tbuckley/cabot-search huggingface dataset:
Inducible nitric oxide synthase: Regulation, structure, and inhibition
Authors: Maris A. Cinelli, Ha T. Do, Galen P. Miley, Richard B. Silverman
Journal: Medicinal Research Reviews (2019)

A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) from l-arginine. Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been accumulated about the roles iNOS plays in different tissues and organs. Additionally, X-ray crystal and cryogenic electron microscopy structures have shed new insights on the structure and regulation of this enzyme. Many potent iNOS inhibitors with high selectivity over related NOS isoforms, neuronal NOS, and endothelial NOS, have been discovered, and these drugs have shown promise in animal models of endotoxemia, inflammatory and neuropathic pain, arthritis, and other disorders. A major issue in iNOS inhibitor development is that promising results in animal studies have not translated to humans; there are no iNOS inhibitors approved for human use. In addition to assay limitations, both the dual modalities of iNOS and NO in disease states (ie, protective vs harmful effects) and the different roles and localizations of NOS isoforms create challenges for therapeutic intervention. This review summarizes the structure, function, and regulation of iNOS, with focus on the development of iNOS inhibitors (historical and recent). A better understanding of iNOS' complex functions is necessary before specific drug candidates can be identified for classical indications such as sepsis, heart failure, and pain; however, newer promising indications for iNOS inhibition, such as depression, neurodegenerative disorders, and epilepsy, have been discovered.
Abstract 16414: Contrast-Enhanced Computed Tomography and the Assessment of Aortic Stenosis
Authors: Timothy R Cartlidge, Jacek Kwiecinski, Tania A Pawade, David E Newby, Marc R Dweck
Journal: Circulation (2017)

Introduction: Non-contrast computed tomography (CT) aortic valve calcium scoring (AVC) provides assessment of disease severity in aortic stenosis (AS). Contrast-enhanced CT has the potential to ass...
AB0780 PERSISTENCE OF MOLL AND WRIGHT CLASSIFICATION CRITERIA OVER TIME
Authors: John Roberts, Lisa a. Mandl, Sergio Schwartzman
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> In 1973 Moll and Wright published the first paper on the classification criteria for Psoriatic arthritis (PsA) which included several phenotypes of PsA: Oligoarticular, Polyarticular, axial, DIP, and Mutilans. Whether these subtypes change over time or are related to treatment response is not known. The hypothesis of this study is that with some exceptions, the Moll and Wright subtype classification criteria are stable over time and the pattern may have important therapeutic implications. <h3>Objectives:</h3> The objective of this study was to evaluate the persistence of the Moll and Wright classification criteria in PsA patients. <h3>Methods:</h3> This study is a retrospective chart review of PsA patients seen at a single center between January 1, 2013 and December 31, 2016. The patients in this study were identified using the ICD-9 or ICD-10 codes for PsA and were then classified using the CASPAR classification criteria for psoriatic arthritis. Patients who met CASPAR classification criteria were subsequently sub-classified using the Moll and Wright classification criteria based on the manifestations of PsA at their index outpatient visit. This subtype was then compared to their Moll and Wright subtype at the last outpatient visit prior to January 3, 2019. While it was possible for patients to display more than one subtype simultaneously, the classification made at baseline and at latest visit reflected the predominant Moll and Wright subtype of the patient, in the opinion of the expert treating rheumatologist. <h3>Results:</h3> 76 patients were identified as meeting entry criteria, with none being in remission at the index visit. Mean age of patients at the latest visit was 60.2 ± 12.6 years, and 47.4% were male. Median time between the index visit and latest visit was 7 years [IQR: 5 to 8 years]. 42.1% of patients had the same Moll and Wright subtype at both visits. Table 1 presents the distribution of Moll and Wright subtypes present at index visit and latest visit. Table 2 reports the changes, or lack thereof, in subtype between visits. 22/76 patients (28.9%) were in remission at the latest visit. Of the patients in remission, 12 (54.5%) were being treated with a biologic, DMARD, and/or steroid. <h3>Conclusion:</h3> In this retrospective analysis there was a persistence of Moll and Wright subtype in 42.1% of psoriatic arthritis patients over the median time of 7 years. Whether patients who maintain Moll and Wright subtypes respond differently to targeted therapy for PsA should be evaluated in prospective trials. <h3>References</h3> [1] Moll J. M. H., Wright V. Psoriatic arthritis. Semin arthritis Rheum. 1973; 3(1): 55-78. <h3>Disclosure of interests:</h3> None declared
PB1887 THE SIGNIFICANCE OF CD43, CD81, CD200, AND ROR1 FOR DIFFERENTIAL DIAGNOSIS OF CLL AS MULTICOLOR FLOW CYTOMETRY
Authors: M. Falay, M. Serdar, S. Dagdas, S. Pepeler, M.A. Ucar, G. Ozet
Journal: HemaSphere (2019)

Background: The scoring system used for CLL cannot make an accurate diagnosis in some cases. Novel markers are available for the differential diagnosis of CLL, especially from MCL. However, these markers are still not incorporated into diagnostic algorithms. Aims: We investigated the role of CD43, CD81, CD200, and ROR1 for the differential diagnosis of CLL and their expression in non-CLL cases. Methods: : We investigated the role of CD43, CD81, CD20, and ROR1 in the differential diagnosis of CLL by incorporating them into the diagnostic panel after studying peripheral blood or bone marrow samples of 165 patients with 8 color flow cytometry. Results: CD43 positivity was sensitive but had a lower specificity for CLL. It had a high diagnostic value for CLL (sensitivity 100%, specificity 88.5%, AUC 98.0%). CD200 was a specific marker for CLL (sensitivity 98%, specificity 90%, AUC: 96%). CD81 expression was highest in the MCL cases, with a median expression rate of 68.5% (range: 54-82.5%). It was negative in all CLL cases. For CLL, CD81 negativity had a sensitivitity of 95%, a specificity of 82%, and an AUC of 92%. ROR1 was positive in all CLL and MCL cases. CD79b, on the other hand, was a fairly sensitive and specific marker for MCL. Summary/Conclusion: CD43, CD81, CD200, and ROR1 should be incorporated into diagnostic algorithms for the differential diagnosis of CLL, especially from MCL.
Exome Sequencing in Clinical Hepatology
Authors: Sílvia Vilarinho, Pramod K. Mistry
Journal: Hepatology (2019)

The clinical relevance of the Human Genome Project and next-generation sequencing technology was demonstrated for the first time in 2009, when whole-exome sequencing (WES) provided the definitive diagnosis of congenital chloride diarrhea in an infant with presumed renal salt-wasting disease. Over the past decade, numerous studies have shown the utility of WES for clinical diagnosis as well as for discovery of novel genetic disorders through analysis of a single or a handful of informative pedigrees. Hence, advances in improving the speed, accuracy, and computational analysis combined with exponential decrease in the cost of sequencing the human genome is transforming the practice of medicine. The impact of WES has been most noticeable in pediatric disorders and oncology, but its utility in the liver clinic is recently emerging. Here, we assess the current status of WES for clinical diagnosis and acceleration of translation research to enhance care of patients with liver disease.
Final Result of a Pilot Study Using Eculizumab to Overcome Platelet Transfusion Refractoriness in Allo-Immunized Patients Receiving HLA Mismatched Platelets
Authors: Phuong Vo, Enkhtsetseg Purev, Kamille West, Emily McDuffee, Tatyana Worthy, Lisa Cook, Geri Hawks, Brian Wells, Reem Shalabi, Patricia Prince, Tom Hughes, Willy Fleigel, Sharon Adams, Robert Reger, Xin Tian, Georg Aue, Richard Childs
Journal: Blood (2017)
Chromatin accessibility plays a key role in selective targeting of Hox proteins
Authors: Damiano Porcelli, Bettina Fischer, Steven Russell, Robert White
Journal: Genome biology (2019)

Hox transcription factors specify segmental diversity along the anterior-posterior body axis in metazoans. While the different Hox family members show clear functional specificity in vivo, they all show similar binding specificity in vitro and a satisfactory understanding of in vivo Hox target selectivity is still lacking.Using transient transfection in Kc167 cells, we systematically analyze the binding of all eight Drosophila Hox proteins. We find that Hox proteins show considerable binding selectivity in vivo even in the absence of canonical Hox cofactors Extradenticle and Homothorax. Hox binding selectivity is strongly associated with chromatin accessibility, being highest in less accessible chromatin. Individual Hox proteins exhibit different propensities to bind less accessible chromatin, and high binding selectivity is associated with high-affinity binding regions, leading to a model where Hox proteins derive binding selectivity through affinity-based competition with nucleosomes. Extradenticle/Homothorax cofactors generally facilitate Hox binding, promoting binding to regions in less accessible chromatin but with little effect on the overall selectivity of Hox targeting. These cofactors collaborate with Hox proteins in opening chromatin, in contrast to the pioneer factor, Glial cells missing, which facilitates Hox binding by independently generating accessible chromatin regions.These studies indicate that chromatin accessibility plays a key role in Hox selectivity. We propose that relative chromatin accessibility provides a basis for subtle differences in binding specificity and affinity to generate significantly different sets of in vivo genomic targets for different Hox proteins.
Abstract 246: Rescuing an Acquired Cardiac Retinoic Acid Deficiency Prevents Hypertrophy and Sudden Cardiac Death in a Pressure Overload/Chronic Catecholamine Model of Hypertrophy and Heart Failure
Authors: Ni Yang, Ting Liu, Robert O’Meally, Kai Kammers, Djahida Bedja, C. Conover Talbot, Robert N Cole, David A Kass, Maureen Kane, Brian O’Rourke, D Brian Foster
Journal: Circulation Research (2017)

Introduction: Recently, we have investigated a pressure-overload/chronic catecholamine guinea pig model (ACi) of cardiac hypertrophy (HYP) and HF with the unique features of acquired long QT syndrome and sudden cardiac death (SCD) by quantitative global-scale proteomics using isobaric tags for relative and absolute quantitation. Hypothesis: By compiling proteins altered significantly both compensated HYP and HF, it may be possible to identify novel early contributors to pressure overload- induced HF pathogenesis. Results: Pathway mapping of proteins differentially regulated in HYP that were also changed in HF (p&lt;0.05 in both HYP and HF) revealed altered “retinoate biosynthesis” (p&lt;0.01) and “RAR Activation” (p&lt;0.05), suggesting that guinea pig HYP &amp;HF might be related to impaired Vitamin A metabolism, specifically, to a deficit in the bioactive metabolite, all-trans retinoic acid. Causal Regulator Analysis indicated that coordinate regulation of ATRA-responsive proteins was unlikely to have occurred by chance (p=1.88x10 -11 ) and that the ATRA program was downregulated (z-score&lt;-1.2). ATRA deficit would attenuate transcriptional programs that control fatty acid oxidation, excitation/contraction-coupling, contraction, and antioxidant defense - all of which were decreased in heart failure. Metabolomic profiling by mass spectrometry showed that ATRA, alone among the resident cardiac retinoids, was downregulated in HYP and HF (Down 32% &amp; 33% respectively p&lt;0.05). Secondly, the specific agonist of RXR signaling, 9-cis RA, is not present in adult guinea pig hearts. Proteome and transcriptome data indicate that the ATRA deficit stems from downregulation of retinaldehyde dehydrogenase 1 (RALDH1) by 23% in HYP and 39% in HF (p&lt;0.01 each). Treatment with ATRA (2mg/kg/day) mitigated heart weight/tibia length (ACi: 0.71 , ACi + ATRA: 0.57; p&lt;0.01), improved fractional shortening (27.4% vs 37.5%, p&lt;0.01) and ejection fraction (50.4% vs. 64.8%, p&lt;0.01). Preliminary studies indicate that ATRA treatment also reduces the incidence of sudden cardiac death (55% vs 15% (p&lt;0.01)) in the guinea pig ACi model. Conclusion: The data support a causal role for ATRA deficiency in the pathogenesis of pressure overload-induced HF and susceptibility to SCD.
Clonal and Non-Clonal Chromosomal Aberrations in Cytopenic Patients without Hematological Malignancies
Authors: Shumpei Uchida, Osamu Imataki, Hiroyuki Kubo, Shigeyuki Yokokura, Makiko Uemura, Naoshi Sugimoto, Norimitsu Kadowaki
Journal: Blood (2017)
Sport and exercise medicine: bringing you up to date
Authors: Polly Baker, Eleanor Tillett
Journal: British Journal of Sports Medicine (2019)

Welcome to the 2019 British Association of Sport & Exercise Medicine (BASEM) issue of the British Journal of Sports Medicine . Bringing this issue together has been an enjoyable experience allowing us as editors to peruse topics in the spotlight for those working within sport and exercise medicine. As a specialty, we have always encompassed a broad subject area from exercise prescription to musculoskeletal medicine and beyond. The governance of our specialty is also gaining increasing prominence both in terms of setting standards for those employed within the specialty and also in the development of position statements for a variety of conditions related to sports medicine. Our role in health protection is highlighted by several articles including Sean Carmody’s editorial on our duty of care to retiring footballers ( see page 788 ) and Aneil Malhotra’s research into emergency response facilities in professional football clubs ( see …
Abstract 15570: DHA and EPA Differentially Modulate the Inflammatory Response Following Myocardial Infarction in Obese and Aging Mice
Authors: Merry L Lindsey, Ganesh V Halade
Journal: Circulation (2013)

Increased linoleic acid intake from a safflower oil (SO) high diet increases coronary heart disease risk, and this effect is blunted by a diet rich in fish oil (FO). Docosahexaenoic acid (DHA) and ...
Assessing the impact of CMF/FEC/FEC-DOC/ETC (dose-dense) adjuvant chemotherapy in dependency of positive axillary lymph nodes on survival: A retrospective multicenter cohort study of 4,526 breast cancer patients receiving adjuvant chemotherapy.
Authors: Lukas Schwentner, Reyn Van Ewijk, Isabell Hoffmann, Rolf Kreienberg, Maria Blettner, Achim Wöckel
Journal: Journal of Clinical Oncology (2013)

1074 Background: Adjuvant chemotherapy has changed dramatically in the last decades. Anthracycline-/taxane-based and dose-dense chemotherapy regimens improved survival in node positive breast cancer. This study tries to answer the following questions: (1) Are there differences in survival dependent on chemotherapy regimens in 0/0-3/4-10/&lt;10 positive lymph nodes? (2) Is it possible to define a cut-off of positive lymph nodes for the use of Taxane-based and dose dense chemotherapy? Methods: This German is a multi-center [17 participating hospitals all are certified as breast cancer centers] retrospective cohort study. We included CMF (1.385), FEC (1.170), FEC-DOC (1.723), and dose-dense ETC (248) into the analysis. Results: In case of 0 LN CMF/FEC/FEC-DOC did not show significant differences in DFS, but OAS was significantly impaired by the use of FEC-DOC in 0 LN [p=0.024; HR=2.02 (95% CI: 1.10-3.73)] (no ETC use in 0 LN). In case of 1-3 positive LN CMF/FEC/FEC-DOC/ETC did not differ significantly in survival parameters. But in 4-10 LN FEC-DOC [p=0.049; HR=0.67 (95% CI: 0.44-0.99)] and ETC [p=0.024; HR=0.56 (95% CI: 0.34-0.93)] demonstrated a significant benefit in DFS and a strong trend in OAS. Dose-dense ETC showed a significant improvement in DFS [p=0.003; HR=0.35 (95% CI: 0.17-0.69)] and OAS [p=0.009; HR=0.35 (95% CI: 0.16-0.77)] in patients with &gt;10 positive LN. Conclusions: Our data confirms that Taxane-based chemotherapy does not improve DFS in LN negative breast cancer, but rather demonstrated an inferior OAS. But in LN positive breast cancer we can demonstrate a benefit by the use of Taxane-based chemotherapy regimens. Furthermore, dose-dense ETC demonstrated a significant benefit in survival in &gt;10 positive LN.
AB0273 THE ANALYSIS OF THE CLINICAL COURSES OF THE ACPA POSITIVE PATIENTS WITHOUT SYNOVITIS: WHETHER TO FOLLOW UP THEM
Authors: Tomoya Nakajima, Yumiko Nobuhara, Takashi Nakazawa
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> ACPA (anti-citrullinated peptide antibody) is a major risk factor for the onset of RA (rheumatoid arthritis)<sup>[1]</sup>. As ACPA becomes a common test in non-rheumatologists, ACPA positive patients not diagnosed with RA are increasing. However, it is unclear whether follow-up of ACPA-positive patients without synovitis leads to early treatment and consequently to the improvement of prognosis. <h3>Objectives</h3> To reveal whether to follow up the ACPA positive patients without synovitis. <h3>Methods</h3> In the four years from January 2015 to December 2018, we extracted the ACPA positive patients introduced from other hospitals, among which patients not diagnosed as RA at the first visit were selected. Then, their clinical courses and ACPA titers were retrospectively analyzed. The 2010 ACR-EULAR classification criteria was used for the diagnosis of RA<sup>[2]</sup>. For the significance test, a χ 2 test and a t test with α = 0.05 were used. <h3>Results</h3> Thirty six patients met the conditions, and then 10 patients, previously treated as RA, and 8 drop-out patients were excluded. In 18 patients remaining, 10 patients developed RA (follow-up days: avg. 404, max. 983) and the other 8 were non-RA, predisease patients (follow-up days: avg. 424, max. 926). All 10 RA patients initially started the treatment with MTX (methotrexate). Five of them reached remission with only MTX. Of the other five, three needed other csDMARDs because of an inadequate amount of MTX due to adverse events, and two had insufficient observation period. The ACPA titer was significantly higher in the RA patients than the predisease patients (468 versus 26.3 U/ml (P=0.0075)). Tenderness of DAS 28 subject joints at the first visit was a significant predictor of RA onset when trying to extract from clinical findings. (10 of 10 in RA patients vs. 2 of 8 in predisease patients (P=0.0044)). <h3>Conclusion</h3> In our research, the predictors of RA onset are not only high ACPA titer but also tenderness of DAS28 subject joints at the first visit. The early treatment with MTX could contribute to improved prognosis, so it would be useful to follow up the ACPA positive patients without synovitis. The frequency of hospital visits and the modality to detect synovitis are the subject of our analysis from now on. <h3>References</h3> [1] Solbritt Rantapaa-Dahlqvist, et al.: Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum., 48 (10),2741-2749,2003. [2] Aletaha,D.,Neogi,T.,Silman,A.,et al.: 2010 Rheumatoid arthritis classification criteria. Arthritis Rheum., 62,2569-2581,2010. <h3>Disclosure of Interests</h3> None declared
Role of Hepatic Artery Infusion Chemotherapy in Treatment of Initially Unresectable Colorectal Liver Metastases
Authors: Jashodeep Datta, Raja R. Narayan, Nancy E. Kemeny, Michael I. D’Angelica
Journal: JAMA Surgery (2019)

<h3>Importance</h3> Although liver metastasis develops in more than half of patients with colorectal cancer, only 15% to 20% of these patients have resectable liver metastasis at presentation. Moreover, patients with initially unresectable colorectal liver metastasis (IU-CRLM) who progress on first-line systemic chemotherapy have limited treatment options. Hepatic arterial infusion chemotherapy (HAIC), in combination with systemic chemotherapy, leverages a multimodality approach to achieving control of hepatic disease and/or expanding resectability in patients with liver-only disease or liver-dominant disease. <h3>Observations</h3> Intra-arterial delivery of agents with high first-pass hepatic extraction (eg, floxuridine) limits systemic toxic effects and allows for administration of systemic chemotherapy at near-full doses. Hepatic arterial infusion chemotherapy in conjunction with systemic chemotherapy augments response rates up to 92% in patients who are chemotherapy naive, and up to 85% in pretreated patients with IU-CRLM. In turn, these responses translate into encouraging rates of conversion to resectability (CTR). Prospective trials have reported CTR rates as high as 52% in heavily pretreated patients with IU-CRLM who have an extensive hepatic disease burden. As such, CTR remains a compelling indication for liver-directed chemotherapy in this subset of patients. This review discusses the biological rationale for HAIC, evolution of rational combinations with systemic chemotherapy, contemporary evidence for CTR using HAIC and systemic chemotherapy, juxtaposition with rates of CTR using systemic chemotherapy alone, and morbidity and toxic effect profiles of HAIC. <h3>Conclusions and Relevance</h3> The argument is made for consideration of earlier initiation of HAIC in patients with IU-CRLM who are chemotherapy naive and for adoption of HAIC strategies to augment rates of resectability in patients who have failed first-line systemic chemotherapy before proceeding to second-line or third-line regimens.