tbuckley/cabot-search huggingface dataset:
Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects <i>Aspergillus</i> Lung Infections <i>In Vivo</i>
Authors: Genna Davies, Anna-Maria Rolle, Andreas Maurer, Philipp R. Spycher, Claudia Schillinger, Djamschid Solouk-Saran, Mike Hasenberg, Juliane Weski, Jesper Fonslet, Adrien Dubois, Frederic Boschetti, Franck Denat, Matthias Gunzer, Martin Eichner, Lauren S Ryder, Mikael Jensen, Roger Schibli, Bernd J. Pichler, Stefan Wiehr, Christopher R. Thornton
Journal: Theranostics (2017)

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy or bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [64Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to Aspergillus. To enable translation of the tracer to the clinical setting, we report here the development of a humanised version of the antibody (hJF5), and pre-clinical imaging of lung infection using a [64Cu]NODAGA-hJF5 tracer. The humanised antibody tracer shows a significant increase in in vivo biodistribution in A. fumigatus infected lungs compared to its radiolabeled murine counterpart [64Cu]NODAGA-mJF5. Using reverse genetics of the pathogen, we show that the antibody binds to the antigenic determinant β1,5-galactofuranose (Galf) present in a diagnostic mannoprotein antigen released by the pathogen during invasive growth in the lung. The absence of the epitope Galf in mammalian carbohydrates, coupled with the enhanced imaging capabilities of the hJF5 antibody, means that the [64Cu]NODAGA-hJF5 tracer developed here represents an ideal candidate for the diagnosis of IPA and translation to the clinical setting.
A Brucella Type IV Effector Targets the COG Tethering Complex to Remodel Host Secretory Traffic and Promote Intracellular Replication
Authors: Cheryl N. Miller, Erin P. Smith, Jennifer A. Cundiff, Leigh A. Knodler, Jessica Bailey Blackburn, Vladimir Lupashin, Jean Celli
Journal: Cell Host & Microbe (2017)
加齢脳における認知機能を最適化するための栄養戦略【Powered by NICT】
Authors: Wahl Devin, C Cogger Victoria, M Solon-Biet Samantha, V R Waern Rosilene, Gokarn Rahul, Pulpitel Tamara, Cabo Rafael de, P Mattson Mark, Raubenheimer David, J Simpson Stephen, G Le Couteur David
Journal: Ageing Research Reviews (2016)
Financial Burden in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Ryan D. Nipp, Anne C. Kirchhoff, Douglas Fair, Julia Rabin, Kelly A. Hyland, Karen Kuhlthau, Giselle K. Perez, Leslie L. Robison, Gregory T. Armstrong, Paul C. Nathan, Kevin C. Oeffinger, Wendy M. Leisenring, Elyse R. Park
Journal: Journal of Clinical Oncology (2017)

Purpose Survivors of childhood cancer may experience financial burden as a result of health care costs, particularly because these patients often require long-term medical care. We sought to evaluate the prevalence of financial burden and identify associations between a higher percentage of income spent on out-of-pocket medical costs (≥ 10% of annual income) and issues related to financial burden (jeopardizing care or changing lifestyle) among survivors of childhood cancer and a sibling comparison group. Methods Between May 2011 and April 2012, we surveyed an age-stratified, random sample of survivors of childhood cancer and a sibling comparison group who were enrolled in the Childhood Cancer Survivor Study. Participants reported their household income, out-of-pocket medical costs, and issues related to financial burden (questions were adapted from national surveys on financial burden). Logistic regression identified associations between participant characteristics, a higher percentage of income spent on out-of-pocket medical costs, and financial burden, adjusting for potential confounders. Results Among 580 survivors of childhood cancer and 173 siblings, survivors of childhood cancer were more likely to have out-of-pocket medical costs ≥ 10% of annual income (10.0% v 2.9%; P < .001). Characteristics of the survivors of childhood cancer that were associated with a higher percentage of income spent on out-of-pocket costs included hospitalization in the past year (odds ratio [OR], 2.3; 95% CI, 1.1 to 4.9) and household income < $50,000 (OR, 5.5; 95% CI, 2.4 to 12.8). Among survivors of childhood cancer, a higher percentage of income spent on out-of-pocket medical costs was significantly associated with problems paying medical bills (OR, 8.9; 95% CI, 4.4 to 18.0); deferring care for a medical problem (OR, 3.0; 95% CI, 1.6 to 5.9); skipping a test, treatment, or follow-up (OR, 2.1; 95% CI, 1.1 to 4.0); and thoughts of filing for bankruptcy (OR, 6.6; 95% CI, 3.0 to 14.3). Conclusion Survivors of childhood cancer are more likely to report spending a higher percentage of their income on out-of-pocket medical costs, which may influence their health-seeking behavior and potentially affect health outcomes. Our findings highlight the need to address financial burden in this population with long-term health care needs.
Y染色体:Y染色体のモザイク欠失に関連する遺伝的バリアントは発がんリスクと重なっており,細胞周期遺伝子の重要性が明らかになる
Authors: Wright Daniel J, Day Felix R, Kerrison Nicola D, Cardona Alexia, Langenberg Claudia, Wareham Nicholas J, Scott Robert A, Ong Ken K, Perry John R B, Zink Florian, Sulem Patrick, Sigurjonsdottir Svanhvit, Gudbjartsson Daniel F, Helgason Agnar, Thorsteindottir Unnur, Stefansson Kari, Thompson Deborah J, Chapman J Ross, Jackson Steve P
Journal: Nature Genetics (2017)
細胞内空間における光動力学的作用を達成するZnOナノ結晶を標的とした癌細胞によるその場第2高調波発生【Powered by NICT】
Authors: Gu Bobo, Pliss Artem, N Kuzmin Andrey, Baev Alexander, Y Ohulchanskyy Tymish, A Damasco Jossana, Yong Ken-Tye, Wen Shuangchun, N Prasad Paras
Journal: Biomaterials (2016)
Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets
Authors: K Karube, A Enjuanes, I Dlouhy, P Jares, D Martin-Garcia, F Nadeu, G R Ordóñez, J Rovira, G Clot, C Royo, A Navarro, B Gonzalez-Farre, A Vaghefi, G Castellano, C Rubio-Perez, D Tamborero, J Briones, A Salar, J M Sancho, S Mercadal, E Gonzalez-Barca, L Escoda, H Miyoshi, K Ohshima, K Miyawaki, K Kato, K Akashi, A Mozos, L Colomo, M Alcoceba, A Valera, A Carrió, D Costa, N Lopez-Bigas, R Schmitz, L M Staudt, I Salaverria, A López-Guillermo, E Campo
Journal: Leukemia (2017)

Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies.
What’s hot that the other lot got
Authors: Janice Ward
Journal: Thorax (2018)

Rapid diagnosis of the gene mutation associated with rifampicin resistance using GeneXpert MTB/RIF has improved the speed of diagnosis of multidrug-resistant TB; however, there are no established rapid techniques to assess for resistance to fluoroquinolones and injectable drugs. Xie et al ( N Engl J Med 2017;377:1043–54)have conducted a multicentre, prospective, blinded study in Korea and China to determine the sensitivity and specificity of a GeneXpert compatible assay which detects genes associated with resistance to isoniazid, moxifloxacin, ofloxacin, amikacin and kanamycin. A total of 405 patients were enrolled from June 2014 to June 2015 with 304 suitable samples included in the final analysis. The sensitivity of the assay for detection of Mycobacterium tuberculosis was 98%, which equalled GeneXpert MTB/RIF. The WHO recommended performance for molecular tests of drug resistance is a sensitivity of 95% and specificity of 98%. Sensitivity for resistance gene detection compared with DNA sequencing ranged from 92.7% for kanamycin to 98.1% for isoniazid; specificity was 99.6% for kanamycin and 100% for the other antibiotics. However, assay performance against phenotypic resistance characterisation was less accurate …
OP0068 Practices participating in the ACR'S rheumatology informatics system for effectiveness (RISE) national registry show improvements in quality of care
Authors: J Yazdany, R Myslinski, T Johansson, S Kazi
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The ACR launched the RISE registry in 2014 to facilitate quality improvement on a national scale. The registry passively extracts electronic health record (EHR) data from rheumatology practices, aggregates and analyzes these data centrally, and feeds performance on quality measures back to clinicians using a web-based dashboard. <h3>Objectives</h3> We used data from RISE to 1) examine variation in performance on quality measures across practices, and 2) evaluate trends in measure performance over time. <h3>Methods</h3> RISE9s informatics platform continuously collects data from the EHRs of participating practices, allowing centralized aggregation and analysis of quality measures. We analyzed data collected between July 1, 2014-July 1, 2016 on all patients seen by 294 clinicians across 63 practices. Measures in the areas of rheumatoid arthritis, drug safety, preventive care and gout were examined. Performance on quality measures, defined as the percentage of eligible patients receiving recommended care, was examined at the practice level. To examine trends in performance over time, we took the subset of practices that continuously participated in RISE since its inception (n=44), and developed 1) control charts and 2) logistic regression models, in which the outcome was practice-level performance each month and the predictor was time. <h3>Results</h3> Data from 289,812 patients was examined. Mean (SD) age was 59 (16) years, 75% were female, 21% were racial/ethnic minorities, and 37% had public insurance. Most rheumatologists were in a group practice (73%); 25% were in solo practice and 2% part of a larger health system. Performance on measures varied significantly across practices (Table). The largest gaps were observed for gout and preventive care. For 4 of 5 measures for which the Medicare program has set national benchmarks, average performance of RISE practices exceeded targets. Of 11 measures, performance improved over time on 5 measures (p&lt;0.05 in logistic models; see Figure for example control chart), was at goal on 4 measures, and saw no improvement on 2 measures (BMI screening and urate target). <h3>Conclusions</h3> We found significant variation in performance on quality measures across RISE practices, with the largest gaps seen in gout care and preventive care. Some practices have achieved a very high level of performance. Over time, RISE practices demonstrated improvement in over half of the measures examined. As rheumatologists aim to improve quality of care, RISE will, by design, allow participants to measure, benchmark, and continuously monitor performance improvement. <h3>Disclosure of Interest</h3> None declared
Incidence of Previously Undiagnosed Atrial Fibrillation Using Insertable Cardiac Monitors in a High-Risk Population
Authors: James A. Reiffel, Atul Verma, Peter R. Kowey, Jonathan L. Halperin, Bernard J. Gersh, Rolf Wachter, Erika Pouliot, Paul D. Ziegler
Journal: JAMA Cardiology (2017)

In approximately 20% of atrial fibrillation (AF)-related ischemic strokes, stroke is the first clinical manifestation of AF. Strategies are needed to identify and therapeutically address previously undetected AF.To quantify the incidence of AF in patients at high risk for but without previously known AF using an insertable cardiac monitor.This prospective, single-arm, multicenter study was conducted from November 2012 to January 2017. Visits took place at 57 centers in the United States and Europe. Patients with a CHADS2 score of 3 or greater (or 2 with at least 1 additional risk factor) were enrolled. Approximately 90% had nonspecific symptoms potentially compatible with AF, such as fatigue, dyspnea, and/or palpitations.Patients underwent monitoring with an insertable cardiac monitor for 18 to 30 months.The primary end point was adjudicated AF lasting 6 or more minutes and was assessed at 18 months. Other analyses included detection rates at points from 30 days to 30 months and among CHADS2 score subgroups. Median time from insertion to detection and the percentage of patients subsequently prescribed oral anticoagulation therapy was also determined.A total of 446 patients were enrolled; 233 (52.2%) were male, and the mean (SD) age was 71.5 (9.9) years. A total of 385 patients (86.3%) received an insertable cardiac monitor, met the primary analysis cohort definition, and were observed for a mean (SD) period of 22.5 (7.7) months. The detection rate of AF lasting 6 or more minutes at 18 months was 29.3%. Detection rates at 30 days and 6, 12, 24, and 30 months were 6.2%, 20.4%, 27.1%, 33.6%, and 40.0%, respectively. At 18 months, AF incidence was similar among patients with CHADS2 scores of 2 (24.7%; 95% CI, 17.3-31.4), 3 (32.7%; 95% CI, 23.8-40.7), and 4 or greater (31.7%; 95% CI, 22.0-40.3) (P = .23). Median (interquartile) time from device insertion to first AF episode detection was 123 (41-330) days. Of patients meeting the primary end point, 13 (10.2%) had 1 or more episodes lasting 24 hours or longer, and oral anticoagulation therapy was prescribed for 72 patients (56.3%).The incidence of previously undiagnosed AF may be substantial in patients with risk factors for AF and stroke. Atrial fibrillation would have gone undetected in most patients had monitoring been limited to 30 days. Further trials regarding the value of detecting subclinical AF and of prophylactic therapies are warranted.clinicaltrials.gov Identifier: NCT01727297.
Coalescing Subcutaneous Nodules
Authors: Jack P. Guccione, Brian Holloway, Jack L. Guccione
Journal: JAMA Dermatology (2017)

A man in his 40s presented with enlarging, nonpainful upper extremity nodules developing over the preceding 9 months; he was renovating a commercial cannabis grow house in California at time of onset and described the construction site as being filled with intoxicating mold. What is your diagnosis?
Antitumor Activity of Tepotinib plus Gefitinib in Asian Patients with Met plus EGFRm plus NSCLC
Authors: Dong-Wan Kim, Ross Soo, James Chih-Hsin Yang, Keunchil Park, Uz Stammberger, Huiiling Xiong, Christian Ihling, Yi-Long Wu, 楊志新
Journal: Journal of Thoracic Oncology (2015)
miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1
Authors: Zheng Fang, Shuai Yin, Ruochuan Sun, Shangxin Zhang, Min Fu, Youliang Wu, Tao Zhang, Junaid Khaliq, Yongxiang Li
Journal: Molecular Cancer (2017)

The aberrant expression of microRNA-140-5p (miR-140-5p) has been described in gastric cancer (GC). However, the role of miR-140-5p in GC remains unclear. In this study, the prognostic relevance of miR-140-5p in GC was investigated and YES1 was identified as a novel target of miR-140-5p in regulating tumor progression. miR-140-5p level was determined in 20 paired frozen specimens through quantitative real-time PCR, and analyzed in tissue microarrays through in situ hybridization. The target of miR-140-5p was verified through a dual luciferase reporter assay, and the effects of miR-140-5p on phenotypic changes in GC cells were investigated in vitro and in vivo. Compared with that in adjacent normal tissues, miR-140-5p expression decreased in cancerous tissues. The downregulated miR-140-5p in 144 patients with GC was significantly correlated with the reduced overall survival of these patients. miR-140-5p could inhibit GC cell proliferation, migration and invasion by directly targeting 3′–untranlated region of YES1. miR-140-5p could also remarkably reduce the tumor size in GC xenograft mice. miR-140-5p serves as a potential prognostic factor in patients with GC, and miR-140-5p mediated YES1 inhibition is a novel mechanism behind the suppressive effects of miR-140-5p in GC.
Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury
Authors: Yang Cao, Naveen Bojjireddy, Maengjo Kim, Tao Li, Peiyong Zhai, Narayani Nagarajan, Junichi Sadoshima, Richard D. Palmiter, Rong Tian
Journal: Circulation Research (2017)

Rationale: AMPK (AMP-activated protein kinase) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart, but the isoform-specific function of AMPK remains unclear. Objective: We sought to determine the role of γ2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the γ-subunit in the heart. Methods and Results: We found that γ2 but not γ1 or γ3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing γ2-subunit phosphorylated and inactivated RNA Pol I (polymerase I)–associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes for rDNA. The subsequent downregulation of pre-rRNA level led to attenuated endoplasmic reticulum (ER) stress and cell death. Deleting γ2-AMPK led to increases in pre-rRNA level, ER stress markers, and cell death during glucose deprivation, which could be rescued by inhibition of rRNA processing or ER stress. To study the function of γ2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of γ2-AMPK (cardiac knockout [cKO]). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of γ1-AMPK, the lack of γ2-AMPK sensitizes the heart to myocardial ischemia/reperfusion injury. The cKO failed to suppress pre-rRNA level during ischemia/reperfusion and showed a greater infarct size. Conversely, cardiac-specific overexpression of γ2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced. Conclusions: The γ2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased γ2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform-specific function of γ2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection.
Don’t Just Do Something, Stand There!
Authors: Pranay Sinha
Journal: JAMA Internal Medicine (2017)

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Insight into the biological activity of a naturally-derived dithiopyrrolone with a wide spectrum activity against metastatic cancer models
Authors: Moulay. Alaoui-Jamali, Liren Tang, Genhui Chen, Bin Li, Michael Lyle, John Webster
Journal: Cancer Research (2007)

LB-325  Mortality from cancer is attributed primarily to the dissemination of primary tumor cells to distant organs, where only limited therapeutic options are available for patients. The newly introduced targeted therapies for metastatic cancer such as trastuzumab have provided encouraging clinical results and reinforced the effectiveness of targeting cancer-associated targets. However, only small subgroups of patients benefit from targeted agents due to the common heterogeneity in target expression and the occurrence of relapses. There is continued drive to identify antimetastatic agents with polyfunctional mechanisms. Here, we report preclinical and biochemical data on a novel molecule (WBI-2100) with structural features that are distinct from those of other anti-cancer agents, and with activity against advanced preclinical cancer models resistant to many chemotherapy drugs and targeted agents.  WBI-2100 is an N-aryl-5-alkylidene-2,5-dihydropyrrol-2-dithiopyrrolone initially isolated from the symbiotic microorganism, Xenorhabdus spp., and further optimized through chemical synthesis. WBI-2100 is a highly tolerated molecule, even after long-term, chronic administration, and displays an excellent biodistribution when administered by intraperitoneal or by oral route to mouse preclinical models. Antitumor activity was seen in melanoma, breast, and liver human xenografts following either intraperitoneal or oral administration. Interestingly, WBI-2100 shows also antimetastatic activity in a human breast cancer model that is highly invasive when implanted into the mammary fat pad of mice, as well as in two rodent metastatic models, e.g. lung Lewis carcinoma and B16-BL6 models. In combination treatment, WBI-2100 showed a superior activity when combined with the chemotherapeutic drugs taxol, dacarbazine, and cisplatin. Biochemical studies have demonstrated that WBI-2100 has potent anti-invasive activity in the Boyden chamber assay and antiangiogenic activity in tube formation and in in vivo matrigel-plug assays, and with its selective induction of apoptosis in human endothelial cells at concentrations that are less toxic to cancer cells. Ongoing molecular and structural studies are dissecting the molecular target(s) for this molecule. In summary, we report a novel naturally-derived small molecule with anti-cancer properties that support a potential clinical utility for advanced human cancer.