tbuckley/cabot-search huggingface dataset:
Detecting human coronary inflammation by imaging perivascular fat
Authors: Alexios S. Antonopoulos, Fabio Sanna, Nikant Sabharwal, Sheena Thomas, Evangelos K. Oikonomou, Laura Herdman, Marios Margaritis, Cheerag Shirodaria, Anna-Maria Kampoli, Ioannis Akoumianakis, Mario Petrou, Rana Sayeed, George Krasopoulos, Constantinos Psarros, Patricia Ciccone, Carl M. Brophy, Janet Digby, Andrew Kelion, Raman Uberoi, Suzan Anthony, Nikolaos Alexopoulos, Dimitris Tousoulis, Stephan Achenbach, Stefan Neubauer, Keith M. Channon, Charalambos Antoniades
Journal: Science Translational Medicine (2017)

Early detection of vascular inflammation would allow deployment of targeted strategies for the prevention or treatment of multiple disease states. Because vascular inflammation is not detectable with commonly used imaging modalities, we hypothesized that phenotypic changes in perivascular adipose tissue (PVAT) induced by vascular inflammation could be quantified using a new computerized tomography (CT) angiography methodology. We show that inflamed human vessels release cytokines that prevent lipid accumulation in PVAT-derived preadipocytes in vitro, ex vivo, and in vivo. We developed a three-dimensional PVAT analysis method and studied CT images of human adipose tissue explants from 453 patients undergoing cardiac surgery, relating the ex vivo images with in vivo CT scan information on the biology of the explants. We developed an imaging metric, the CT fat attenuation index (FAI), that describes adipocyte lipid content and size. The FAI has excellent sensitivity and specificity for detecting tissue inflammation as assessed by tissue uptake of 18F-fluorodeoxyglucose in positron emission tomography. In a validation cohort of 273 subjects, the FAI gradient around human coronary arteries identified early subclinical coronary artery disease in vivo, as well as detected dynamic changes of PVAT in response to variations of vascular inflammation, and inflamed, vulnerable atherosclerotic plaques during acute coronary syndromes. Our study revealed that human vessels exert paracrine effects on the surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can be monitored using a CT imaging approach. This methodology can be implemented in clinical practice to noninvasively detect plaque instability in the human coronary vasculature.
A multicenter cohort study on transarterial chemoembolization with or without sorafenib for intermediate-stage hepatocellular carcinoma: Reconsidering combination-therapy trial design.
Authors: Yan Zhao, Hailiang Li, Wei Bai, Jueshi Liu, Weifu Lv, Sheng Guan, Xiao Qin, Wenhui Wang, Weixin Ren, Wei Mu, Weidong Guo, Shanzhi Gu, Yilong Ma, Zhanxin Yin, Wengang Guo, Yongji Wang, Jielai Xia, Rafael Duran, Daiming Fan, Guohong Han
Journal: Journal of Clinical Oncology (2015)

4080 Background: The proof of the superiority of combination therapy with sorafenib and transarterial chemoembolization (TACE) over TACE alone for hepatocellular carcinoma (HCC) in term of survival is lacking. We conducted this multicenter retrospective study to evaluate the efficacy of combination therapy over TACE alone, and to compare the overall survival (OS) between patients with ≥ grade 2 sorafenib-related dermatologic adverse events (AEs) in the combination therapy group and patients treated with TACE alone. Methods: From January 2009 to December 2012, 606 consecutive patients with intermediate stage HCC, Eastern Cooperative Oncology Group performance status 0-1, and Child-Pugh class A-B ( ≤ 7) were included. Of them 202 received combination therapy and 404 received TACE alone therapy, respectively. Results: There was no significant difference between the two groups in median OS although a trend toward longer survival was observed in the combination therapy group (22.3 vs. 18.1 months, P= 0.281). After propensity score matching the difference in OS was still not different (22.3 vs. 17.9 months, P= 0.343). Of note, in the combination therapy group, 119 patients with ≤ grade 1 dermatologic AEs within the first two months of sorafenib initiation, which were defined as non-responders, had increased risk of death compared with 83 patients with ≥ grade 2 dermatologic AEs which were defined as responders (HR = 1.85; 95%CI 1.27-2.68; P= 0.001). By using the second propensity score matching to balance the baseline differences between responders subgroup and TACE alone group, a significantly prolonged median OS was observed in the responders subgroup (27.9 vs.18.3 months, P= 0.046). Conclusions: Combination therapy, not in all, but in responders to sorafenib, results in longer overall survival than TACE alone. Sorafenib-related dermatologic AEs may be considered a possible clinical marker to stratify responders from all patients. Before the appearance of any assured biomarkers, the design of prospective comparative studies needs to focus on the responders to treatment who are evaluated by clinical markers.
Regulation on Toll-like Receptor 4 and Cell Barrier Function by Rab26 siRNA-loaded DNA Nanovector in Pulmonary Microvascular Endothelial Cells
Authors: Hongli Li, Binfeng He, Xueping Liu, Jingtong Li, Qian Liu, Weijie Dong, Zhi Xu, Guisheng Qian, Hua Zuo, Changhua Hu, Hang Qian, Chengde Mao, Guansong Wang
Journal: Theranostics (2017)

The small GTPase Rab26 is involved in multiple processes, such as vesicle-mediated secretion and autophagy.However, the mechanisms and functions of Rab26 in the human pulmonary microvascular endothelial cells (HPMVECs) are not clear.In this study, we thoroughly investigated the role and novel mechanism of Rab26 in permeability and apoptosis of HPMVECs using a self-assembled Rab26 siRNA loaded DNA Y-motif nanoparticle (siRab26-DYM) and Rab26 adenovirus.We found that siRab26-DYM could be efficiently transfected into HPMVECs in a timeand dose-dependent manner.Importantly, the siRab26-DYM nanovector markedly aggravated the LPS-induced apoptosis and hyper-permeability of HPMVECs by promoting the nuclear translocation of Foxo1, and subsequent activation of Toll-like receptor 4 (TLR4) signal pathway.Overexpression of Rab26 by Rab26 adenoviruses partially inactivated LPS-induced TLR4 signaling pathway, suppressed the cell apoptosis and attenuated the hyperpermeability of HPMVECs.These results suggest that the permeability and apoptosis of HPMVECs can be modulated by manipulating Rab26 derived TLR4 signaling pathway, and that Rab26 can be potential therapeutic target for the treatment of vascular diseases related to endothelial barrier functions.
Outcomes for stage IVA squamous cell carcinoma of the oral cavity according to staging subtypes.
Authors: Kristen Marrone, Michael Otremba, Roman Groisberg, Hari Anant Deshpande, Forrest Crawford, Carlos Rodrigo Acevedo-Gadea, Bonnie Gould Rothberg, Benjamin Judson, Daniel Morgensztern
Journal: Journal of Clinical Oncology (2013)

6076 Background: Patients with locoregionally advanced squamous cell carcinoma of the oral cavity (SCCOC), defined as stages III to IVB without T4b, are treated similarly and combined for enrollment into most clinical trials. There are several combinations of tumor (T) and lymph node (N) categories for stage IVA. We evaluated the differences in outcomes according to subtypes of patients with stage IVA SCCOC. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with stage IVA SCCOC diagnosed between 1988 and 2007. Patients were subdivided according to tumor (T) and lymph node (N) status. Overall survival (OS) was estimated by the Kaplan-Meier method and compared by using log-rank test. Cox proportional hazard regression models were used for multivariate analyses. Results: Among the 3,904 patients meeting inclusion criteria, most patients underwent surgery, either alone (24%) or with radiation (59%). There was a significant difference in outcomes according to AJCC subsets (T4aN0, T4aN1, T1N2, T2N2, T3N2 and T4N2), with 5-year OS ranging from 15.8% in T4aN2 to 41.3% in T4aN0 (HR 2.3; 95% CI 2.03-2.62, p &lt; 0.001). Since the 5-year OS was similar for patients with T1N2-T2N2 and T3N2-T4aN2, these groups were further subdivided according to the T (T1-2 or T3-4a) and N2 subsets. The 5-year OS was significantly different according to the subgroups, ranging from 11.8% in T3-4aN2c to 37.5% in T1-2N2a (Table). The stage subgroups remained independent predictors for survival after adjusting for age, gender, race and treatment. Conclusions: Stage IVA SCCOC is a heterogeneous disease with significant differences in outcomes according to its subsets. If these findings are confirmed in additional studies, further subdivision of stage IVA may be warranted. [Table: see text]
Clinical and Morphologic Characteristics of MEK Inhibitor–Associated Retinopathy
Authors: Jasmine H. Francis, Larissa A. Habib, David H. Abramson, Lawrence A. Yannuzzi, Murk Heinemann, Mrinal M. Gounder, Rachel N. Grisham, Michael A. Postow, Alexander N. Shoushtari, Ping Chi, Neil H. Segal, Rona Yaeger, Alan L. Ho, Paul B. Chapman, Federica Catalanotti
Journal: Ophthalmology (2017)
P53 Protein Expression Correlates with Adverse Outcome in Low-Risk Myelodysplastic Syndromes
Authors: Francesca Donatelli, Austin G. Kulasekararaj, Alexander e Smith, Jon Salisbury, Syed A Mian, Robin M. Ireland, Abu Arqoub Hadil, Victoria T Potter, Ghulam J. Mufti
Journal: Blood (2016)
Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
Authors: Kerstin Cornils, Lars Thielecke, Doreen Winkelmann, Tim Aranyossy, Mathias Lesche, Andreas Dahl, Ingo Roeder, Boris Fehse, Ingmar Glauche
Journal: Molecular Cancer (2017)

Clonal competition in cancer describes the process in which the progeny of a cell clone supersedes or succumbs to other competing clones due to differences in their functional characteristics, mostly based on subsequently acquired mutations. Even though the patterns of those mutations are well explored in many tumors, the dynamical process of clonal selection is underexposed. We studied the dynamics of clonal competition in a BcrAbl-induced leukemia using a γ-retroviral vector library encoding the oncogene in conjunction with genetic barcodes. To this end, we studied the growth dynamics of transduced cells on the clonal level both in vitro and in vivo in transplanted mice. While we detected moderate changes in clonal abundancies in vitro, we observed monoclonal leukemias in 6/30 mice after transplantation, which intriguingly were caused by only two different BcrAbl clones. To analyze the success of these clones, we applied a mathematical model of hematopoietic tissue maintenance, which indicated that a differential engraftment capacity of these two dominant clones provides a possible explanation of our observations. These findings were further supported by additional transplantation experiments and increased BcrAbl transcript levels in both clones. Our findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context.
High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA
Authors: Junxiao Ye, Ergang Liu, Junbo Gong, Jianxin Wang, Yongzhuo Huang, Huining He, Victor C. Yang
Journal: Theranostics (2017)

Because of the unparalleled efficiency and universal utility in treating a variety of disease types, siRNA agents have evolved as the future drug-of-choice.Yet, the inability of the polyanionic siRNA macromolecules to cross the cell membrane remains as the bottleneck of possible clinical applications.With the cell penetrating peptides (CPP) being discovered lately, the most effective tactic to achieve the highest intracellular siRNA delivery deems to be by covalently conjugating the drug to a CPP; for instance, the arginine-rich Tat or low molecular weight protamine (LMWP) peptides.However, construction of such a chemical conjugate has been referred by scientists in this field as the "Holy Grail" challenge due to self-assembly of the cationic CPP and anionic siRNA into insoluble aggregates that are deprived of the biological functions of both compounds.Based on the dynamic motion of PEG, we present herein a concise coupling strategy that is capable of permitting a high-yield synthesis of the cell-permeable, cytosol-dissociable LMWP-siRNA covalent conjugates.Cell culture assessment demonstrates that this chemical conjugate yields by far the most effective intracellular siRNA delivery and its corresponded gene-silencing activities.This work may offer a breakthrough advance towards realizing the clinical potential of all siRNA therapeutics and, presumably, most anionic macromolecular drugs such as anti-sense oligonucleotides, gene compounds, DNA vectors and proteins where conjugation with the CPP encounters with problems of aggregation and precipitation.To this end, the impact of this coupling technique is significant, far-reaching and wide-spread.
Health Effects of Overweight and Obesity in 195 Countries over 25 Years
Journal: New England Journal of Medicine (2017)

Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain.We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015.In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease.The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem. (Funded by the Bill and Melinda Gates Foundation.).
Evaluation of eight plasma proteins as candidate blood-based biomarkers for malignant gliomas.
Authors: Ryan P. Lange, Allen Everett, Pratima Dulloor, Frederick K. Korley, Chetan Bettegowda, Cherie Blair, Stuart A. Grossman, Matthias Holdhoff
Journal: Journal of Clinical Oncology (2014)

e13011 Background: Peripheral blood biomarkers are a critical component of detection and care for many cancer types. No blood biomarker of clinical use is available to glioma patients despite the urgent need for improved assessment of disease response and progression. The objective of this study was to explore eight candidate biomarkers in their ability to differentiate glioblastomas (WHO grade IV) from low grade gliomas (WHO grade II) and healthy controls. Methods: Candidate proteins were selected based on previous glioma biomarker studies, or as novel candidates due to their association with brain tumors or brain injury. We collected pre-operative plasma from 34 patients with gliomas (WHO grade IV, n=23; WHO grade II, n=11) as well as plasma from healthy subjects as controls (n=15). Using enzyme-linked immunosorbent assays, we measured plasma concentrations of glial fibrillary acidic protein (GFAP), neurogranin, brain derived neurotrophic factor (BDNF), intracellular adhesion molecule 5 (ICAM-5), metallothionein-3 (MT3), beta-synuclein, S100B, and neuron specific enolase (NSE) in all available samples. Results: Plasma concentrations showed extensive overlap among brain tumor patients and healthy subjects, with detectable levels in all patient and healthy groupings alike. Statistically significant differences between WHO grade IV tumors and healthy controls were detected only for ICAM-5 (p < 0.01, increased in grade IV) and BDNF (p < 0.05 decreased in grade IV), however not for the other markers tested. Timing of blood collection as pre- or post-anesthesia affected some protein levels significantly (p < 0.05). Gliosarcomas (WHO grade IV, n=2) had a noticeably different plasma biomarker profile than either glioblastomas or healthy subjects. Conclusions: These findings suggest these eight proteins are not glioma-specific plasma biomarkers. The effect of anesthesia on protein levels in plasma is an important consideration for future brain tumor biomarker studies. Gliosarcomas were under-represented in our sample but appear to have substantially higher levels of some of the studied proteins which deserves further evaluation.
Cost effectiveness of sorafenib versus best supportive care in advanced renal cell carcinoma in Canada
Authors: B. Jaszewski, X. Gao, P. Reddy, T. Bhardwaj, G. Bjarnason, A. Finelli, A. Kapoor, A. Abugaber
Journal: Journal of Clinical Oncology (2007)

5111 Background: Sorafenib is an oral multi-kinase inhibitor that targets tumour cell proliferation and tumour angiogenesis. In the TARGETs study (phase III trial), sorafenib plus best supportive care (BSC) significantly prolonged progression-free survival (PFS) compared with BSC alone (P&lt;0.000001) in patients with advanced renal cell carcinoma (RCC). The objective of this study was to evaluate the costeffectiveness of sorafenib plus BSC versus BSC alone in advanced RCC from a Canadian provincial Ministry of Health perspective. Methods: A Markov model was developed to project the lifetime survival and costs associated with the two treatment groups. The model tracked patients with advanced RCC through three disease states - PFS, progression, and death. Resource utilization included drug, drug administration, physician visits, monitoring, and adverse events. Costs and survival benefits were discounted annually at 5%. Results: The lifetime per patient costs were $62,426 CDN and $18,898 CDN for sorafenib + BSC and BSC alone, respectively. The life-years gained (LYG) were higher for sorafenib relative to BSC. The incremental cost-effectiveness ratio (ICER) of sorafenib plus BSC versus BSC alone over a lifetime horizon was $36,046/LYG CDN (with a half cycle correction). Univariate sensitivity analyses yielded ICERs below $70,000/LYG CDN. Probabilistic sensitivity analyses showed that the results were moderately sensitive to the clinical variables and less sensitive to the cost variables, yielding ICERs below $100,000/LYG CDN in most cases. Conclusion: Sorafenib is cost effective with an ICER of $36,046/LYG CDN which is below the suggested cost effectiveness threshold of $100,000/QALY ($CDN 1992) or $130,860/QALY ($CDN 2006). [Table: see text]
Report on the Vth International Symposium on Comparative Leukemia Research, Sept. 13–17, Padova, Italy
Authors: Herberman, B.
Journal: JNCI Journal of the National Cancer Institute (1972)

Journal Article Report on the Vth International Symposium on Comparative Leukemia Research, Sept. 13–17, Padova, Italy Get access B. Herberman B. Herberman Associate Editor Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 48, Issue 3, March 1972, Page 841, https://doi.org/10.1093/jnci/48.3.841 Published: 01 March 1972
USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity
Authors: Shimin An, Ling‐Ping Zhao, Li‐Jun Shen, Siyuan Wang, Kuo Zhang, Yu Qi, Jilin Zheng, Xiao‐Jing Zhang, Xue‐Yong Zhu, Rong Bao, Ling Yang, Yue‐Xin Lu, Zhi‐Gang She, Yi‐Da Tang
Journal: Hepatology (2017)

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low‐grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin‐specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down‐regulated in the livers of nonalcoholic steatohepatitis patients and high‐fat diet (HFD)–induced or genetically obese mice. When challenged with HFD, hepatocyte‐specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18–hepatocyte‐specific transgenic mice and promoted in USP18–hepatocyte‐specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorβ‐activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c‐Jun N‐terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD‐fed USP18–hepatocyte‐specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD‐fed mice injected with active‐site mutant USP18 failed to inhibit hepatic steatosis. Conclusion: USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (H epatology 2017;66:1866–1884)