tbuckley/cabot-search huggingface dataset:
P188Co-stimulation dependent CD8 T cell activation protects vein graft disease
Authors: K H Simons, HAB Peters, R Arens, J W Jukema, M R De Vries, PHA Quax
Journal: Cardiovascular Research (2018)

Background: Zinc ions (Zn2þ) are released from activated platelets and are important regulators of coagulation.The majority of plasma Zn2þ are bound to human serum albumin (HSA), yet binding of free fatty acids (FFAs) to HSA alters the protein conformation disrupting Zn2þ binding.Elevated concentrations of plasma FFAs are associated with certain disease states characterised by increased incidence of thrombotic complications.It is therefore important to understand this dynamic and the roles zinc plays in coagulation.Among these roles is modulation of histidine-richglycoprotein (HRG) and fibrinogen interactions with heparins, important natural anticoagulants which are "neutralised" by these interactions.Aims: The primary aims of this project were to: 1) Investigate the interplay between binding of FFAs and Zn2þ to HSA. 2) Determine the effect of this dynamic upon Zn2þ -dependent neutralisation of heparin by fibrinogen and HRG and on fibrin clot formation/lysis.These constitute two potential mechanisms by which Zn2þ can influence clotting.Methods: Isothermal titration calorimetry (ITC) was carried out to study the effect of FFAs of different length on the binding of Zn2þ to HSA.ITC and ELISA-based binding assays were then used to study the effect of Zn2þ on those interactions.Finally the effect of Zn2þ and FFAs on fibrin clot parameters was investigated in both a purified fibrinogen system and in citrated plasma by turbidity assays.Results: ITC data showed that when FFA concentration (0 to 5 mol.eq.) or chain length (C8:0 to C18:0) increase, the availability of the major Zn2þ binding site on albumin decreases up to being completely abolished.ITC and ELISA-based binding assays were then used to study the effect of this freed Zn2þ on heparin neutralisation.It was found that the affinity of HRG for unfractionated heparins (UFHs) (but not low-molecular-weight heparins (LMWHs)) was increased in the presence of 1 mM ZnCl2 (Kd[with zinc] ¼ 5 nM compared to Kd[no zinc] ¼ 33 nM) and that that of fibrinogen for UFHs and LMWHs was increased by the presence of 10 mM ZnCl2 (Kd[with zinc] ¼ 24 nM compared to Kd[no zinc] ¼ 56 nM).The effect of Zn2þ and FFAs on fibrin clot parameters was then investigated.In the purified fibrinogen system, Zn2þ caused an enhanced clot formation and an increase in clot maximum absorbance associated with prolongation in clot lysis time and reduced clot lysis rate, effects that were accentuated in presence of FFAs.Similar results were obtained using plasma samples where clot maximum absorbance increased in presence of Zn2þ and FFAs.Conclusion: These results confirm that FFAs directly affect Zn2þ levels and that Zn2þ is likely to influence coagulation through modulation of HRG and fibrinogen interactions with heparins.This suggests that the increased thrombotic risk in patient with high level of plasma fatty acids is acting through serum albumin and plasma Zn2þ levels.
21-Gene Recurrence Score Assay Predicts Benefit of Post-Mastectomy Radiotherapy in T1-2 N1 Breast Cancer
Authors: Chelain R. Goodman, Brandon-Luke L. Seagle, Masha Kocherginsky, Eric D. Donnelly, Shohreh Shahabi, Jonathan B. Strauss
Journal: Clinical Cancer Research (2018)

Purpose: Post-mastectomy radiotherapy (PMRT) yields improvements in both locoregional control and overall survival (OS) for women with T1-2 N1 breast cancer. The value of PMRT in this population has been questioned given advances in systemic therapy. The 21-gene recurrence score (RS) assay was evaluated as a predictor of OS among women with T1-2 N1 breast cancer who received or did not receive PMRT.Experimental Design: An observational cohort study was performed on women with T1-2 N1 estrogen receptor-positive breast cancer from the National Cancer Database (NCDB) and, as a validation cohort, from the surveillance, epidemiology, and end results (SEER) registry who underwent mastectomy and were evaluated for RS. Multivariable parametric accelerated failure time models were used to estimate associations of RS and PMRT with OS using propensity score-adjusted matched cohorts.Results: In both the NCDB (N = 7,332) and SEER (N = 3,087) cohorts, there was a significant interaction of RS and PMRT with OS (P = 0.009 and P = 0.03, respectively). PMRT was associated with longer OS in women with a low RS [NCDB: time ratio (TR) = 1.70; 95% CI (confidence interval), 1.30-2.22; P < 0.001; SEER: TR = 1.85; 95% CI, 1.33-2.57; P < 0.001], but not in women with an intermediate RS (NCDB: TR = 0.89; 95% CI, 0.69-1.14; P = 0.35; SEER: TR = 0.84; 95% CI, 0.62-1.14; P = 0.26), or a high RS (NCDB: TR = 1.10; 95% CI, 0.91-1.34; P = 0.33; SEER: TR = 0.79; 95% CI, 0.50-1.23; P = 0.28).Conclusions: Longer survival associated with PMRT was limited to women with a low RS. PMRT may confer the greatest OS benefit for patients at the lowest risk of distant recurrence. These results caution against omission of PMRT among women with low RS. Clin Cancer Res; 24(16); 3878-87. ©2018 AACR.
Utilization and Short‐Term Outcomes of Primary Total Hip and Knee Arthroplasty in the United States and Canada
Authors: Peter Cram, Bruce E. Landon, John Matelski, Vicki Ling, Therese A. Stukel, J. Michael Paterson, Rajiv Gandhi, Gillian A. Hawker, Bheeshma Ravi
Journal: Arthritis & Rheumatology (2017)

Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are common and effective surgical procedures. This study sought to compare utilization and short-term outcomes of primary TKA and THA in adjacent regions of Canada and the United States.The study was designed as a retrospective cohort study of patients who underwent primary TKA or THA, comparing administrative data from New York and Ontario in 2012-2013. Demographic features of the TKA and THA patients, per capita utilization rates, and short-term outcomes were compared between the jurisdictions.A higher percentage of New York hospitals performed TKA compared to Ontario hospitals (75.7% versus 42.1%; P < 0.001), and the mean annual procedural volume for TKAs was lower in New York hospitals (mean 179 versus 327 in Ontario hospitals; P < 0.001). After direct standardization, utilization was significantly lower in New York compared to Ontario, both for TKA (16.1 TKAs versus 21.4 TKAs per 10,000 population per year; P < 0.001) and for THA (10.5 THAs versus 11.5 THAs per 10,000 population per year; P < 0.001). For those who underwent TKA, the length of stay in Ontario hospitals was significantly longer (mean 3.7 days versus 3.4 days in New York hospitals; P < 0.001). A smaller percentage of New York patients were discharged directly home (46.2% versus 90.9% of Ontario patients; P < 0.001), but 30-day and 90-day readmission rates were higher in New York compared to Ontario (30-day rates, 4.6% versus 3.9% [P < 0.001]; 90-day rates, 8.4% versus 6.7% [P < 0.001]). For the THA cohorts, the results with regard to length of stay, discharge disposition, and readmission rates were similar to those for TKA.Ontario has higher utilization of total joint arthroplasty than New York but has a smaller percentage of hospitals performing these procedures. Patients are more likely to be discharged home and less likely to be readmitted in Ontario. Our results suggest areas where each jurisdiction could improve.
Enterovirus and Parechovirus Surveillance — United States, 2014–2016
Authors: Glen R. Abedi, John T. Watson, W. Allan Nix, M. Steven Oberste, Susan I. Gerber
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Infections caused by enteroviruses (EV) and parechoviruses (PeV), members of the Picornaviridae family, are associated with various clinical manifestations, including hand, foot, and mouth disease; respiratory illness; myocarditis; meningitis; and sepsis; and can result in death. The genus Enterovirus includes four species of enterovirus (A-D) known to infect humans, and the genus Parechovirus includes one species (A) that infects humans. These species are further divided into types, some of which are associated with specific clinical manifestations. During 2014-2016, a total of 2,967 U.S. cases of EV and PeV infections were reported to the National Enterovirus Surveillance System (NESS). The largest number of reports during that time (2,051) occurred in 2014, when a large nationwide outbreak of enterovirus D68 (EV-D68) occurred, accounting for 68% of cases reported to NESS that year (1). Reports to the National Respiratory and Enteric Virus Surveillance System (NREVSS) during 2014-2016 indicated that circulation of EV peaks annually in the summer and early fall. Because the predominant types of EV and PeV circulating from year to year tend to vary, tracking these trends requires consistent and complete reports from laboratories with the capacity to perform typing.
Regression of fibrosis stage after treatment in patients with HFE haemochromatosis and severe fibrosis at diagnosis: relevance to hepatocellular carcinoma
Authors: E. Bardou-Jacquet, M. Emilie, A. Gregory, G. Ramm, L. Ramm, M. Jeff, D. Jeannette, C. Andrew, L. Fabrice, T. Bruno, L. Powell, Y. Deugnier
Journal: Journal of Hepatology (2018)
Secondary Prevention After Coronary Artery Bypass Graft Surgery
Authors: Alexander Kulik, Marc Ruel, Hani Jneid, T. Bruce Ferguson, Loren F. Hiratzka, John S. Ikonomidis, Francisco Lopez-Jimenez, Sheila M. McNallan, Mahesh Patel, Véronique L. Roger, Frank W. Sellke, Domenic A. Sica, Lani Zimmerman
Journal: Circulation (2015)
Structural Insights into <i>N</i> <b>6</b>-Methyladenosine (m<b>6</b>A) Modification in the Transcriptome
Authors: Jinbo Huang, Ping Yin
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract More than 100 types of chemical modifications in RNA have been well documented. Recently, several modifications, such as N6-methyladenosine (m6A), have been detected in mRNA, opening the window into the realm of epitranscriptomics. The m6A modification is the most abundant modification in mRNA and non-coding RNA (ncRNA). At the molecular level, m6A affects almost all aspects of mRNA metabolism, including splicing, translation, and stability, as well as microRNA (miRNA) maturation, playing essential roles in a range of cellular processes. The m6A modification is regulated by three classes of proteins generally referred to as the “writer” (adenosine methyltransferase), “eraser” (m6A demethylating enzyme), and “reader” (m6A-binding protein). The m6A modification is reversibly installed and removed by writers and erasers, respectively. Readers, which are members of the YT521-B homology (YTH) family proteins, selectively bind to RNA and affect its fate in an m6A-dependent manner. In this review, we summarize the structures of the functional proteins that modulate the m6A modification, and provide our insights into the m6A-mediated gene regulation.
Novel Effector Phenotype of Tim-3+ Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients
Authors: Zhuqing Liu, Elizabeth L. McMichael, Gulidanna Shayan, Jing Li, Kevin Chen, Raghvendra Srivastava, Lawrence P. Kane, Binfeng Lu, Robert L. Ferris
Journal: Clinical Cancer Research (2018)

Purpose: Regulatory T (Treg) cells are important suppressive cells among tumor-infiltrating lymphocytes (TIL). Treg cells express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T-cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear.Experimental Design: CD4+CTLA-4+CD25high Treg cells were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene-expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg.Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naïve T-cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39, and IFN-γ receptor. Exogenous IFN-γ treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs.Conclusions: Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T-cell proliferation despite high PD-1 expression. IFN-γ induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression. Clin Cancer Res; 24(18); 4529-38. ©2018 AACR.
Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women
Authors: Angela Huttner, Anna Kowalczyk, Adi Turjeman, Tanya Babich, Caroline Brossier, Noa Eliakim-Raz, Katarzyna Kosiek, Begoña Martinez de Tejada, Xavier Roux, Shachaf Shiber, Ursula Theuretzbacher, Elodie von Dach, Dafna Yahav, Leonard Leibovici, Maciek Godycki-Cwirko, Johan W. Mouton, Stephan Harbarth
Journal: JAMA (2018)

The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI).To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis.Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel.Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection.The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events.Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively).Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion.ClinicalTrials.gov Identifier: NCT01966653.
Abstract 13739: Progression of Mitral Stenosis in Patients With Severe Mitral Annular Calcification and Chronic Kidney Disease
Authors: Rayji S Tsutsui, Zoran B Popovic
Journal: Circulation (2015)

Background: Severe mitral annular calcification (MAC) is recognized as a rare cause of mitral stenosis. However, little is known regarding its relationship with chronic kidney’s disease (CKD). We evaluated progression of mean mitral valve (MV) gradients and the right ventricular systolic pressures (RVSP) over time in patients with CKD. Methods: Database for the years 1996 through 2013 was searched for patients with severe MAC. MAC was graded in a semi-quantitative manner. Patients were included if they had severe MAC at their index study, had ≥ 2 studies in the period of ≥ 2 years, and had glomerular filtration rate estimated ≤ 3 months from the index study. Patients with prior MV surgery, rheumatic heart disease, or other MV disease were excluded. CKD was classified by 5 conventional stages. The slope of regression line using all studies of a given patient was used to determine the progression rate. Results: 924 patients (7002 studies) were included. Data are expressed as mean ± standard deviation. Study population age was 72 ± 11 years. Follow up time was 4.8 ± 2.8 years. Number of echocardiograms performed per patient was 8 ± 5. Index MV gradient was 3.9 ± 3.2 mmHg with progression rate 0.13 ± 0.86 mmHg / year (p = 0.0001). Index RVSP was 39 ± 15 mmHg with progression rate 0.97 ± 4.49 mmHg / year (p = 0.0001). Progression appeared slower in younger (&lt;65, n=189) than older (≥65, n = 735) patients (MV gradient p=0.07, RVSP p= 0.10). 66 patients had MV surgery with MV gradient at the time of surgery being 13.76 ± 4.15 mmHg. There were no significant differences in the progression rate among CKD stages (MV gradient p = 0.11, RVSP p = 0.87) or with dialysis status (n=41, MV gradient p= 0.50, RVSP p= 0.13). Conclusion: While there tended to be faster rate of progression of mitral stenosis in older patients with severe MAC, CKD class was not a differentiating factor. It appears that mitral stenosis in patients with severe MAC progress more in older patients but not necessarily in patients with poor kidney function.
The prognostic value of monosomal karyotype (MK) in higher‐risk patients with myelodysplastic syndromes treated with 5‐Azacitidine: A retrospective analysis of the Hellenic (Greek) Myelodysplastic syndromes Study Group
Authors: Sotirios G. Papageorgiou, Diamantina Vasilatou, Christos K. Kontos, Ioannis Kotsianidis, Argiris Symeonidis, Athanasios G. Galanopoulos, Eleftheria Hatzimichael, Aekaterini Megalakaki, Elias Poulakidas, Panagiotis Diamantopoulos, Theodoros P. Vassilakopoulos, Panagiotis Zikos, Helen Papadaki, Despoina Mparmparousi, Eleni Bouronikou, Panayiotis Panayiotidis, Nora‐Athina Viniou, Vassiliki Pappa
Journal: American Journal of Hematology (2018)

In this study, we investigated the incidence and prognostic impact of monosomal karyotype (MK) in 405 higher-risk Myelodysplastic Syndromes (MDS) patients treated with 5-AZA. The MK was present in 66 out of 405 (16.3%) patients, most of whom had complex karyotype (CK). MK was strongly associated with CK and the cytogenetic risk defined according to IPSS-R, as well as with high-risk disease, according to IPSS (P = .029), IPSS-R (P < .001), and WPSS (P < .001) classification systems. The overall response rate (ORR) was not different between MK+ and MK- patients (46.6% vs. 46.2%). At 28 months median follow-up, the median duration of response was 11 months in the entire cohort, 9.5 months in MK+ patients and 11 months in MK-patients (P = .024). The estimated median time to transformation to acute myeloid leukemia for MK+ patients was 17 months vs. 23 months for MK- patients (P = .025). The estimated median OS for MK+ patients was 12 months vs. 18 months for MK- patients (P < .001). Multivariate Cox regression analysis revealed that performance status (P < .001), IPSS-R (P < .001), and MK (P = .002) were independently associated with overall survival (OS). In a subgroup consisting of high and very-high risk patients according to IPSS-R, MK- patients showed better OS rates compared to MK+ patients (estimated median OS: 17 months vs. 12 months, P = .002). In conclusion, we found that MK is associated with reduced OS in patients with higher-risk MDS treated with 5-AZA. Furthermore, we showed that in MDS with high or very-high IPSS-R risk score, MK can further distinguish patients with worse outcome.
Quality of Life in Patients With Glioblastoma Treated With Tumor-Treating Fields
Authors: Kevin Kwan, Julia R. Schneider, John A. Boockvar
Journal: JAMA (2018)

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About Chemical Strategies to Fabricate Cell‐Instructive Biointerfaces with Static and Dynamic Complexity
Authors: Gülistan Koçer, Pascal Jonkheijm
Journal: Advanced Healthcare Materials (2018)

Abstract Properly functioning cell‐instructive biointerfaces are critical for healthy integration of biomedical devices in the body and serve as decisive tools for the advancement of our understanding of fundamental cell biological phenomena. Studies are reviewed that use covalent chemistries to fabricate cell‐instructive biointerfaces. These types of biointerfaces typically result in a static presentation of predefined cell‐instructive cues. Chemically defined, but dynamic cell‐instructive biointerfaces introduce spatiotemporal control over cell‐instructive cues and present another type of biointerface, which promises a more biomimetic way to guide cell behavior. Therefore, strategies that offer control over the lateral sorting of ligands, the availability and molecular structure of bioactive ligands, and strategies that offer the ability to induce physical, chemical and mechanical changes in situ are reviewed. Specific attention is paid to state‐of‐the‐art studies on dynamic, cell‐instructive 3D materials. Future work is expected to further deepen our understanding of molecular and cellular biological processes investigating cell‐type specific responses and the translational steps toward targeted in vivo applications.