancer screening abnormalities.
Authors: Marjory Charlot, M. Christina Santana, Clara A Chen, Joseph N Palmisano, Sharon Bak, Timothy C Heeren, Tracy Ann Battaglia, Karen M Freund
Journal: Journal of Clinical Oncology (2012)

6097 Background: Patient navigators have been shown to reduce cancer disparities among racial/ethnic minorities by improving timely diagnosis and treatment of cancer. For a group of navigators who received cultural competency training, we sought to determine if racial/ ethnic concordance of the navigator and patient improved time to diagnostic resolution of cancer screening abnormalities. Methods: Demographic data on 1466 patients and their 23 navigators from the Boston Patient Navigation Research Program were used to assess concordance by race and ethnicity. All participants with either breast (n=751) or cervical (n=715) screening abnormalities were followed up to one year. Kaplan-Meier survival curves and proportional hazards regression models examined the effect of race/ethnicity concordance on time to definitive diagnosis, adjusting for age, race, language, economic status, insurance status, and severity of screening abnormality. Analyses were performed separately for the breast and cervical groups. Results: Of the 1466 patients, 32% were White, 27% Black, 31% Hispanic, and 10% Asian. Navigators were 61% White, 17% Black, 13% Hispanic and 9% Asian. Fifty eight percent of patient-navigator pairs were concordant by race/ethnicity. Overall rate of diagnostic resolution of cancer screening abnormalities within 365 days was high at 90%. In both the breast and cervical cancer screening groups, racial/ethnic concordance was not associated with time to diagnostic resolution, with an aHR 1.03 (95% CI: 0.85, 1.25) for breast patients and HR 1.02 (95% CI: 0.85, 1.21) for cervical patients. Conclusions: Patient-navigator racial/ethnic concordance is not associated with time to diagnostic resolution of cancer screening abnormalities, in part because overall rates of diagnostic resolution were high. Our data suggest that with cultural competency training, navigators can be equally effective with patients from different ethnic and cultural backgrounds.
Periodontal Infection and Risk of Myocardial Infarction: A Population-Based Case-control Study
Authors: Maurizio Trevisan, Sara G Grossi, Karen L Falkner, Tiejian Wu, Alex Ho, Julie Baker, Robert J Genco
Journal: Circulation (2001)

P34 Epidemiological studies have demonstrated a significant association between periodontal disease and increased risk of cardiovascular disease. Periodontal organisms were hypothesized to be the underlying factor for the association. This study investigated the relation of myocardial infarction (MI) with both periodontal health status and presence of periodontal pathogens in subgingival plaque. The study sample included 171 MI cases and 574 controls who had at least 6 teeth and were residents of Erie and Niagara counties of New York. Periodontal assessments included pocket depth and attachment loss. Subgingival plaque was sampled and tested using immunofluorescence microscopic technique for the presence of Bacteriodes forsythus (BF), Porphyromouas gingivilis (PG), Prevotella intermedia (PI), and Campyglobacter recta (CR). Results: Mean (SD) pocket depth (mm) was 2.2 (0.7) for MI cases and 2.0 (0.5) for controls (p&lt;0.01). Mean (SD) attachment loss (mm) was 2.6 (1.2) and 2.2 (0.7) for cases and controls (p&lt;0.01), respectively. Presence of periodontal pathogens was significantly more frequent among MI cases than controls. For the four bacteria (BF, PG, PI, and CR), the prevalence (%) of subgingival bacterum presence was 45.0, 14.6, 39.8, and 12.3 among MI cases, and 26.8, 8.2, 31.2, and 5.1 among controls. After adjustment for sex, age, education, smoking status, alcohol use, body mass index, diabetes status, and dental plaque index using logistic regression, the odds ratios (95% confidence intervals) of MI were 1.62 (1.17-2.25) for pocket depth (per 1 mm change), 1.36 (1.10-1.69) for attachment loss (per 1 mm change), 1.93 (1.30-2.88) for BF, 1.41 (0.81-2.48) for PG, 1.18 (0.80-1.73) for PI, and 1.83 (0.96-3.52) for CR presence in subgingival plaque. In conclusion, this case-control study demonstrated that poorer periodontal status and presence of specific bacteria such as BF in subgingival plaque were associated with an increased risk of MI.
The <i>TCF7L2</i> Locus: A Genetic Window Into the Pathogenesis of Type 1 and Type 2 Diabetes
Authors: Struan F.A. Grant
Journal: Diabetes Care (2019)

Over the past ∼15 years there has been great progress in our understanding of the genetics of both type 1 diabetes and type 2 diabetes. This has been driven principally by genome-wide association studies (GWAS) in increasingly larger sample sizes, where many distinct loci have now been reported for both traits. One of the loci that dominates these studies is the TCF7L2 locus for type 2 diabetes. This genetic signal has been leveraged to explore multiple aspects of disease risk, including developments in genetic risk scores, genetic commonalities with cancer, and for gaining insights into diabetes-related molecular pathways. Furthermore, the TCF7L2 locus has aided in providing insights into the genetics of both latent autoimmune diabetes in adults and various presentations of type 1 diabetes. This review outlines the knowledge gained to date and highlights how work with this locus leads the way in guiding how many other genetic loci could be similarly used to gain insights into the pathogenesis of diabetes.
Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies
Authors: Philip L. Mar, Satish R. Raj
Journal: Annual Review of Medicine (2019)

Postural orthostatic tachycardia syndrome (POTS) is a clinically heterogeneous disorder with multiple contributing pathophysiologic mechanisms manifesting as symptoms of orthostatic intolerance in the setting of orthostatic tachycardia (increase in heart rate by at least 30 beats per minute upon assuming an upright position) without orthostatic hypotension. The three major pathophysiologic mechanisms include partial autonomic neuropathy, hypovolemia, and hyperadrenergic state. Patients often will exhibit overlapping characteristics from more than one of these mechanisms. The approach to the treatment of POTS centers on treating the underlying pathophysiologic mechanism. Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. Exercise and volume expansion are the main treatment strategies for hypo-volemic POTS. For hyperadrenergic POTS, beta-blockers and avoidance of norepinephrine reuptake inhibitors is important. Attempts should be made to discern which pathophysiologic mechanism(s) may be afflicting patients so that treatment regimens can be individualized.