tbuckley/cabot-search huggingface dataset:
Diagnostic value of symptoms and signs for identifying urinary tract infection in older adult outpatients: Systematic review and meta-analysis
Authors: Oghenekome A. Gbinigie, José M. Ordóñez-Mena, Thomas R. Fanshawe, Annette Plüddemann, Carl Heneghan
Journal: Journal of Infection (2018)

To critically appraise and evaluate the diagnostic value of symptoms and signs in identifying UTI in older adult outpatients, using evidence from observational studies.We searched Medline and Medline in process, Embase and Web of Science, from inception up to September 2017. We included studies assessing the diagnostic accuracy of symptoms and/or signs in predicting UTI in outpatients aged 65 years and above. Study quality was assessed using the QUADAS-2 tool.We identified 15 eligible studies of variable quality, with a total of 12,039 participants (range 65-4259), and assessed the diagnostic accuracy of 66 different symptoms and signs in predicting UTI. A number of symptoms and signs typically associated with UTI, such as nocturia, urgency and abnormal vital signs, were of limited use in older adult outpatients. Inability to perform a number of acts of daily living were predictors of UTI: For example, disability in feeding oneself, + ve LR: 11.8 (95% CI 5.51-25.2) and disability in washing one's hands and face, + ve LR: 6.84 (95% CI 4.08-11.5).The limited evidence of varying quality shows that a number of symptoms and signs traditionally associated with UTI may have limited diagnostic value in older adult outpatients.
Age and Treatment of Nonmelanoma Skin Cancer
Authors: Dane Hill, Bobbak Mansouri, Chad Housewright
Journal: JAMA Surgery (2018)

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Familial aggregation and heritability of sarcoidosis: a Swedish nested case−control study
Authors: Marios Rossides, Johan Grunewald, Anders Eklund, Susanna Kullberg, Daniela Di Giuseppe, Johan Askling, Elizabeth V. Arkema
Journal: European Respiratory Journal (2018)

Sarcoidosis is believed to be caused by both genetic and environmental risk factors, but the proportion of the susceptibility to sarcoidosis that is mediated by genetics remains unknown. We aimed to estimate the familial aggregation and heritability of sarcoidosis using a case-control-family study design and population-based Swedish registers.We identified 23 880 individuals with visits for sarcoidosis in the Swedish National Patient Register using International Classification of Diseases codes (1964‒2013). Information on Löfgren's syndrome was available for a subset diagnosed at Karolinska University Hospital (Stockholm, Sweden). General population controls were matched to cases (10:1). Relatives of cases and controls were identified from the Swedish Multi-Generation Register and ascertained for sarcoidosis in the National Patient Register. We estimated familial relative risks for sarcoidosis using conditional logistic regression and heritability using biometric models.Having at least one first-degree relative with sarcoidosis was associated with a 3.7-fold increase in the risk of sarcoidosis (95% CI 3.4-4.1). The relative risk increased in those with two or more relatives (relative risk 4.7) and in Löfgren's syndrome (relative risk 4.1). The heritability was 39% (95% CI 12-65%).This large investigation showed that having a relative with sarcoidosis is a very strong risk factor for the disease. Genetic variation is an important, albeit partial, contributing factor to the risk for sarcoidosis.
Rapid Cue-Specific Remodeling of the Nascent Axonal Proteome
Authors: Roberta Cagnetta, Christian K. Frese, Toshiaki Shigeoka, Jeroen Krijgsveld, Christine E. Holt
Journal: Neuron (2018)

Axonal protein synthesis and degradation are rapidly regulated by extrinsic signals during neural wiring, but the full landscape of proteomic changes remains unknown due to limitations in axon sampling and sensitivity. By combining pulsed stable isotope labeling of amino acids in cell culture with single-pot solid-phase-enhanced sample preparation, we characterized the nascent proteome of isolated retinal axons on an unparalleled rapid timescale (5 min). Our analysis detects 350 basally translated axonal proteins on average, including several linked to neurological disease. Axons stimulated by different cues (Netrin-1, BDNF, Sema3A) show distinct signatures with more than 100 different nascent protein species up- or downregulated within the first 5 min followed by further dynamic remodeling. Switching repulsion to attraction triggers opposite regulation of a subset of common nascent proteins. Our findings thus reveal the rapid remodeling of the axonal proteomic landscape by extrinsic cues and uncover a logic underlying attraction versus repulsion.
Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer
Authors: Sana D. Karam, Krishna Reddy, Patrick J. Blatchford, Tim Waxweiler, Alicia M. DeLouize, Ayman Oweida, Hilary Somerset, Carrie Marshall, Christian Young, Kurtis D. Davies, Madeleine Kane, Aik Choo Tan, Xiao Jing Wang, Antonio Jimeno, Dara L. Aisner, Daniel W. Bowles, David Raben
Journal: Clinical Cancer Research (2018)

Purpose: Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib, with cetuximab and fractionated intensity-modulated radiotherapy for patients with locally advanced head and neck cancer and heavy smoking histories.Patients and Methods: Patients with ≥10 packs/year history of smoking were treated with olaparib at doses ranging from 25-200 mg orally twice daily beginning approximately 10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a time-to-event continual reassessment method model. Cetuximab was administered starting approximately 5 days prior to radiation per standard of care.Results: A total of 16 patients were entered onto the study, with 15 evaluable for acute toxicity. The most common treatment-related grade 3-4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The MTD was determined to be 50 mg orally twice daily, but the recommended phase II dose was deemed to be 25 mg orally twice daily. At a median follow-up of 26 months, the actuarial median overall survival was 37 months, but was not reached for other endpoints. Two-year overall survival, progression-free survival, local control, and distant control rates were 72%, 63%, 72%, and 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. MYC and KMT2A were identified as potential correlatives of response on gene amplification and mutational analysis.Conclusions: Olaparib at 25 mg orally twice daily with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Response rates were promising for this high-risk population. Clin Cancer Res; 24(20); 4949-59. ©2018 AACR.
Abstract 2998: Dynamic 3d chromosomal landscapes in acute leukemia
Authors: Palaniraja Thandapani, Andreas Kloetgen, Charalampos Lazaris, Xufeng Chen, Panagiotis Ntziachristos, Aristotelis Tsirigos, Iannis Aifantis
Journal: Cancer Research (2018)

Abstract T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 10-15% of pediatric and 25% of adult ALL cases. Despite improved prognosis driven by the significant advances in the molecular understanding of T-ALL, the outcome of T-ALL patients with primary resistant and relapsed leukemia remains poor. Recent evidences have highlighted a role for changes in 3D chromatin architecture in cancer progression. Herein, for the first time we explored genomewide changes in chromatin organization in primary T-ALL samples relative to T cells from healthy donors. We show how the organization of topologically associated domains (TADs) influences key oncogenic and tumor-suppressive loci by modifying the promoter-enhancer landscape, deregulating the transcriptional program and ultimately causing disease progression. To comprehensively characterize the chromatin landscape of clinically relevant loci in T-ALL, we sought to identify changes in intra-TAD activity and TAD disruptions on a genome-wide scale. We developed and implemented new computational approaches for Hi-C data analysis with a focus on Hi-C data integration with ChIP-Seq and RNA-Seq. We found significant correlations of TAD activity with CTCF occupancy, super-enhancer activity and gene expression of leukemia relevant loci. Furthermore, among the dozens of TAD disruptions we identified, we found a novel TAD “fusion” event around the MYC locus, which allows for chromatin interactions between a recently reported Notch-dependent MYC super-enhancer and promoter to drive overexpression of MYC. This particular TAD fusion is accompanied by a complete CTCF loss in the TAD boundary and increased MYC expression in T-ALL samples. Overall, this study sheds new light into how changes in chromatin architecture influence disease progression by restructuring oncogene and tumor suppressor landscapes. Citation Format: Palaniraja Thandapani, Andreas Kloetgen, Charalampos Lazaris, Xufeng Chen, Panagiotis Ntziachristos, Aristotelis Tsirigos, Iannis Aifantis. Dynamic 3d chromosomal landscapes in acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2998.
Antithrombotic therapy for venous thromboembolism in myeloproliferative neoplasms
Authors: Valerio De Stefano, Guido Finazzi, Tiziano Barbui
Journal: Blood Cancer Journal (2018)

Abstract In myeloproliferative neoplasms (MPNs) the incidence of venous thromboembolism (VTE) is 0.6–1.0 per 100 pt-years, and the rate of recurrence after VTE is 6.0–6.5 per 100 pt-yrs. Vitamin K-antagonists (VKA) reduces the risk of recurrence after VTE at usual sites (i.e., deep venous thrombosis (DVT) of the legs and pulmonary embolism (PE)) by 48–69%, with a rate of recurrent thrombosis per 100 pt-yrs of 3.4–4.7 on VKA and 8.9–9.6 off VKA; VKA discontinuation produces a 2.2-fold increased risk of novel thrombotic events with respect to continuation. However, the rate of both recurrent thrombosis and major bleeding on VKA is higher in MPN patients than in non-MPN patients, and the risk-benefit balance of long-term VKA treatment is challenging. In the absence of strong evidence, the tailored management of MPN-related VTE should operatively consider the risk categories for recurrence and bleed well established in the non-MPN setting. In summary, MPN patients with VTE are candidates for life-long VKA treatment, especially after unprovoked proximal DVT and PE. Aspirin can offer a moderate benefit in those patients who stop anticoagulation. The use of direct oral anticoagulants should be explored aiming to ameliorate the rate of bleeding.
Data Error and Incorrect Table Headings in: Patient-Reported Long-term Outcomes After Conventional and High-Dose Combined Proton and Photon Radiation for Early Prostate Cancer
Journal: JAMA (2010)

a number and corresponding percent were incorrectly stated in the text.On page 1051, center column, second paragraph, the second sentence should have read, "Of the original 393 participants in PROG 9509, 55 (14%) died and an additional 58 patients (14.8%) did not participate in the survey, reducing study power and raising the possibility of bias.
Epithelial cell adhesion efficacy of a novel peptide identified by panning on a smooth titanium surface
Authors: Hidemichi Kihara, David M. Kim, Masazumi Nagai, Toshiki Nojiri, Shigemi Nagai, Chia-Yu Chen, Cliff Lee, Wataru Hatakeyama, Hisatomo Kondo, John Da Silva
Journal: International Journal of Oral Science (2018)

Epithelial attachment via the basal lamina on the tooth surface provides an important structural defence mechanism against bacterial invasion in combating periodontal disease. However, when considering dental implants, strong epithelial attachment does not exist throughout the titanium-soft tissue interface, making soft tissues more susceptible to peri-implant disease. This study introduced a novel synthetic peptide (A10) to enhance epithelial attachment. A10 was identified from a bacterial peptide display library and synthesized. A10 and protease-activated receptor 4-activating peptide (PAR4-AP, positive control) were immobilized on commercially pure titanium. The peptide-treated titanium showed high epithelial cell migration ability during incubation in platelet-rich plasma. We confirmed the development of dense and expanded BL (stained by Ln5) with pericellular junctions (stained by ZO1) on the peptide-treated titanium surface. In an adhesion assay of epithelial cells on A10-treated titanium, PAR4-AP-treated titanium, bovine root and non-treated titanium, A10-treated titanium and PAR4-AP-treated titanium showed significantly stronger adhesion than non-treated titanium. PAR4-AP-treated titanium showed significantly higher inflammatory cytokine release than non-treated titanium. There was no significant difference in inflammatory cytokine release between A10-treated and non-treated titanium. These results indicated that A10 could induce the adhesion and migration of epithelial cells with low inflammatory cytokine release. This novel peptide has a potentially useful application that could improve clinical outcomes with titanium implants and abutments by reducing or preventing peri-implant disease.
Abstract 2409: The effect of heme on mitochondrial biogenesis and function of NSCLC cells
Authors: Sagar Shashikant Sohoni, Chantal Vidal, Li Zhang
Journal: Cancer Research (2018)

Abstract Heme is a central molecule for mitochondrial function and for many processes involved in oxygen utilization. Heme serves as a prosthetic group or a cofactor for a number of oxidative phosphorylation enzymes and other oxygen-utilizing hemoproteins. Heme also directly regulates the synthesis, translocation, and assembly of these enzyme complexes. Most, if not all, human cells can synthesize and uptake heme from the circulation. A number of epidemiologic studies have shown that high heme intake is associated with increased risk of cancer, including lung cancer. To assess the status of heme metabolism in lung cancer cells, we performed a series of experiments in non-small cell lung cancer (NSCLC) cell lines and compared the results with an immortalized normal lung cell line, HBEC30KT. We observed significant increase in rates of heme synthesis and heme uptake in NSCLC cells compared to HBEC30KT. Previous studies carried out in our lab showed intensified mitochondrial respiration and increased levels of heme as well as hemoproteins in NSCLCs. NSCLCs were also found to exhibit significantly high expressions of proteins involved in mitochondrial biogenesis such as SIRT-1, PGC1α, NRF-1, NRF-2, and TFAM. Expression levels of these proteins correlate with oxygen consumption and total heme content in NSCLCs, suggesting a possibility of role of heme in mitochondrial biogenesis. Immunofluoresence studies showed that heme depletion and add-back significantly affected localization and expression levels of these proteins. Studies are currently under way to determine how heme depletion affects the interactions of various transcription factors involved in mitochondrial biogenesis and function. Citation Format: Sagar Shashikant Sohoni, Chantal Vidal, Li Zhang. The effect of heme on mitochondrial biogenesis and function of NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2409.
Abstract 2618: The thymidine kinase 1 (TK1) protein concentration in sera from Hodgkin lymphoma patients: A marker for cell death and disruption of malignant cells
Authors: Jagarlamudi Kiran Kumar, Staffan Eriksson, Johan Mattsson Ulfstedt, Per Venge, Daniel Molin
Journal: Cancer Research (2018)

Abstract TK activity measurements have been used for many years to monitor cancer disease activity. However, what the blood concentrations of TK1 protein reflect is still uncertain. A TK1 immunoassay, the AroCell TK 210 ELISA, has been developed based on specific monoclonal antibodies against the C-terminal region of TK1. We utilized this assay to monitor the blood concentrations of TK1 in a cohort of patients with Hodgkin lymphoma (HL) before and after conventional treatment. TK1 concentrations in serum or plasma were measured using the AroCell TK 210 ELISA. For comparison, a large number of other biomarkers and cells were measured in blood such as C-reactive protein (CRP), Lactate dehydrogenase (LDH), hemoglobin, WBC, platelet counts, erythrocyte sedimentation rates (ESR), albumin, liver enzymes, creatinine. Fifty-eight patients with HL were included before start of treatment. Seventy three percent had the nodular sclerosis subtype and 52% stages I-II and 48% stages III-IV disease. Blood was sampled before treatment, during treatment and twice after completion of treatment. The upper normal TK1 concentration of healthy subjects (n=250) was 0.45 μg/L with a median of 0.25 μg/L (range 0.15-0.66 μg/L) as compared to HL, which was 0.26 μg/L (range 0.03-17 μg/L). The differences in ranges were significant (p&amp;lt;0.0001, F-statistics). Nodular sclerosis patients had higher TK1 levels as compared to the other subtypes (p=0.03). TK1 increased after treatment (p=0.001) in patients with normal concentrations from start i.e. &amp;lt;0.45 μg/L, whereas the concentrations decreased in 5/6 patients with TK1 &amp;gt;0.45 μg/L. TK1 concentrations before start of treatment was correlated to high CRP (p=0.01), low Hemoglobin (p=0.03), high WBC (p&amp;lt;0.001) and high platelet counts (p&amp;lt;0.01), but not to albumin or ESR or any other of the measured biomarkers. In a multivariate regression analysis, TK1 was correlated to LDH as the only independent variable (p&amp;lt;0.0001). In Hodgkin lymphoma patients, serum or plasma concentrations of TK1 may reflect malignant cell death and cell disruption rather than cell proliferation during treatment. Our results and hypothesis may help to interpret TK1 protein measurements as clinical tools in cancer management. Citation Format: Jagarlamudi Kiran Kumar, Staffan Eriksson, Johan Mattsson Ulfstedt, Per Venge, Daniel Molin. The thymidine kinase 1 (TK1) protein concentration in sera from Hodgkin lymphoma patients: A marker for cell death and disruption of malignant cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2618.
Can we further SPARkle the SPAR model?
Authors: Chengappa G Kavadichanda, Vir Singh Negi
Journal: Annals of the Rheumatic Diseases (2018)

We read with great interest the simple prediction model (SPAR) for the prediction of progress of early interstitial lung disease (ILD) in systemic sclerosis.1 The prospect of identifying such a predictor is both exciting and thought provoking. While the finding of lower oxygen saturation at baseline and after the 6 min walk test predicting progress …
VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance
Authors: Signe R Michaelsen, Mikkel Staberg, Henriette Pedersen, Kamilla E Jensen, Wiktor Majewski, Helle Broholm, Mette K Nedergaard, Christopher Meulengracht, Thomas Urup, Mette Villingshøj, Slávka Lukacova, Jane Skjøth-Rasmussen, Jannick Brennum, Andreas Kjær, Ulrik Lassen, Marie-Thérése Stockhausen, Hans S Poulsen, Petra Hamerlik
Journal: Neuro-Oncology (2018)

Glioblastoma ranks among the most lethal cancers, with current therapies offering only palliation. Paracrine vascular endothelial growth factor (VEGF) signaling has been targeted using anti-angiogenic agents, whereas autocrine VEGF/VEGF receptor 2 (VEGFR2) signaling is poorly understood. Bevacizumab resistance of VEGFR2-expressing glioblastoma cells prompted interrogation of autocrine VEGF-C/VEGFR2 signaling in glioblastoma.Autocrine VEGF-C/VEGFR2 signaling was functionally investigated using RNA interference and exogenous ligands in patient-derived xenograft lines and primary glioblastoma cell cultures in vitro and in vivo. VEGF-C expression and interaction with VEGFR2 in a matched pre- and post-bevacizumab treatment cohort were analyzed by immunohistochemistry and proximity ligation assay.VEGF-C was expressed by patient-derived xenograft glioblastoma lines, primary cells, and matched surgical specimens before and after bevacizumab treatment. VEGF-C activated autocrine VEGFR2 signaling to promote cell survival, whereas targeting VEGF-C expression reprogrammed cellular transcription to attenuate survival and cell cycle progression. Supporting potential translational significance, targeting VEGF-C impaired tumor growth in vivo, with superiority to bevacizumab treatment.Our results demonstrate VEGF-C serves as both a paracrine and an autocrine pro-survival cytokine in glioblastoma, promoting tumor cell survival and tumorigenesis. VEGF-C permits sustained VEGFR2 activation and tumor growth, where its inhibition appears superior to bevacizumab therapy in improving tumor control.
Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis
Authors: Ajit S. Divakaruni, Wei Yuan Hsieh, Lucía Minarrieta, Tin N. Duong, Kristen K.O. Kim, Brandon R. Desousa, Alexander Y. Andreyev, Caitlyn E. Bowman, Kacey Caradonna, Brian P. Dranka, David A. Ferrick, Marc Liesa, Linsey Stiles, George W. Rogers, Daniel Braas, Theodore P. Ciaraldi, Michael J. Wolfgang, Tim Sparwasser, Luciana Berod, Steven J. Bensinger, Anne N. Murphy
Journal: Cell Metabolism (2018)