tbuckley/cabot-search huggingface dataset:
Biliary cannulation technique with ultraslim endoscope for a patient with Billroth II gastrectomy
Authors: Yosuke Saragai, Daisuke Uchida, Hironari Kato, Takeshi Tomoda, Kazuyuki Matsumoto, Shigeru Horiguchi, Hiroyuki Okada
Journal: Endoscopy (2018)

Overtube-assisted enteroscopy procedures, such as double-balloon enteroscopy (DBE), can facilitate endoscopic retrograde cholangiopancreatography (ERCP) in patients who have undergone gastrointestinal surgery, for example Billroth II gastrectomy [1] [2] [3]. Also peroral direct cholangioscopy has been described in patients with surgically altered gastrointestinal anatomy [4] [5]. The success rates of overtube-assisted enteroscopy and ERCP were high in such patients; however, cannulation was usually difficult and sometimes impossible, especially in patients with a naïve papilla.
Prussian blue nanosphere-embedded in situ hydrogel for photothermal therapy by peritumoral administration
Authors: Jijun Fu, Bo Wu, Minyan Wei, Yugang Huang, Yi Zhou, Qiang Zhang, Lingran Du
Journal: Acta Pharmaceutica Sinica B (2018)

To establish an injectable hydrogel containing Prussian blue (PB) nanospheres for photothermal therapy against cancer, PB nanospheres were prepared by one-pot synthesis and the thermosensitive Pluronic F127 was used as the hydrogel matrix. The PB nanospheres and the hydrogel were characterized by shape, particle size, serum stability, photothermal performance upon repeated 808 nm laser irradiation, as well as the rheological features. The effect of the PB nanospheres and the hydrogel were evaluated qualitatively and quantitatively in 4T1 mouse breast cancer cells. The retention, photothermal efficacy, therapeutic effects and systemic toxicity of the hydrogel were assessed in a tumor-bearing mouse model. The PB nanospheres had a diameter of about 150 nm and exhibited satisfactory serum stability, photo-heat convert ability and repeated laser exposure stability. The hydrogel encapsulation did not negatively influence the above features of the photothermal agent. The nanosphere-containing hydrogel showed a phase transition at body temperature and, as a result, a long retention time in vivo. The photothermal agent-embedded hydrogel displayed promising photothermal therapeutic effects in the tumor-bearing mouse model with little-to-no systemic toxicity after peritumoral administration.
GP who filmed inspection and posted his comments online is suspended for two months
Authors: Clare Dyer
Journal: BMJ (2018)

A GP who covertly recorded a visit by Care Quality Commission inspectors and then posted the video to YouTube and his practice website, along with comments critical of the regulator, has been suspended from the UK medical register for two months.

Hendrik Beerstecher, 55, refused to stop the video recording when the inspectors realised it was happening and failed to take down his online videos of CQC inspectors when asked.

Beerstecher told the medical practitioners tribunal that he grew frustrated when he learnt that the CQC planned to publish its report on the inspection without considering a list he had sent of what he called factual inaccuracies. The report found his practice “inadequate” in the “safety” and “well led” categories, though “good” …
Investigation of molecular aggregation mechanism of glipizide/cyclodextrin complexation by combined experimental and molecular modeling approaches
Authors: Tianhe Huang, Qianqian Zhao, Yan Su, Defang Ouyang
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of water-insoluble drugs. However, the aggregation mechanism of drug-cyclodextrin complexes is still unclear. This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods. Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method. Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide. Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations. Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin. The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation. This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation. This research will also benefit the formulation development of cyclodextrin solubilization.
esiCancer: Evolutionary <i>In Silico</i> Cancer Simulator
Authors: Darlan Conterno Minussi, Bernardo Henz, Mariana dos Santos Oliveira, Eduardo C. Filippi-Chiela, Manuel M. Oliveira, Guido Lenz
Journal: Cancer Research (2018)

Abstract The evolution of cancer is inferred mainly from samples taken at discrete points that represent glimpses of the complete process. In this study, we present esiCancer as a cancer-evolution simulator. It uses a branching process, randomly applying events to a diploid oncogenome, altering probabilities of proliferation and death of the affected cells. Multiple events that occur over hundreds of generations may lead to a gradual change in cell fitness and the establishment of a fast-growing population. esiCancer provides a platform to study the impact of several factors on tumor evolution, including dominance, fitness, event rate, and interactions among genes as well as factors affecting the tumor microenvironment. The output of esiCancer can be used to reconstruct clonal composition and Kaplan-Meier–like survival curves of multiple evolutionary stories. esiCancer is an open-source, standalone software to model evolutionary aspects of cancer biology. Significance: This study provides a customizable and hands-on simulation tool to model the effect of diverse types of genomic alterations on the fate of tumor cells.
AB0899 Ankylosing spondylitis and pregnancy: data from the questionnaire survey-based pilot study
Authors: Z. Gandaloeva, O. Kritchevskaya, T. Dubinina, N. Kosheleva, S. Erdes
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To study parity and pregnancy outcomes, as well as causes for not getting pregnant in women with ankylosing spondylitis (AS). <h3>Methods</h3> 326 AS female patients were covered by questionnaire survey during the period from November 2016 until October 2017. Mean age of the participants was 32 [28:36] years, mean AS duration – 102 [48:168] months. The questionnaire items covered such issues as prior pregnancies, maternal and neonatal outcomes and potential reasons for not getting pregnant. <h3>Results</h3> 194 (59%) (mean age 34,1±5,4 y) females out of 326 surveyed had from 1 to 8 pregnancies, totally 396. Pregnancy outcomes are presented in the table 1. There were no pregnancies in 132 (41%) surveyed females (mean age 29,1±5,4 y). Reasons and causes for not getting pregnant in 132 AS females: - 48% cases – social, household/domestic and familial, including spouses' unwillingness to have children; - 44% – presence of AS (fear of teratogenic effect of pharmacotherapeutic agents – 18%, fear of AS inheriting by the baby – 3%, physician's forewarnings – 8%, a combination of abovementioned causes – 15%); - 8% – infertility. <h3>Conclusions</h3> Therefore, data from questionnaire survey of females with AS demonstrates that presence of AS does not increase the incidence of unfavourable maternal outcomes of pregnancies, or negatively affects anthropometric parameters of neonates. Of notice is the fact, that women's choice abortions become more rare after AS diagnosis is established. The rate of Caesarean sections is higher in AS patients. Fear of potentially harmful effects of the disease and it's therapy on the fetus and the baby underlies 30% of all not getting pregnant cases among AS female patients of child-bearing age. <h3>Disclosure of Interest</h3> None declared
Choosing the Best Chemotherapy Agent to Boost Immune Checkpoint Inhibition Activity
Authors: Marina Chiara Garassino, Valter Torri, Mario Paolo Colombo, Antonio Sica
Journal: Cancer Research (2018)

Abstract Despite the fact that reactivation of specific antitumor immunity through inhibition of immune checkpoints represents a formidable therapeutic weapon against cancer, many patients are poorly reactive to this treatment. To overcome this limitation, efforts are being made to characterize the immunostimulatory properties of chemotherapeutic agents and how they can be best combined with immune checkpoint inhibitors. The work by Wanderley and colleagues indicates that the TLR4 agonist taxol can restore the anticancer activity of tumor-associated macrophages and improve the clinical efficacy of immune checkpoint inhibitors. Cancer Res; 78(20); 5729–30. ©2018 AACR. See related article by Wanderley et al., p. 5891
Tissue Resident CCR2− and CCR2+ Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury
Authors: Geetika Bajpai, Andrea Bredemeyer, Wenjun Li, Konstantin Zaitsev, Andrew L. Koenig, Inessa Lokshina, Jayaram Mohan, Brooke Ivey, His-Min Hsiao, Carla Weinheimer, Attila Kovacs, Slava Epelman, Maxim Artyomov, Daniel Kreisel, Kory J. Lavine
Journal: Circulation Research (2019)

Recent advancements have brought to light the origins, complexity, and functions of tissue-resident macrophages. However, in the context of tissue injury or disease, large numbers of monocytes infiltrate the heart and are thought to contribute to adverse remodeling and heart failure pathogenesis. Little is understood about the diversity of monocytes and monocyte-derived macrophages recruited to the heart after myocardial injury, including the mechanisms that regulate monocyte recruitment and fate specification.We sought to test the hypothesis that distinct subsets of tissue-resident CCR2- (C-C chemokine receptor 2) and CCR2+ macrophages orchestrate monocyte recruitment and fate specification after myocardial injury.We reveal that in numerous mouse models of cardiomyocyte cell death (permanent myocardial infarction, reperfused myocardial infarction, and diphtheria toxin cardiomyocyte ablation), there is a shift in macrophage ontogeny whereby tissue-resident macrophages are predominately replaced by infiltrating monocytes and monocyte-derived macrophages. Using syngeneic cardiac transplantation to model ischemia-reperfusion injury and distinguish tissue-resident from recruited cell populations in combination with intravital 2-photon microscopy, we demonstrate that monocyte recruitment is differentially orchestrated by distinct subsets of tissue-resident cardiac macrophages. Tissue-resident CCR2+ macrophages promote monocyte recruitment through an MYD88 (myeloid differentiation primary response 88)-dependent mechanism that results in release of MCPs (monocyte chemoattractant proteins) and monocyte mobilization. In contrast, tissue-resident CCR2- macrophages inhibit monocyte recruitment. Using CD (cluster of differentiation) 169-DTR (diphtheria toxin receptor) and CCR2-DTR mice, we further show that selective depletion of either tissue-resident CCR2- or CCR2+ macrophages before myocardial infarction results in divergent effects on left ventricular function, myocardial remodeling, and monocyte recruitment. Finally, using single-cell RNA sequencing, we show that tissue-resident cardiac macrophages differentially instruct monocyte fate specification.Collectively, these observations establish the mechanistic basis by which monocytes are initially recruited to the injured heart and provide new insights into the heterogeneity of monocyte-derived macrophages.
Optical diagnosis expanded to small polyps: post-hoc analysis of diagnostic performance in a prospective multicenter study
Authors: Jasper Vleugels, Yark Hazewinkel, Marcel Dijkgraaf, Lianne Koens, Paul Fockens, Evelien Dekker
Journal: Endoscopy (2018)

Abstract Background: Optical diagnosis can replace histopathology of diminutive (1 – 5 mm) polyps if surveillance intervals based on optical diagnosis of polyps have ≥ 90 % agreement with intervals based on polyp histology and if the negative predictive value (NPV) for predicting neoplastic histology in the rectosigmoid is ≥ 90 %. This study aims to assess whether small (6 – 9 mm) polyps can be included in optical diagnosis strategies. Method: This is a post-hoc analysis of a prospective multicenter study in which 27 endoscopists, all performing endoscopies for the Dutch screening program, were trained in optical diagnosis. For 1 year, endoscopists recorded the predicted histology for all lesions detected using narrow-band imaging during 3144 consecutive colonoscopies after a positive fecal immunochemical test, along with confidence levels. Surveillance interval agreement and NPV were calculated for high confidence predictions for polyps of 1 – 9 mm and compared with histopathology. Surveillance interval agreement was calculated using the European Society of Gastrointestinal Endoscopy surveillance guideline. Results: Surveillance interval agreement was 95.4 % (confidence interval [CI] 94.2 % – 96.4 %), and NPV for predicting neoplastic histology in the rectosigmoid 90.0 % (CI 87.3 % – 92.2 %). The reduction in histology (45.9 % vs. 30.5 %) and the proportion of patients who could have received direct surveillance advice (15.6 % vs. 7.3 %) was higher when small polyps were included (P &lt; 0.001). T1 cancer was found in seven small polyps (0.33 %), five of which would have been discarded without histopathology. Conclusion: Including small polyps in the optical diagnosis strategy improves its efficacy while maintaining performance thresholds. However, there is a small risk of missing T1 cancers when small polyps are included in the optical diagnosis strategy.
Abstract 17125: Predictors of Residual Plaque Progression Despite Achieving Low Levels of LDL-C With the PCSK9 Inhibitor, Evolocumab
Authors: Satoshi Honda, Rishi Puri, Todd Anderson, John J Kastelein, Danielle M Brennan, Helina Kassahun, Ransi Somaratne, Scott M Wasserman, Steven E Nissen, Stephen J Nicholls
Journal: Circulation (2017)

Background: Addition of the PCSK9 inhibitor, evolocumab, to background statin therapy produced regression of coronary atherosclerosis in association with very low levels of LDL-C levels. However, 3...
Disconnect between Fibrotic Response and Right Ventricular Dysfunction
Authors: Slaven Crnkovic, Bakytbek Egemnazarov, Rachel Damico, Leigh M. Marsh, Bence M. Nagy, Philipp Douschan, Kwame Atsina, Todd M. Kolb, Stephen C. Mathai, Jody E. Hooper, Bahil Ghanim, Walter Klepetko, Friedrich Fruhwald, Dirk Lassner, Andrea Olschewski, Horst Olschewski, Paul M. Hassoun, Grazyna Kwapiszewska
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension.Objectives: To investigate the consequences of RV fibrosis modulation and the accompanying cellular changes on RV function.Methods: Expression of fibrotic markers was assessed in the RV of patients with pulmonary hypertension, the murine pulmonary artery banding, and rat monocrotaline and Sugen5416/hypoxia models. Invasive hemodynamic and echocardiographic assessment was performed on galectin-3 knockout or inhibitor-treated mice.Measurements and Main Results: Established fibrosis was characterized by marked expression of galectin-3 and an enhanced number of proliferating RV fibroblasts. Galectin-3 genetic and pharmacologic inhibition or antifibrotic treatment with pirfenidone significantly diminished RV fibrosis progression in the pulmonary artery banding model, without improving RV functional parameters. RV fibrotic regions were populated with mesenchymal cells coexpressing vimentin and PDGFRα (platelet-derived growth factor receptor-α), but generally lacked αSMA (α-smooth muscle actin) positivity. Serum levels of galectin-3 were increased in patients with idiopathic pulmonary arterial hypertension but did not correlate with cardiac function. No changes of galectin-3 expression were observed in the lungs.Conclusions: We identified extrapulmonary galectin-3 as an important mediator that drives RV fibrosis in pulmonary hypertension through the expansion of PDGFRα/vimentin-expressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.
Seamless Designs: Current Practice and Considerations for Early-Phase Drug Development in Oncology
Authors: Brian P Hobbs, Pedro C Barata, Yada Kanjanapan, Channing J Paller, Jane Perlmutter, Gregory R Pond, Tatiana M Prowell, Eric H Rubin, Lesley K Seymour, Nolan A Wages, Timothy A Yap, David Feltquate, Elizabeth Garrett-Mayer, William Grossman, David S Hong, S Percy Ivy, Lillian L Siu, Steven A Reeves, Gary L Rosner
Journal: JNCI Journal of the National Cancer Institute (2018)

Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns. A working group formed by the National Cancer Institute convened to consider and discuss opportunities and challenges for such trials as well as encourage responsible use of these designs. We reviewed all abstracts presented at American Society of Clinical Oncology annual meetings from 2010 to 2017 for FiH trials enrolling at least 100 patients. We identified 1786 early-phase trials enrolling 57 559 adult patients. Fifty-one of the trials (2.9%) investigated 50 investigational new drugs, were seamless, and accounted for 14.6% of the total patients. The seamless trials included a median of 3 (range = 1-13) expansion cohorts. The overall risk of clinically significant treatment-related adverse events (grade 3-4) was 49.1% (range = 0.0-100%), and seven studies reported at least one toxic death. Rapid expansion of FiH trials may lead to earlier drug approval and corresponding widespread patient access to active therapeutics. Nevertheless, seamless designs must adhere to established ethical, scientific, and statistical standards. Protocols should include prospectively planned analyses of efficacy in disease- or biomarker-defined cohorts of sufficient rigor to support accelerated approval.
Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes
Authors: Carmen Unzu, Evarist Planet, Nathalie Brandenberg, Floriane Fusil, Marco Cassano, Jimena Perez‐Vargas, Marc Friedli, François‐Loïc Cosset, Matthias P. Lutolf, Barbara E. Wildhaber, Didier Trono
Journal: Hepatology (2018)

The liver is an organ with strong regenerative capacity, yet primary hepatocytes have a low amplification potential in vitro, a major limitation for the cell‐based therapy of liver disorders and for ex vivo biological screens. Induced pluripotent stem cells (iPSCs) may help to circumvent this obstacle but often harbor genetic and epigenetic abnormalities, limiting their potential. Here, we describe the pharmacological induction of proliferative human hepatic progenitor cells (HPCs) through a cocktail of growth factors and small molecules mimicking the signaling events involved in liver regeneration. Human HPCs from healthy donors and pediatric patients proliferated vigorously while maintaining their genomic stability and could be redifferentiated in vitro into metabolically competent cells that supported the replication of hepatitis B and delta viruses. Redifferentiation efficiency was boosted by three‐dimensional culture. Finally, transcriptome analysis showed that HPCs were more closely related to mature hepatocytes than iPSC‐derived hepatocyte‐like cells were. Conclusion: HPC induction holds promise for a variety of applications such as ex vivo disease modeling, personalized drug testing or metabolic studies, and development of a bioartificial liver.
Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery
Authors: Hongyue Jin, Yang He, Pengfei Zhao, Ying Hu, Jin Tao, Jiang Chen, Yongzhuo Huang
Journal: Theranostics (2018)

Epithelial-mesenchymal transition (EMT) is closely associated with the development of drug resistance.Lipid metabolism plays an important role in EMT.This work was to study the cholesterol-lowering drug simvastatin for reversing EMT-associated resistance to chemotherapy via lipid metabolism.Methods: The combination of simvastatin and paclitaxel was used to overcome the EMT-associated drug resistance.For dual-action on both cancer cells and tumor-associated macrophages (TAM), the tumor microenvironment-activatable multifunctional liposomes were developed for drug codelivery.The liposomes were modified with a hairpin-structured, activatable cell-penetrating peptide that is specifically responsive to the tumor-associated protease legumain.Results: It was revealed simvastatin can disrupt lipid rafts (cholesterol-rich domains) and suppress integrin-β3 and focal adhesion formation, thus inhibiting FAK signaling pathway and re-sensitizing the drug-resistant cancer cells to paclitaxel.Furthermore, simvastatin was able to re-polarize tumor-associated macrophages (TAM), promoting M2-to-M1 phenotype switch via cholesterol-associated LXR/ABCA1 regulation.The repolarization increased TNF-α, but attenuated TGF-β, which, in turn, remodeled the tumor microenvironment and suppressed EMT.The liposomal formulation achieved enhanced treatment efficacy.Conclusion: This study provides a promising simvastatin-based nanomedicine strategy targeting cholesterol metabolism to reverse EMT and repolarize TAM to treat drug-resistant cancer.The elucidation of the molecular pathways (cholesterol/lipid raft/integrin β3/FAK and cholesterol-associated LXR/ABCA1 regulation) for anti-EMT and the new application of simvastatin should be of clinical significance.