tbuckley/cabot-search huggingface dataset:
Target identification by phosphoproteomics: RIN1 modulation of sorafenib-induced cytotoxicity in renal cell carcinoma
Authors: A. G. Grozav, B. Willard, M. Kinter, S. A. Vaziri, R. M. Bukowski, B. I. Rini, M. K. Ganapathi, R. Ganapathi
Journal: Journal of Clinical Oncology (2009)

e14543 Background: Sorafenib (SFB) is a multi-tyrosine kinase inhibitor clinically useful in treatment of metastatic renal cancer. While the inhibition of angiogenesis is considered a major mechanism of action, identification of targets regulating growth inhibitory effects of SFB is necessary to further improve its efficacy and reduce toxicity. Methods: In this study we used targeted phosphoproteomics to identify tyrosine phosphorylated proteins that are differentially affected in control and SFB-treated human CAKI-1 renal cell carcinoma cells. The strategy involved immunoaffinity isolation of phosphotyrosine containing proteins and liquid chromatography - tandem mass spectrometry (MS) for identification of candidate proteins. Results: Among identified proteins, signal transducer and activator of transcription 1 (STAT1) and Ras and Rab interactor 1 (RIN1) were found to be hypophosphorylated in SFB-treated compared to untreated CAKI-1 cells based on quantitative MS analysis, by peptide counts and native peptide reference method. A ∼4-fold decrease in expression and phosphorylation of STAT1 was observed in cells treated with 10 μM SFB for 48h. Up to 8-fold SFB dose-dependent (5–15 μM) decrease in phosphorylation of RIN1 at tyrosine 36, but not in total RIN1 expression, was observed. Similar effects on decreased phosphorylation of STAT1 and RIN1 were also observed in 786-O renal cell carcinoma treated with SFB. Hypophosphorylation of RIN1 at tyrosine 36 was observed in CAKI-1 cells treated with 5 μM sunitinib but not with imatinib (≤ 10 μM). Treatment of CAKI-1 cells with RIN1 targeted, but not control si-RNA led to down-regulation of RIN1 expression and attenuation of antiproliferative effects of SFB. Notably, ∼2-fold higher expression of RIN1 protein (total and phosphorylated) was observed in CAKI-1 cells selected for resistance following continuous exposure to 7.5 μM SFB. However, unlike parent CAKI-1 cells, prolonged exposure of these SFB-resistant CAKI-1 cells to 7.5 μM SFB did not completely abrogate phosphorylation of RIN1 at tyrosine 36. Conclusions: These results demonstrate that RIN1, a Ras effector protein with multiple biochemical functions, is a target for the anti-tumor effects of SFB in kidney cancer cells. [Table: see text]
Epigenetics at the base of alternative splicing changes that promote colorectal cancer
Authors: Alberto R. Kornblihtt
Journal: Journal of Clinical Investigation (2017)

Chromatin modification influences gene expression by either repressing or activating genes, depending on the specific histone mark. Chromatin structure can also influence alternative splicing of transcripts; however, the mechanisms by which epigenetic marks influence splicing are poorly understood. A report in the current issue of the JCI highlights the biological importance of the coordinated control of alternative pre-mRNA splicing by chromatin structure and transcriptional elongation. Yuan et al. found that mutation of the histone methyl transferase SEDT2 affects alternative splicing fates of several key regulatory genes, including those involved in Wnt signaling. As a consequence, loss of SEDT2 in the intestine aggravated Wnt/β-catenin signaling effects, thereby leading to colorectal cancer.
Artificial Hearts — Permanent and Temporary
Authors: Arnold S. Relman
Journal: New England Journal of Medicine (1986)

A little more than three years ago, at the University of Utah in Salt Lake City, Dr. William DeVries implanted a Jarvik-7 artificial heart in a 61-year-old patient named Barney Clark. The patient lived 112 days with the device before succumbing to renal failure, infection, and pseudomembranous colitis.1 His stormy clinical course had been marked by seizures and episodes of mental confusion, recurrent acute tubular necrosis, postoperative subcutaneous emphysema due to ruptured pulmonary blebs, and sudden congestive heart failure due to a fractured mitral-valve prosthesis (which necessitated emergency replacement of the prosthetic left ventricle on the 13th postoperative day).Since . . .
SAT0572 Levels of serum procalcitonine as diagnosis discerning tool between gout and septic arthritis
Authors: CA Guillen-Astete, M Terán-Tinedo
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> In a previous study we demonstrated the potential usefulness of the procalcitonine serum measure in order to diagnose septic arthritis. This utility is quite important on the differential diagnosis of knee arthritis in patients with known gout or other inflammatory joint disease which can express as a monoarthritis. <h3>Objectives</h3> Due to that, this study aims to determine sensibility, specificity, positive predictor value and negative predictor value of procalcinonine sereum measure (PCT) in patients with knee arthritis for the diagnosis of septic arthritis. <h3>Methods</h3> We reviewed the registries of patients who consulted due to knee acute monoarthritis between 2013 and 2015 in which a PCT was obtained. Registries were grouped according to the final diagnosis (gouty arthritis only (group I) and septic arthritis with or without gout (group II). Based on a previous study, PCT value of 1.47ng/mL was considered the cut point. Validation tests were applied fixed to demographic and clinical specific scenarios. <h3>Results</h3> Registries of 121 patients with gout and 47 patients with septic arthritis (SA) were included. From the 47 patients with SA, 9 were previously diagnosed by gout. All diagnosed were based on guidelines and clinical recomendations for SA and gout (Coakley et al. Rheumatology, 2006 and Zhang et al. Ann Rheum Dis, 2006). Using the cut point of 1.47 ng/mL, test validation results were as follows: sensibility of 87.2%, specificity of 92.5%, PPV of 82.0% and NPV of 94.9%. Excluding patients with less than 48 hours of onset, there were 44 registries of patients with SA and 83 with gout. In this scenario the results of the validation tests were as follows: Sensibility of 93.1%, specificity of 96.3%, PPV of 93.1% and NPV of 96.38%. Excluding all patients with body temperature above 37.5°C there remained 11 with SA and 81 with gout. In this scenario the results of the validation tests were as follows: Sensibility of 72.7%, specificity of 95.1%, PPV of 66.6% and NPV of 96.2%. <h3>Conclusions</h3> This is the first study aimed to validate previous observations about the usefulness of PCT determination in patients with acute knee monoarthritis. Altough the global results in the validation test are a bit inferior that our original observations in a shorter pilot study in terms of sensibility, the NPV remains over 95% in scenarios where the differential diagnosis could be harder to establish such as recent onset flares or cases without an associated febrile syndrome. <h3>Disclosure of Interest</h3> None declared
Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial.
Authors: Sebastian Stintzing, Pratyaksha Wirapati, Heinz-Josef Lenz, Daniel Neureiter, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christoph Kahl, Frank Kullmann, Markus H. Moehler, Werner Scheithauer, Swantje Held, Dominik Paul Modest, Andreas Jung, Thomas Kirchner, Sabine Tejpar, Volker Heinemann
Journal: Journal of Clinical Oncology (2017)

3510 Background: FIRE-3 compared 1 st -line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients. CMS is grouping CRCs according to their gene-signature in 4 different types. Relevance of CMS for the treatment of mCRC remains unclear. Methods: Patients were grouped according to tumor CRC-CMSs. Using ALMAC’s Xcel tissue array, gene signatures of FIRE-3 tumor samples were analyzed. Survival was compared using Kaplan-Meier estimation and log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. Results: CMS classification could be determined in 385 specimens available from the ITT population (n = 592). In this KRAS exon 2 wt population (n = 385), frequencies were: CMS1 (10.4%), CMS2 (36.6%), CMS3 (11.7%), CMS4 (29.1%), non-consensus (12.2%). In RAS wt (n = 315), frequencies were: CMS1 (11.1%), CMS2 (38.1%), CMS3 (9.5%), CMS4 (29.5%), non-consensus (11.7%). Independent of the treatment, CMS was a strong prognosticator for ORR (p = 0.023), PFS (p &lt; 0.001) and OS (p &lt; 0.001). For data on CMS and treatment efficacy in the RAS wt population see the following table. Conclusions: CMS classification is prognostic for mCRC. The survival benefit in RAS wt previously observed for FOLFIRI cetuximab vs. FOLFIRI bevacizumab is not significantly different across CMS groups, although there are trends when comparing OS HR between categories with CMS4 showing the best HR. [Table: see text]
Review: CPAP improves QoL in obstructive sleep apnea; effects not as clear for mandibular advancement devices
Authors: Fergal O’Donoghue, Christine McDonald
Journal: Annals of Internal Medicine (2017)

Source Citation Kuhn E, Schwarz EI, Bratton DJ, Rossi VA, Kohler M. Effects of CPAP and mandibular advancement devices on health-related quality of life in OSA: a systematic review and meta-analysis. Chest. 2017;151:786-94. 28130044
Abstracts From the World Congress of Cardiology Scientific Sessions
Authors: Bai Ming, Qiang Li, Zheng Zhang, Aiyun Deng, Tao Wang, Shijie Wang, Suyu Yao, Haibo Yu, Dongmei Wang, Hongyun Zang, Donghong Zhang, Yun Tian, Yaling Han, Zhang Lili, Bo Yu, Shufeng Li, Shuo Zhang, Leonardo Ribeiro, Jose Pachon, Clizenaldo Timothe, Allan Leonel, Mohamed Hussain, Juan Pachon, Remy Vargas, Amanda Sousa, Carlos Morillo, Zhao Qingyan, Huang He, Tang Yanhong, Wang Xi, Huang Congxin, Xiaorong Hu, Hong Jiang, Xiaoya Zhou, Bo Cui, Changwu Xu, Zhibing Lu
Journal: Circulation (2010)

Introduction:The detrimental effects of right ventricular apical pacing on left ventricular function has driven interest in selective site pacing, predominantly on the right ventricular mid-sepal pacing.There is currently no information on long-term ventricular lead electrical performance from this site.To investigate the feasibility and safety in patients with right ventricular mid-sepal pacing with active fixation lead compared to passive fixation in right ventricular apex.Methods: All patients who underwent successful implantation of permanent pacemakers between January 2005 and April 2008 were retrospectively analyzed, included 101 cases with right ventricular mid-septal pacing (RVSP) and 126 cases selected in at the same time with standard right ventricular apical pacing (RVAP).Guided by X ray, The right ventricular septum was divided into six segments, and active leads were fixed in mid-septum accurately.X-ray exposure time, parameters of leads implantation, ECG were recorded during operation.The follow-up data of 3 months, 6 months and 12 months post implantation were recorded too.Results: X-ray exposure time (6.98Ϯ4.12min vs. 6.79Ϯ3.69,PϾ0.05)was similar between two groups.Pacing QRS duration in RVSP group was shorter than that in RVAP group significantly (98.19Ϯ22.30vs. 120.80Ϯ24.14,PϽ0.01).There was no difference in R wave height during leads implantation (10.11Ϯ4.73 vs. 11.61Ϯ6.62,PϾ0.05).Stimulation threshold, electric current and impedance had significant difference (RVSP vs. RVAP is 0.76Ϯ0.30Vvs 0.39Ϯ0.10V, 0.98Ϯ0.52mAvs. 0.36Ϯ0.19mA, respectively, PϽ0.01), the difference showed the trend of decrease in period of follow-up, but was statistically different (stimulation threshold comparison of 6 months, PϽ0.05, and the other parameters of follow-up, PϽ0.01).However, ventricular lead parameters were acceptable with stable long-term stimulation thresholds and impedance.All the patients came through the operation without complications.There was no case of lead dislocation, high pacing thresholds or inadequate sensing.Conclusion: By the guidance of ventricular septum subarea under X ray, active leads were fixed in mid-septum accurately and rapidly.X-ray exposure time was short, and pacing QRS duration was shorter.In long term follow-up, the parameters were stable and acceptable.There was no case of lead dislocation, high pacing thresholds or inadequate sensing.The site of Right ventricular mid-septal pacing is feasible and safe, should be used widely in clinical practice.
A prospective multicentre study of the epidemiology and outcomes of bloodstream infection in cirrhotic patients
Authors: M. Bartoletti, M. Giannella, R. Lewis, P. Caraceni, S. Tedeschi, M. Paul, C. Schramm, T. Bruns, M. Merli, N. Cobos-Trigueros, E. Seminari, P. Retamar, P. Muñoz, M. Tumbarello, P. Burra, M. Torrani Cerenzia, B. Barsic, E. Calbo, A.E. Maraolo, N. Petrosillo, M.A. Galan-Ladero, G. D'Offizi, N. Bar Sinai, J. Rodríguez-Baño, G. Verucchi, M. Bernardi, P. Viale, C. Campoli, G. Siccardi, S. Ambretti, A. Stallmach, M. Venditti, C. Lucidi, S. Ludovisi, M. De Cueto, M.D. Navarro, E. Lopez Cortes, E. Bouza, M. Valerio, A. Eworo, R. Losito, M. Senzolo, E. Nadal, A. Ottobrelli, M. Varguvic, C. Badia, G. Borgia, I. Gentile, A.R. Buonomo, E. Boumis, A. Beteta-Lopez, A. Rianda, G. Taliani, S. Grieco
Journal: Clinical Microbiology and Infection (2017)
B-cell receptor sequencing of anti-citrullinated protein antibody (ACPA) IgG-expressing B cells indicates a selective advantage for the introduction of <i>N</i> -glycosylation sites during somatic hypermutation
Authors: Rochelle D Vergroesen, Linda M Slot, Lise Hafkenscheid, Marvyn T Koning, Ellen I H van der Voort, Christine A Grooff, George Zervakis, Hendrik Veelken, Tom W J Huizinga, Theo Rispens, Hans U Scherer, René E M Toes
Journal: Annals of the Rheumatic Diseases (2017)

The majority of patients with rheumatoid arthritis (RA) harbours IgG antibodies targeting citrullinated protein antigens (ACPA). Recently, we showed that >90% of ACPA-IgG in serum are glycosylated in the variable domain.1  N -linked glycosylation requires a consensus sequence in the protein backbone (N-X-S/T (asparagine-X-serine/threonine), where X is any amino acid except proline), which is scarce in germline-encoded Ig variable region genes.2 3 Accordingly, hyperglycosylation of ACPA-IgG requires either clonal expansion of B cells expressing B-cell receptors (BCR) containing germline-encoded N -glycosylation sites or generation of de novo sites through somatic hypermutation (SHM).4

Here, we analysed the BCR repertoire of ACPA-expressing B cells to understand the molecular basis of this remarkable glycosylation. ACPA-expressing B cells were sorted as pools (10 cells per pool) from peripheral blood mononuclear cells of eight patients with ACPA-positive RA.5 Anchoring reverse transcription of immunoglobulin sequences and amplification by nested (ARTISAN) PCR-based BCR sequencing6 followed by full-length variable region IgG transcript analysis revealed high nucleotide mutation rates in 97 unique ACPA-IgG heavy chains (HC; mean ±SD: 52.86±16.73; figure 1A). 81% of these contained one or more N -glycosylation sites.



Figure 1 
A high degree of somatic hypermutation in antibodies targeting citrullinated protein antigens (ACPA)-IgG clones which does not correlate with the frequency of N -glycosylation sites. Pool and single cells were sorted as described.5 All independent clones are defined as identical V, D, J genes and …
Application of 1 H NMR-based metabolomics for discrimination of different parts and development of a new processing workflow for Cistanche deserticola
Authors: Pingping Zou, Yuelin Song, Wei Lei, Jun Li, Pengfei Tu, Yong Jiang
Journal: Acta Pharmaceutica Sinica B (2017)

Cistanche deserticola (CD) is one of the two authoritative source plants of Cistanches Herba, a well-known medicinal plant. Herein, 1H NMR spectroscopy was employed to characterize the chemical profile and to distinguish the different parts, as well as to propose a new processing workflow for CD. Signal assignment was achieved by multiple one and two dimensional NMR spectroscopic techniques in combination with available databases and authentic compounds. The upper parts of the plant were distinguished from the lower parts by combining 1H NMR spectroscopic dataset with multivariate statistical analysis. A new processing method that hyphenated steaming with freeze-drying, was demonstrated to be superior to either steaming coupled with oven-drying or direct freeze-drying via holistic 1H NMR-based metabolomic characterization. Phenylethanoid glycosides, mainly echinacoside and acteoside, were screened out and confirmed as the chemical markers responsible for exhibiting the superiority of the new processing workflow, whereas serial primary metabolites, especially carbohydrates and tricarboxylic acid cycle metabolites, were found as the primary molecules governing the discrimination between the upper and lower parts of the plant. Collectively, 1H NMR spectroscopy was demonstrated as a versatile analytical tool to characterize the chemical profile and to guide the in-depth exploitation of CD by providing comprehensive qualitative and quantitative information.
A hyaluronic acid conjugate engineered to synergistically and sequentially deliver gemcitabine and doxorubicin to treat triple negative breast cancer
Authors: Douglas R. Vogus, Michael A. Evans, Anusha Pusuluri, Alexandra Barajas, Mengwen Zhang, Vinu Krishnan, Maksymilian Nowak, Stefano Menegatti, Matthew E. Helgeson, Todd M. Squires, Samir Mitragotri
Journal: Journal of Controlled Release (2017)
The evolution of analytic thought?
Authors: Gordon Pennycook, David G. Rand
Journal: Behavioral and Brain Sciences (2017)

Abstract We argue that the truly unique aspect of human intelligence is not the variety of cognitive skills that are ontogenetically constructed, but rather the capacity to decide when to develop and apply said skills. Even if there is good evidence for g in nonhuman animals, we are left with major questions about how the disposition to think analytically can evolve.
The Effect of Variation in Oxygen Tension and Sulfhydryl Concentration on Nuclear Growth and Fission in Amoeba Proteus
Authors: Chalkley, H. W., Voegtlin, Carl
Journal: JNCI Journal of the National Cancer Institute (1940)

Journal Article The Effect of Variation in Oxygen Tension and Sulfhydryl Concentration on Nuclear Growth and Fission in Amoeba Proteus Get access H. W. Chalkley, H. W. Chalkley physiologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Carl Voegtlin Carl Voegtlin Chief National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 1, Issue 1, 1940-1941, Pages 63–75, https://doi.org/10.1093/jnci/1.1.63 Published: 01 August 1940
Interferon-γ-Driven iNOS: A Molecular Pathway to Terminal Shock in Arenavirus Hemorrhagic Fever
Authors: Melissa M. Remy, Mehmet Sahin, Lukas Flatz, Tommy Regen, Lifen Xu, Mario Kreutzfeldt, Benedict Fallet, Camille Doras, Toni Rieger, Lukas Bestmann, Uwe-Karsten Hanisch, Beat A. Kaufmann, Doron Merkler, Daniel D. Pinschewer
Journal: Cell Host & Microbe (2017)
Phosphatidylserine Exposing-Blood Cells and Microparticles Induce Procoagulant Activity in Non-Valvular Atrial Fibrillation
Authors: Lixiu Wang, Lu Zhao, Yan Zhang, Zhipeng Yao, Tao Li, Muhua Cao, Ruishuang Ma, Xiaoming Wu, Junjie Kou, Jialan Shi, Yayan Bi
Journal: Blood (2016)
Abstract 20: Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality: the Cardiovascular Health Study
Authors: Jason H Wu, Rozenn Lemaitre, Irena King, Xiaoling Song, David Siscovick, Dariush Mozaffarian
Journal: Circulation (2014)

Background: While omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce CHD, controversy remains about benefits vs. harms, including depending on types of n-6 PUFA and diseases examined. Aims: To assess associations of circulating n-6 PUFA including linoleic acid (LA, the major dietary PUFA), Γ-linoleic acid (GLA), dihomo-Γ-linoleic acid (DGLA), and arachidonic acid (AA),with incident total and cause-specific mortality in the Cardiovascular Health Study (CHS), a community-based US cohort. Methods: Among 2,692 participants age≥65y and free of CVD at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total (fatal or nonfatal) incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA biomarkers with risk were assessed by multivariable Cox regression. Results: During 33,091 person-years of follow-up (1992-2010), 1920 deaths occurred (including 660 cardiovascular deaths), as well as 414 fatal and 410 nonfatal CHD events, and 150 fatal and 384 nonfatal strokes. In multivariable models, higher LA was associated with lower risk of total mortality, with extreme quintile HR 0.84 (95% CI 0.71-0.98, P- trend 0.002). Lower death was largely attributable to CVD rather than non-CVD causes, especially nonarhythmic CHD mortality (HR 0.50, 95% CI 0.31-0.80, P- trend 0.001). Phospholipid GLA, DGLA, and AA levels were not associated with total or cause-specific mortality; e.g., for AA and CHD death, the extreme quintile HR was 0.98 (95% CI 0.71-1.37, P- trend 0.72). Evaluated semi-parametrically, LA showed graded (monotonic) inverse associations with total mortality ( Figure 1A ). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA (Bonferroni corrected P =NS, Figure 1B ). Conclusion: Higher circulating LA, but not other n-6 PUFA, is inversely associated with total and CHD mortality in older adults.
(&lt;italic&gt;Note&lt;/italic&gt;) An Improved Method of Producing Hormone-Cholesterol Pellets&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Ronald Wieder, Michael B. Shimkin
Journal: JNCI Journal of the National Cancer Institute (1964)

Journal Article (Note) An Improved Method of Producing Hormone-Cholesterol Pellets Get access Ronald Wieder, Ronald Wieder Fels Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael B. Shimkin Michael B. Shimkin Fels Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 32, Issue 4, April 1964, Pages 957–958, https://doi.org/10.1093/jnci/32.4.957 Published: 01 April 1964 Article history Received: 08 January 1964 Published: 01 April 1964