tbuckley/cabot-search huggingface dataset:
Succinylated whey protein isolate as a sustained-release excipient of puerarin derivative oral tablets: Preparation, optimization and pharmacokinetics
Authors: Rui Zhang, Yu Zhang, Yue Wu, Jun Liu, Tiantian Ye, Shujun Wang
Journal: Asian Journal of Pharmaceutical Sciences (2018)

This work was done to investigate succinylated commercial whey protein isolate (S-WPI) as an oral sustained-release delivery carrier for puerarin 5 (PR-5). The succinylation conditions were established for S-WPIs by optimization of single factor study and Box-Beehnken design. The effect of succinylation degree on S-WPIs solubility was evaluated. Physicochemical properties of S-WPIs dried by different three methods on their flow ability, particle size, morphology and in vitro release behavior were studied. After preparing PR-5 sustained release protein tablets with S-WPIs as the carrier by direct powder compression method, the drug release were studied in vitro and the oral pharmacokinetics and bioavailability was evaluated using in vivo dog model. It was observed that concentration of substrate has a significant effect on succinylation. Release behavior in vitro showed spry dried S-WPIs with 100% succinylation rate and 30% drug loading would be applied to the preparation of PR-5 sustained-release protein tablets based on the swelling mechanism (protein loss). Compared with PR-5 conventional tablet with oral administration, Tmax value of PR-5 sustained-release protein tablets was approximately 1.58 fold greater than those of the conventional tablets as further evidenced by the significantly prolonged MRT and T1/2. The findings demonstrated that spray-dried S-WPIs has potential as a promising functional excipient for the design of PR-5 oral sustained-release tablets which can fully improve sustained-release effect and oral bioavailability.
Abstract 14698: Does Autologous Stem Cell Transplantation Improve Cardiac Function in Patients With Systemic AL amyloidosis?
Authors: Shawn Pun, Heather J Landau, Anthony Yu, Shivani Verma, Christina Bello, Elton Mara, Hani Hassoun, Richard M Steingart, Jennifer Liu
Journal: Circulation (2015)

Introduction: Autologous stem cell transplantation (ASCT) is an effective therapy for prolonging survival in patients with systemic AL amyloidosis (ALA). Cardiac dysfunction due to amyloid involvement is a strong determinant of mortality. Whether ASCT can improve cardiac function is not well understood. Hypothesis: To assess changes in conventional echocardiographic parameters and global longitudinal strain (GLS) at baseline and 1 year post-ASCT and to determine predictors of 1 year mortality post-ASCT. Methods: Our study included fifty-one patients with newly diagnosed, biopsy-proven systemic AL amyloidosis undergoing ASCT. Cardiac biomarkers and echocardiographic measurements were obtained in all patients at baseline and at 1 year post-ASCT in 1 year survivors. Speckle-tracking global longitudinal strain (GLS) was retrospectively analyzed using vendor neutral software (TomTec Imaging Systems GmbH). Results: The mean age was 56.4 +/- 7.9 and 47.1% were female. Cardiac involvement was present in 68.6% based on consensus criteria. The mean baseline EF was 64.9 +/- 8.3. Complete hematologic response at 1 year was 55.8%. Mortality was 15.7% at 1 year. Long-term mortality was 27.5% (mean follow-up 4.0 +/- 2.6 years). Predictors of 1 year mortality were baseline GLS, troponin, BNP, septal thickness and E/A ratio. Age, gender and creatinine were not predictive. Among survivors at 1 year post-ASCT, there was no significant change in the biomarker or echocardiographic indices compared to baseline, regardless of hematologic response. Conclusions: Markers of cardiac dysfunction at baseline are predictive of 1 year mortality in patients with systemic ALA. Among those who survived to 1 year post-ASCT, there was no change in cardiac function assessed by echocardiography or biomarkers compared to baseline.
A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma
Authors: Patrick C. Gedeon, Teilo H. Schaller, Satish K. Chitneni, Bryan D. Choi, Chien-Tsun Kuan, Carter M. Suryadevara, David J. Snyder, Robert J. Schmittling, Scott E. Szafranski, Xiuyu Cui, Patrick N. Healy, James E. Herndon, Roger E. McLendon, Stephen T. Keir, Gary E. Archer, Elizabeth A. Reap, Luis Sanchez-Perez, Darell D. Bigner, John H. Sampson
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Conventional therapy for malignant glioma fails to specifically target tumor cells. In contrast, substantial evidence indicates that if appropriately redirected, T cells can precisely eradicate tumors. Here we report the rational development of a fully human bispecific antibody (hEGFRvIII-CD3 bi-scFv) that redirects human T cells to lyse malignant glioma expressing a tumor-specific mutation of the EGFR (EGFRvIII). Experimental Design: We generated a panel of bispecific single-chain variable fragments and optimized design through successive rounds of screening and refinement. We tested the ability of our lead construct to redirect naïve T cells and induce target cell–specific lysis. To test for efficacy, we evaluated tumor growth and survival in xenogeneic and syngeneic models of glioma. Tumor penetrance following intravenous drug administration was assessed in highly invasive, orthotopic glioma models. Results: A highly expressed bispecific antibody with specificity to CD3 and EGFRvIII was generated (hEGFRvIII-CD3 bi-scFv). Antibody-induced T-cell activation, secretion of proinflammatory cytokines, and proliferation was robust and occurred exclusively in the presence of target antigen. hEGFRvIII-CD3 bi-scFv was potent and target-specific, mediating significant lysis of multiple malignant glioma cell lines and patient-derived malignant glioma samples that heterogeneously express EGFRvIII. In both subcutaneous and orthotopic models, well-engrafted, patient-derived malignant glioma was effectively treated despite heterogeneity of EGFRvIII expression; intravenous hEGFRvIII-CD3 bi-scFv administration caused significant regression of tumor burden (P &amp;lt; 0.0001) and significantly extended survival (P &amp;lt; 0.0001). Similar efficacy was obtained in highly infiltrative, syngeneic glioma models, and intravenously administered hEGFRvIII-CD3 bi-scFv localized to these orthotopic tumors. Conclusions: We have developed a clinically translatable bispecific antibody that redirects human T cells to safely and effectively treat malignant glioma. On the basis of these results, we have developed a clinical study of hEGFRvIII-CD3 bi-scFv for patients with EGFRvIII-positive malignant glioma. Clin Cancer Res; 24(15); 3611–31. ©2018 AACR.
David Oliver: Learning from deaths in hospital
Authors: David Oliver
Journal: BMJ (2018)

The secretary of state for health and social care, Jeremy Hunt, has spoken of “750 avoidable deaths in hospitals in England every month”1—the equivalent of a passenger plane falling out of the sky each week. The source of this figure was a methodologically rigorous, peer reviewed study by a respected group, published in The BMJ in 2015.2

But the researchers who conducted the study had expressed caution about the limitations of their methods and baseline data, saying that their metric was no reliable indicator of the quality of care. They had reviewed 100 random sets of case notes from 34 hospitals, estimating that 3.6% of deaths had at least a 50% chance of being …
A universal offer of blood borne virus testing substantially increases diagnosis and treatment of hepatitis C in prisons
Authors: S. Morey, A. Hamoodi, M. Valappil, D. Jones, C. Thompson, J. Dhuny, M. Hewett, E. Buchanan, C. Miller, T. Young, E. Hunter, S. Mcpherson
Journal: Journal of Hepatology (2018)
Golimumab Tapering Strategy Based on Serum Drug Levels in Patients With Spondyloarthritis
Authors: Cristina Redondo, Ana Martínez‐Feito, Chamaida Plasencia‐Rodríguez, Victoria Navarro‐Compán, Laura Nuño‐Nuño, Diana Peiteado, Alejandro Villalba, Andrea Jochems, Dora Pascual‐Salcedo, Alejandro Balsa
Journal: Arthritis & Rheumatology (2018)
Dub-second induction of a4 integrin clustering by immobilized chemokines stimulates luekocyte tethering and rolling on endothelial VCAM-1 under flow conditions
Authors: V. Grabovsky, S. Feigelson, C.Y. Chen, D.A. Bleijs, A. Peled, G. Cinamon, F. Baleux, F. Aenzana-Seisdedos, T. Lapidot, Y. van Kooyk, R.R. Lobb, R. Alon
Journal: The Journal of Experimental Medicine (2000)
Establishment of an ex vivo model of human fibrotic liver slices culture: characterization of intrahepatic immune cells and TH17 cytokines
Authors: Daria Kartasheva-Ebertz, Jesintha Gaston, Pierre-Philippe Massault, Sébastien Gaujoux, Olivier Scatton, Jean-Christophe Vaillant, Vladimir A. Morozov, Stanislas Pol, Sylvie Lagaye
Journal: Journal of Hepatology (2018)
YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC
Authors: Wonyoung Choi, Jeongsik Kim, Jaeoh Park, Da-Hye Lee, Daehee Hwang, Jeong-Hwan Kim, Hassan Ashktorab, Duane Smoot, Seon-Young Kim, Chan Choi, Gou Young Koh, Dae-Sik Lim
Journal: Cancer Research (2018)

Abstract YAP and TAZ play oncogenic roles in various organs, but the role of YAP/TAZ in gastric cancer remains unclear. Here, we show that YAP/TAZ activation initiates gastric tumorigenesis in vivo and verify its significance in human gastric cancer. In mice, YAP/TAZ activation in the pyloric stem cell led to step-wise tumorigenesis. RNA sequencing identified MYC as a decisive target of YAP, which controls MYC at transcriptional and posttranscriptional levels. These mechanisms tightly regulated MYC in homeostatic conditions, but YAP activation altered this balance by impeding miRNA processing, causing a shift towards MYC upregulation. Pharmacologic inhibition of MYC suppressed YAP-dependent phenotypes in vitro and in vivo, verifying its functional role as a key mediator. Human gastric cancer samples also displayed a significant correlation between YAP and MYC. We reanalyzed human transcriptome data to verify enrichment of YAP signatures in a subpopulation of gastric cancers and found that our model closely reflected the molecular pattern of patients with high YAP activity. Overall, these results provide genetic evidence of YAP/TAZ as oncogenic initiators and drivers for gastric tumors with MYC as the key downstream mediator. These findings are also evident in human gastric cancer, emphasizing the significance of YAP/TAZ signaling in gastric carcinogenesis. Significance: YAP/TAZ activation initiates gastric carcinogenesis with MYC as the key downstream mediator. Cancer Res; 78(12); 3306–20. ©2018 AACR.
Genomic Status of<i>MET</i>Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors
Authors: Jacqueline D. Peacock, Matthew G. Pridgeon, Elizabeth A. Tovar, Curt J. Essenburg, Megan Bowman, Zachary Madaj, Julie Koeman, Elissa A. Boguslawski, Jamie Grit, Rebecca D. Dodd, Vadim Khachaturov, Diana M. Cardona, Mark Chen, David G. Kirsch, Flavio Maina, Rosanna Dono, Mary E. Winn, Carrie R. Graveel, Matthew R. Steensma
Journal: Cancer Research (2018)

Malignant peripheral nerve sheath tumors (MPNST) are highly resistant sarcomas that occur in up to 13% of individuals with neurofibromatosis type I (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/ko;lox-stop-loxMETtg/+;Plp-creERTtg/+ ; referred to as NF1-MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1ko/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1ko/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs.Significance: Longitudinal genomic analysis reveals a positive selection for MET and HGF copy number gain early in malignant peripheral nerve sheath tumor progression. Cancer Res; 78(13); 3672-87. ©2018 AACR.
The Continuing Challenge of Metallo-β-Lactamase Inhibition: Mechanism Matters
Authors: Lin-Cheng Ju, Zishuo Cheng, Walter Fast, Robert A. Bonomo, Michael W. Crowder
Journal: Trends in Pharmacological Sciences (2018)

Clinical resistance to β-lactam-containing antibiotics due to bacterial expression of metallo-β-lactamases (MBLs) is becoming more prevalent and problematic. MBL inhibitors have been reported, but the mechanism of inhibition is unknown for many of these inhibitors. Mechanism of inhibition impacts the reversibility, selectivity, and interpretation of structure–activity relationships and should be strongly considered in inhibitor development. Biochemical and structural studies can be used to demonstrate the mechanism of inhibition and this information can be used to guide lead optimization. Metallo-β-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all β-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure–activity relationship interpretation. This review surveys the mechanisms of MBL inhibitors and describes methods that determine the mechanism of inhibition to guide development of future therapeutics. Metallo-β-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all β-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure–activity relationship interpretation. This review surveys the mechanisms of MBL inhibitors and describes methods that determine the mechanism of inhibition to guide development of future therapeutics. enzyme groups that participate in the nucleophilic attack on substrate. In serine β-lactamases, a serine hydroxide (on the side chain) is the catalytic nucleophile that attacks the β-lactam carbonyl. In MBLs, the bridging hydroxide is thought to be the catalytic nucleophile that attacks the β-lactam carbonyl. a region of the enzyme that is not the active site. Often exosites are called allosteric sites. the concentration of an inhibitor that causes 50% inhibition of the enzyme. complex of three distinct entities. In this review, ternary complex refers to a complex of MBL, Zn(II), and inhibitor.
Early endovenous ablation achieves faster healing of venous leg ulcers than compression therapy, study finds
Authors: Susan Mayor
Journal: BMJ (2018)

Early use of endovenous ablation to close varicose veins in patients with leg ulcers achieves significantly faster healing and more time free from ulcers than treatment with compression therapy alone followed by deferred endovascular ablation if required, a randomised trial has shown.1

“With this trial, we have shown that by intervening early you improve the healing of the leg ulcer, and help a patient recover quicker,” said lead author Alun Davies, from Imperial College London, UK. He added, “We recommend that patients are referred to a vascular clinic upon diagnosis with a venous ulcer, to see …
Endoscopic treatment of a symptomatic duodenal duplication cyst
Authors: Nikkie Schils, Vincent Vandecaveye, Lode Van Overbeke, Wim Laleman
Journal: Endoscopy (2018)

We present the case of a 36-year-old man without previous medical history who was admitted because of protracted colic-like abdominal pain in the right upper quadrant. His symptoms had started a few days previously, but had persisted and were accompanied by vomiting. In his history, the patient mentioned having experienced several previous attacks of similar pain over a period of several years. Clinical examination was unremarkable. A work-up, first by means of computed tomography ([Fig. 1]) and later by magnetic resonance imaging ([Fig. 2]), showed a bulging mass-like cystic lesion at the level of the papilla with retention of what appeared to be an intralesional stone. The biliopancreatic duct system seemed intact.
PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness
Authors: Jianfeng Shen, Wei Zhao, Zhenlin Ju, Lulu Wang, Yang Peng, Marilyne Labrie, Timothy A. Yap, Gordon B. Mills, Guang Peng
Journal: Cancer Research (2018)

Abstract PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS–STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. Significance: This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.
Breast Cancer With a Poor Prognosis Diagnosed After Screening Mammography With Negative Results
Authors: Anne Marie McCarthy, William E. Barlow, Emily F. Conant, Jennifer S. Haas, Christopher I. Li, Brian L. Sprague, Katrina Armstrong
Journal: JAMA Oncology (2018)

This study of data from the PROSPR consortium assesses the incidence of and risk factors associated with breast cancer with a poor prognosis after undergoing screening mammography with negative results.
Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study
Authors: Cyril Pottier, Xiaolai Zhou, Ralph B Perkerson, Matt Baker, Gregory D Jenkins, Daniel J Serie, Roberta Ghidoni, Luisa Benussi, Giuliano Binetti, Adolfo López de Munain, Miren Zulaica, Fermin Moreno, Isabelle Le Ber, Florence Pasquier, Didier Hannequin, Raquel Sánchez-Valle, Anna Antonell, Albert Lladó, Tammee M Parsons, NiCole A Finch, Elizabeth C Finger, Carol F Lippa, Edward D Huey, Manuela Neumann, Peter Heutink, Matthis Synofzik, Carlo Wilke, Robert A Rissman, Jaroslaw Slawek, Emilia Sitek, Peter Johannsen, Jørgen E Nielsen, Yingxue Ren, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Elizabeth Christopher, Melissa E Murray, Kevin F Bieniek, Bret M Evers, Camilla Ferrari, Sara Rollinson, Anna Richardson, Elio Scarpini, Giorgio G Fumagalli, Alessandro Padovani, John Hardy, Parastoo Momeni, Raffaele Ferrari, Francesca Frangipane, Raffaele Maletta, Maria Anfossi, Maura Gallo, Leonard Petrucelli, EunRan Suh, Oscar L Lopez, Tsz H Wong, Jeroen G J van Rooij, Harro Seelaar, Simon Mead, Richard J Caselli, Eric M Reiman, Marwan Noel Sabbagh, Mads Kjolby, Anders Nykjaer, Anna M Karydas, Adam L Boxer, Lea T Grinberg, Jordan Grafman, Salvatore Spina, Adrian Oblak, M-Marsel Mesulam, Sandra Weintraub, Changiz Geula, John R Hodges, Olivier Piguet, William S Brooks, David J Irwin, John Q Trojanowski, Edward B Lee, Keith A Josephs, Joseph E Parisi, Nilüfer Ertekin-Taner, David S Knopman, Benedetta Nacmias, Irene Piaceri, Silvia Bagnoli, Sandro Sorbi, Marla Gearing, Jonathan Glass, Thomas G Beach, Sandra E Black, Mario Masellis, Ekaterina Rogaeva, Jean-Paul Vonsattel, Lawrence S Honig, Julia Kofler, Amalia C Bruni, Julie Snowden, David Mann, Stuart Pickering-Brown, Janine Diehl-Schmid, Juliane Winkelmann, Daniela Galimberti, Caroline Graff, Linn Öijerstedt, Claire Troakes, Safa Al-Sarraj, Carlos Cruchaga, Nigel J Cairns, Jonathan D Rohrer, Glenda M Halliday, John B Kwok, John C van Swieten, Charles L White, Bernardino Ghetti, Jill R Murell, Ian R A Mackenzie, Ging-Yuek R Hsiung, Barbara Borroni, Giacomina Rossi, Fabrizio Tagliavini, Zbigniew K Wszolek, Ronald C Petersen, Eileen H Bigio, Murray Grossman, Vivianna M Van Deerlin, William W Seeley, Bruce L Miller, Neill R Graff-Radford, Bradley F Boeve, Dennis W Dickson, Joanna M Biernacka, Rosa Rademakers
Journal: The Lancet Neurology (2018)
Oral health in China: from vision to action
Authors: Xuedong Zhou, Xin Xu, Jiyao Li, Deyu Hu, Tao Hu, Wei Yin, Yujiang Fan, Xingdong Zhang
Journal: International Journal of Oral Science (2018)

Abstract Chinese president Xi Jinping made clear at the National Health and Wellness Conference that health is the prerequisite for people’s all-around development and a precondition for the sustainable development of China. Oral health is an indispensable component of overall health in humans. However, the long neglect of oral health in overall health agendas has made oral diseases an increasing concern. With this perspective, we described the global challenges of oral diseases, with an emphasis on the challenges faced by China. We also described and analyzed the recently released health policies of the Chinese government, which aim to guide mid-term and long-term oral health promotion in China. More importantly, we called for specific actions to fulfill the larger goal of oral health for the nation. The implementation of primordial prevention efforts against oral diseases, the integration of oral health into the promotion of overall health, and the management of oral diseases in conjunction with other chronic non-communicable diseases with shared risk factors were highly recommended. In addition, we suggested the reform of standard clinical residency training, the development of domestic manufacturing of dental equipment and materials, the revitalization traditional Chinese medicine for the prevention and treatment of oral diseases, and integration of oral health promotion into the Belt and Road Initiative. We look forward to seeing a joint effort from all aspects of the society to fulfill the goal of Healthy China 2030 and ensure the oral health of the nation.