tbuckley/cabot-search huggingface dataset:
Scalable Production of Therapeutic Protein Nanoparticles Using Flash Nanoprecipitation
Authors: Zhipeng Zeng, Cong Dong, Pengfei Zhao, Zhijia Liu, Lixin Liu, Hai‐Quan Mao, Kam W. Leong, Xiaohu Gao, Yongming Chen
Journal: Advanced Healthcare Materials (2018)

Abstract Flash nanoprecipitation (FNP) by fast mixing of drug‐containing organic solvent and water in a microchamber is a powerful and scalable technology to produce solid drug nanoparticles with high payload. The embedded therapeutic drugs, however, are largely limited to hydrophobic small molecules. By transferring proteins into organic solvent via hydrophobic ion pairing, the scope of FNP applications is expanded. This platform technology is capable of producing protein nanoparticles with tunable sizes (from ≈30 nm to sub‐micrometers), high‐production scale (grams per hour), high drug loading efficiency (&gt;90%), and excellent reproducibility, opening a new paradigm for formulation of biological pharmaceuticals. As a proof‐of‐concept, insulin nanoparticles are made to address a major medical challenge; oral administration. A relative insulin bioavailability of 13.2% is achieved, enabling sustained reduction of blood glucose levels in a diabetic rat model.
IL‐2Rα up‐regulation is mediated by latent membrane protein 1 and promotes lymphomagenesis and chemotherapy resistance in natural killer/T‐cell lymphoma
Authors: Liang Wang, Xi‐wen Bi, Yu‐jia Zhu, Ying‐zhi He, Qiu‐yu Lai, Zhong‐jun Xia, Qing‐qing Cai
Journal: Cancer Communications (2018)

Abstract Background Natural killer/T‐cell lymphoma (NKTCL) is a highly aggressive non‐Hodgkin lymphoma often resistant to chemotherapy. Serum level of soluble IL‐2 receptor α (IL‐2Rα) is elevated in NKTCL patients and correlates significantly with treatment response and survival. In the current study we examined the potential role of IL‐2Rα by over‐expressing IL‐2Rα in representative cell lines. Methods Levels of IL‐2Rα were evaluated in the human natural killer cell line NK‐92 and the NKTCL cell line SNK‐6. Lentiviral vectors were used to express latent membrane protein 1 (LMP1) in NK‐92 cells, and IL‐2Rα in both NK‐92 and SNK‐6 cells. The biological effects of these genes on proliferation, apoptosis, cell cycle distribution, and chemosensitivity were analyzed. Results Expression of IL‐2Rα was significantly higher in SNK‐6 cells than in NK‐92 cells. Expressing LMP1 in NK‐92 cells remarkably up‐regulated IL‐2Rα levels, whereas selective inhibitorss of the proteins in the MAPK/NF‐κB pathway significantly down‐regulated IL‐2Rα. IL‐2Rα overexpression in SNK‐6 cells promoted cell proliferation by altering cell cycle distribution, and induced resistance to gemcitabine, doxorubicin, and asparaginase. These effects were reversed by an anti‐IL‐2Rα antibody. Conclusions Our results suggest that LMP1 activates the MAPK/NF‐κB pathway in NKTCL cells, up‐regulating IL‐2Rα expression. IL‐2Rα overexpression promotes growth and chemoresistance in NKTCL, making this interleukin receptor a potential therapeutic target.
Abstract 16735: Effect of Communicating Phenotypic and Genetic Risk of Coronary Heart Disease Alongside Web-based Lifestyle Advice - The Inform Randomized Clinical Trial
Authors: Barbora Silarova, Stephen J Sharp, Juliet A Usher-Smith, Joanne Lucas, Rupert A Payne, Guy Shefer, Carmel Moore, Christine Girling, Kathryn Lawrence, Zoe Tolkien, Matthew Walker, Adam S Butterworth, Emanuele Di Angelantonio, John Danesh, Simon Griffin
Journal: Circulation (2016)

Introduction: Coronary heart disease (CHD) risk scores based on phenotypic information are routinely used in primary care. It has been suggested that genetics could be used to more precisely identify individuals at high risk of developing disease and to more effectively motivate individuals to change their lifestyle. However, there is a lack of adequately powered randomized trials using objective measures to evaluate the effect of provision of phenotypic and genetic CHD risk information on health behaviours. Hypothesis: We aimed to quantify the short-term (12 weeks) effects of provision of phenotypic and genetic CHD risk information, alongside lifestyle advice, on change in objectively-measured health behaviours and cardiovascular risk factors. Methods: In a parallel-group, open randomized trial, we allocated 956 male and female blood donors (mean (SD) age = 56.7 (8.8)) with no previous history of CHD to either no intervention (control group) or to one of three active intervention groups: i) web-based lif...
Case 32-2018: A 36-Year-Old Pregnant Woman with Newly Diagnosed Adenocarcinoma
Authors: Janet E. Murphy, Kimberly Shampain, Laura E. Riley, Jeffrey W. Clark, Kristen M. Basnet
Journal: New England Journal of Medicine (2018)

A 36-year-old pregnant woman was evaluated at 33 weeks of gestation because of newly diagnosed adenocarcinoma. One week earlier, severe pain in the lower back had developed; computed tomography revealed hypoattenuating hepatic lesions. Management decisions were made.
Preparation, characterization, and in vitro/vivo evaluation of polymer-assisting formulation of atorvastatin calcium based on solid dispersion technique
Authors: Wenxiang Dong, Xitong Su, Meng Xu, Mingming Hu, Yinghua Sun, Peng Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Due to low solubility and bioavailability, atorvastatin calcium is confronted with challenge in conceiving appropriate formulation. Solid dispersion of atorvastatin calcium was prepared through the solvent evaporation method, with Poloxamer 188 as hydrophilic carriers. This formulation was then characterized by scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction and fourier transform infrared spectroscopy. Moreover, all these studies suggested the conversion of crystalline atorvastatin calcium. In addition, the drug solubility studies as well as dissolution rates compared with bulk drug and market tablets Lipitor were also examined. Furthermore, the study investigated the pharmacokinetics after oral administration of Lipitor and solid dispersion. And the AUC0-8 h and Cmax increased after taking ATC-P188 solid dispersion orally compared with that of Lipitor. All these could be demonstrated that ATC-P188 solid dispersions would be prospective means for enhancing higher oral bioavailability of ATC.
Combination treatment with the PARP inhibitor niraparib and chemotherapeutics in a preclinical model of KRAS/BRAF mutated colorectal cancer cell lines across the four consensus molecular subtypes
Authors: P.P. Vitiello, C. Cardone, D. Ciardiello, V. Belli, N. Matrone, C. Borrelli, L. Poliero, V. De Falco, E.F. Giunta, P. Vitale, N. Zanaletti, G. Tirino, T. Troiani, F. Ciardiello, E. Martinelli
Journal: Annals of Oncology (2018)
KRAS mutant and RAS/BRAF wild type colorectal cancer cells exhibit differences in the rewiring of signal transduction that can impact on future therapeutic strategies
Authors: A. Georgiou, A. Stewart, P. Thavasu, E.A. Coker, S. Poelsterl, B. Al-Lazikani, D. Cunningham, S. Whittaker, U. Banerji
Journal: Annals of Oncology (2018)
P3.CR-07 Comprehensive Genomic Profiles for a Mediastinal Tumor Suspected of Synovial Sarcoma: A Case Report
Authors: K. Araki, K. Shien, K. Namba, J. Soh, S. Miyauchi, A. Miura, Y. Takahashi, E. Kurihara, Y. Ogoshi, H. Yamamoto, S. Sugimoto, M. Yamane, S. Toyooka
Journal: Journal of Thoracic Oncology (2018)
Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor
Authors: Emma-Ruoqi Xu, Sören von Bülow, Po-Chia Chen, Peter J. Lenting, Katra Kolšek, Camilo Aponte-Santamaría, Bernd Simon, Jaelle Foot, Tobias Obser, Reinhard Schneppenheim, Frauke Gräter, Cécile V. Denis, Matthias Wilmanns, Janosch Hennig
Journal: Blood (2018)
PIEZO2 mediates injury-induced tactile pain in mice and humans
Authors: Marcin Szczot, Jaquette Liljencrantz, Nima Ghitani, Arnab Barik, Ruby Lam, James H. Thompson, Diana Bharucha-Goebel, Dimah Saade, Aaron Necaise, Sandra Donkervoort, A. Reghan Foley, Taylor Gordon, Laura Case, M. Catherine Bushnell, Carsten G. Bönnemann, Alexander T. Chesler
Journal: Science Translational Medicine (2018)

The stretch-gated ion channel PIEZO2 is required for inflammation-induced tactile allodynia.
Long-Term Exposure to Ambient Fine Particulate Matter and Chronic Kidney Disease: A Cohort Study
Authors: Ta-Chien Chan, Zilong Zhang, Bo-Cheng Lin, Changqing Lin, Han-Bing Deng, Yuan Chieh Chuang, Jimmy W.M. Chan, Wun Kai Jiang, Tony Tam, Ly-yun Chang, Gerard Hoek, Alexis K.H. Lau, Xiang Qian Lao
Journal: Environmental Health Perspectives (2018)

Background: Chronic kidney disease (CKD) is a serious global public health challenge, but there is limited information on the connection between air pollution and risk of CKD. Objective: The aim of this study was to investigate the association between long-term exposure to particulate matter (PM) with an aerodynamic diameter of less than 2.5μm (PM2.5) and the development of CKD in a large cohort. Methods: A total of 100,629 nonCKD Taiwanese residents age 20 y or above were included in this study between 2001 and 2014. Ambient PM2.5 concentration was estimated at each participant's address using a satellite-based spatiotemporal model. Incident CKD cases were identified by an estimated glomerular filtration rate (eGFR) of less than 60mL/min/1.73 m2. We collected information on a wide range of potential confounders/modifiers during the medical examinations. Cox proportional hazard regression was applied to calculate hazard ratios (HRs). Results: During the follow-up, 4,046 incident CKD cases were identified, and the incidence rate was 6.24 per 1,000 person-years. In contrast with participants with the first quintile exposure of PM2.5, participants with the fourth and fifth quintiles exposure of PM2.5 had increased risk of CKD development, adjusting for age, sex, educational level, smoking, drinking, body mass index, systolic blood pressure, fasting glucose, total cholesterol, and self-reported heart disease or stroke, with an HR [95% confidence interval (CI)] of 1.11 (1.02, 1.22) and 1.15 (1.05, 1.26), respectively. A significant concentration–response trend was observed (p<0.001). Every 10 μg/m3 increment in the PM2.5 concentration was associated with a 6% higher risk of developing CKD (HR: 1.06, 95% CI: 1.02, 1.10). Sensitivity and stratified analyses yielded similar results. Conclusions: Long-term exposure to ambient PM2.5 was associated with an increased risk of CKD development. Our findings reinforce the urgency to develop global strategies of air pollution reduction to prevent CKD. https://doi.org/10.1289/EHP3304
Prognostic factors of neuroendocrine tumors (NETs) in a Mexican cohort.
Authors: Vanessa Rosas Camargo, Fidel David Huitzil-Melendez, Armando Gamboa-Dominguez, Fernando Cano Garia, Gabriel Galvan Salazar, Eucario Leon-Rodriguez
Journal: Journal of Clinical Oncology (2013)

e15186 Background: NETs comprise a heterogeneous group of neoplasms regarding clinical behavior. Our aim was to identify clinical and pathological variables associated with survival in a mexican cohort. Methods: We retrospectively reviewed the medical records of all gastroenteropancreatic(GEP)-NETs with histopathological confirmation evaluated at our Institution from January 2000 to December 2011. Relevant clinical and histopatholocical features were recorded. Overall survival (OS) was estimated using Kaplan Meier method and survival distributions were compared using the Log rank test. Results: 175 patients with GEP-NETs were identified in the study period. We excluded 35 patients with insulinomas and 40 patients with lesions amenable to endoscopic resection given 100% cancer specific survival. Therefore, 100 patients with GEP-NETs (61% gastrointestinal / 39% pancreatic) with malignant potential were analyzed: median age 53 y/o, 55% were male, 39% were localized, 4% had regional spread and 57% were metastatic at presentation. 35% of patients harbored functional tumors. 32% of patients showed isolated liver metastasis while 24% of patients showed hepatic and extrahepatic metastatic disease. 37% were NETs grade 1/2, 56% were neuroendocrine carcinomas and 6% were mixed neuroendocrine carcinoma / adenocarcinoma. Median OS was 79.6 months. Univariate analysis identified clinical stage (P=0.002), weight loss (P=0.000), jaundice at presentation (P=0.036), ECOG performance status (P=0.000), resection of primary tumor (P=0.000) and resection of metástasis (P=0.001) as significantly associated with survival. Multivariate analysis excluded resection of primary tumor only. Conclusions: In this mexican cohort, clinical factors were the most important determinants of prognosis.
Associations of Pre- and Postdiagnosis Diet Quality With Risk of Mortality Among Men and Women With Colorectal Cancer
Authors: Mark A. Guinter, Marjorie L. McCullough, Susan M. Gapstur, Peter T. Campbell
Journal: Journal of Clinical Oncology (2018)

Purpose Dietary patterns, indicators of overall diet quality, are associated with colorectal cancer (CRC) incidence but less consistently with mortality among CRC survivors. We prospectively evaluated associations of diet quality pre- and postdiagnosis with risk of mortality among men and women with CRC. Patients and Methods In the Cancer Prevention Study-II Nutrition Cohort, 2,801 participants were cancer free at baseline in 1992/1993 and subsequently diagnosed with invasive, nonmetastatic CRC during follow-up through June 2013. Pre- and postdiagnosis diet data were available for 2,671 and 1,321 participants, respectively, among whom 1,414 and 722 died. Concordance with the Dietary Approaches to Stop Hypertension (DASH), American Cancer Society nutrition guidelines (ACS-score), prudent, and Western dietary patterns was used to evaluate diet quality. Results Extreme scoring group comparisons showed that prediagnosis ACS-score was inversely associated with all-cause (hazard ratio high v low [HR High v Low ], 0.78; 95% CI, 0.65 to 0.95) and CRC-specific (HR High v Low , 0.74; 95% CI, 0.54 to 1.03) mortality, whereas the Western diet score was associated with higher all-cause mortality (HR High v Low , 1.30; 95% CI, 1.03 to 1.64). For postdiagnosis diet, the ACS-score was associated with lower risk of all-cause (HR High v Low , 0.62; 95% CI, 0.47 to 0.83) and CRC-specific (HR High v Low , 0.35; 95% CI, 0.17 to 0.73) mortality, the DASH score was inversely associated with all-cause (HR High v Low , 0.79; 95% CI, 0.62 to 0.99) and CRC-specific (HR High v Low , 0.56; 95% CI, 0.35 to 0.89) mortality, and the prudent score was inversely associated with all-cause mortality (HR High v Low , 0.72; 95% CI, 0.56 to 0.93). Among participants with a low diet quality before diagnosis, improved DASH (HR, 0.54; 95% CI, 0.31 to 0.92) and prudent (HR, 0.53; 95% CI, 0.29 to 0.95) scores from pre- to postdiagnosis were inversely associated with CRC-specific mortality. Conclusion Dietary patterns reflective of high intakes of plant foods and low intakes of animal products before and after CRC diagnosis are associated with longer survival.
Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma
Authors: Sumita Khatri, Wendy Moore, Peter G. Gibson, Richard Leigh, Arnaud Bourdin, Jorge Maspero, Manuel Barros, Roland Buhl, Peter Howarth, Frank C. Albers, Eric S. Bradford, Martyn Gilson, Robert G. Price, Steven W. Yancey, Hector Ortega
Journal: Journal of Allergy and Clinical Immunology (2018)

Mepolizumab has demonstrated favorable safety and efficacy profiles in placebo-controlled trials of 12 months' duration or less; however, long-term data are lacking.We sought to evaluate the long-term safety and efficacy of mepolizumab in patients with severe eosinophilic asthma (SEA).COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects, NCT01691859) was an open-label extension study in patients with SEA previously enrolled in DREAM (Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma, NCT01000506). Patients received 100 mg of subcutaneous mepolizumab every 4 weeks plus standard of care until a protocol-defined stopping criterion was met. Safety end points included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Efficacy end points included annualized exacerbation rates, changes from baseline in Asthma Control Questionnaire 5 scores, and blood eosinophil counts. Immunogenicity was also assessed.Overall, 347 patients were enrolled for an average of 3.5 years (maximum, 4.5 years; total exposure, 1201 patient-years). On-treatment AEs were reported in 94% of patients (exposure-adjusted rate, 3688 events/1000 patient-years). The most frequently reported on-treatment AEs were respiratory tract infection, headache, bronchitis, and asthma worsening. Seventy-nine (23%) patients experienced 1 or more on-treatment serious AEs; there were 6 deaths, none of which were assessed as related to mepolizumab. For patients with 156 weeks or greater enrollment, the exacerbation rate was 0.74 events/y (weeks 0-156), a 56% reduction from the off-treatment period between DREAM and COLUMBA. For all patients, at the first postbaseline assessment, the mean Asthma Control Questionnaire 5 score was reduced by 0.47 points, and blood eosinophil counts were reduced by 78%, with similar improvements maintained throughout the study. The immunogenicity profile (8% anti-drug antibodies) was consistent with previous studies.These data support the long-term safety and efficacy of mepolizumab in patients with SEA.
Abstract 18660: P2Y2 Nucleotide Receptor Overexpression: Letting Blind Cardiac Progenitor Cells ‘See’ Again
Authors: Farid Khalafalla, Steven Greene, Jonathan Nguyen, Hashim Khan, Mark Sussman
Journal: Circulation (2016)

Heart failure (HF) is a leading cause of death in the US due to limited capability of adult mammalian heart to regenerate after myocardial infarction (MI). Autologous stem cell therapy holds promis...
Michael Robert William King
Authors: Angelique Beling, Pete Osborn, Manish Patel
Journal: BMJ (2018)

Michael Robert William King (“Mike”) was born in Chichester, son of Peter and Sally and brother of Elizabeth. He studied natural sciences at Robinson College, Cambridge, and subsequently undertook an MSc in engineering and physical science in medicine at Imperial College, London, before completing his medical degree at King’s College, London. Mike was appointed as a consultant radiologist at Queen Alexandra Hospital, Portsmouth, in 2008 and became director of breast screening in 2012. He later also became joint clinical director.

At medical school, Mike was a popular student and excelled academically, gaining a distinction in medical finals. He was equally adept at parodying himself, as well as his peers, and could have fellow students in fits of laughter as he impersonated the professors around the wards. His …
Temporal autoregulation during human PU.1 locus SubTAD formation
Authors: Daniel Schuetzmann, Carolin Walter, Boet van Riel, Sabrina Kruse, Thorsten König, Tabea Erdmann, Alexander Tönges, Eric Bindels, Andre Weilemann, Claudia Gebhard, Klaus Wethmar, Chiara Perrod, Julia Minderjahn, Michael Rehli, Ruud Delwel, Georg Lenz, Stefan Gröschel, Martin Dugas, Frank Rosenbauer
Journal: Blood (2018)
Cardiovascular Pharmacogenomics: Does It Matter If You're Black or White?
Authors: Tanima De, C. Sehwan Park, Minoli A. Perera
Journal: The Annual Review of Pharmacology and Toxicology (2018)

Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are multifactorial with some portion associated with genomic variation. The field of pharmacogenomics aims to predict drug response in patients prior to medication administration and to uncover the biological underpinnings of drug response. The field of human genetics has long recognized that genetic variation differs in frequency between ancestral populations, with some single nucleotide polymorphisms found solely in one population. Thus far, most pharmacogenomic studies have focused on individuals of European and East Asian ancestry, resulting in a substantial disparity in the clinical utility of genetic prediction for drug response in US minority populations. In this review, we discuss the genetic factors that underlie variability to drug response and known pharmacogenomic associations and how these differ between populations, with an emphasis on the current knowledge in cardiovascular pharmacogenomics.
OP0246 Inflammation on mri of spine and sacroiliac joints is highly predictive of structural damage in axial spondyloarthritis: the 5 years data of the desir cohort
Authors: A. Sepriano, S. Ramiro, R. Landewé, M. Dougados, D. van der Heijde
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The effect of local inflammation on structural damage in patients (pts) with axial spondyloarthritis is not well known. <h3>Objectives</h3> We aimed to test the possible effect of inflammation on structural damage both assessed by MRI and at the level of the spine and the SIJ. <h3>Methods</h3> Pts with recent onset (≤3 years) axSpA (according to the treating rheumatologist) from the DESIR cohort were included. MRI of the SIJ (MRI-SIJ) and spine (MRI-spine) were obtained at baseline (BL), 2 and 5 years and scored by 3 trained central readers unaware of the chronology. Bone Marrow Oedema (BME) at MRI-SIJ was assessed according to ASAS definition and at the MRI-spine by the presence of ≥3 lesions. Structural damage in the SIJ (MRI-SIJ-STR) and in the spine (MRI-spine-STR) was defined by ≥3 fatty lesions. The% of structural net progression (number of 'progressors' minus the number of 'regressors' divided by the total number of pts) was assessed in subgroups according to CRP and BME status at BL. The effect of BME on MRI-SIJ on MRI-SIJ-STR and of BME on MRI-spine on MRI-spine-STR was evaluated using two types of binomial generalised estimating equations (GEE) models: i. effect at BL on 5 years incorporating measurements from all readers (GEE adjusted for reader); ii. effect of BME over 5 years (longitudinal time-lagged models with auto-regression). The final models were adjusted for variables proved to confound the association of interest (variables tested: age, gender, HLA-B27, smoking status, CRP, BASDAI, ASDAS, treatment with NSAIDs and TNFi). <h3>Results</h3> In total, 151 and 145 pts had complete 5 year MRI-SIJ and MRI-spine data available from 3 readers, respectively. Of the 151 pts with complete MRI-SIJ data, the net% pts who switched from MRI-SIJ-STR negative to positive ranged from 3.8% to 24% according to the presence of objective signs of inflammation at BL (figure 1). Low number of pts did not allow for similar analysis in the spine. In the multivariable analysis, both the presence of BME at MRI-SIJ (OR=4.2 [95% CI: 2.4 to 7.3]), and BME at MRI-spine (OR=8.9 [95% CI: 2.1–38.7]) at baseline were highly predictive of MRI-SIJ and MRI-spine structural progression respectively 5 years later, adjusting for CRP (only factor found to confound the association of interest). Similar positive associations were found in the longitudinal models testing the effect of BME on MRI-SIJ-STR and MRI-spine-STR over 5 years (table 1). <h3>Conclusions</h3> Our results show that local inflammation is strongly associated with the development of structural damage over 5 years both in the SIJ and spine in early axSpA and that this effect is independent of systemic inflammation. <h3>Disclosure of Interest</h3> None declared