tbuckley/cabot-search huggingface dataset:
Swimming against the stream: the fishbowl discussion method as an interactive tool for medical conferences: experiences from the 11th European Lupus Meeting
Authors: Johanna Mucke, Hans-Joachim Anders, Martin Aringer, Gamal Chehab, Rebecca Fischer-Betz, Falk Hiepe, Hanns-Martin Lorenz, Andreas Schwarting, Christof Specker, Reinhard E Voll, Matthias Schneider
Journal: Annals of the Rheumatic Diseases (2018)

Based on both historical development and functional advantages, such as in emergencies, hierarchical aspects dominate all levels of medicine. Doubtlessly, the high degree of respect for experts and their opinions may impede exchange between different levels of hierarchy. At medical conferences, discussions usually take place between experts, while patients, young doctors and students only listen and rarely actively participate.

For the 11th European Lupus Meeting in Dusseldorf in March 2018, we have tried the fishbowl method to increase participation at all levels. Fishbowl is an interactive and dynamic technique with a group of discussants sitting in an inner circle that contains an additional empty chair and surrounded by the audience in an outer circle.1 The empty chair can be occupied by any member of the outer circle at any time to join the discussion immediately. After the additional discussant of the auditorium has made his/her statement, he or she will leave the chair again to create an opportunity for another member of the audience (figure 1).



Figure 1 
The fishbowl method. A group …
Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice
Authors: Richard Gordon, Eduardo A. Albornoz, Daniel C. Christie, Monica R. Langley, Vinod Kumar, Susanna Mantovani, Avril A. B. Robertson, Mark S. Butler, Dominic B. Rowe, Luke A. O’Neill, Anumantha G. Kanthasamy, Kate Schroder, Matthew A. Cooper, Trent M. Woodruff
Journal: Science Translational Medicine (2018)

Parkinson's disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein-rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein-mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for PD.
Lenalidomide for second-line treatment of advanced hepatocellular cancer (HCC): A Brown University Oncology Group phase II study.
Authors: Howard Safran, Kevin Charpentier, Andreas Kaubisch, Gregory Dubel, Kimberly Perez, Katherine E. Faricy-Anderson, Thomas J. Miner, Joel Victor, Angela Marie Taber, Pamela Bakalarski, Patti Wingate, Kalyan C Mantripragada, Denise Luppe, Kayla Rosati, Joseph Espat, Debora Isdale, Yoko Eng, Diane Martel, David Berz, Jack Wands
Journal: Journal of Clinical Oncology (2012)

4098 Background: Lenalidomide inhibits fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and multiple tumor growth pathways. There is no standard of care for patients who progress after sorafenib. Therefore, we performed a phase II study to determine the activity of lenalidomide in second-line HCC therapy. Methods: Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible. Prior chemoembolization, RFA, or surgery were allowed. Eligibility criteria also included bilirubin &lt;4 mg/dL, AST and ALT &lt;5 times upper limit of normal, ECOG performance status 0-2, platelet count &gt;60,000/mm 3 , absolute neutrophil count &gt;1000/mm 3 , and creatinine &lt;2mg/dL. Patients were treated with lenalidomide 25mg orally days 1-21 of a 28 day cycle until disease progression or unacceptable toxicities. The planned original sample size was 25 patients but when early activity was demonstrated the study was expanded to 40 patients. Results: The study has completed accrual of 40 patients. The median age was 60.5 years (17-88 years). Nineteen patients were Child-Pugh A, 16 patients were B, and 5 patients were C. Twenty four patients had extrahepatic disease. Preliminary data is available on the first 37 patients. One patient had grade 4 neutropenia. Grade 3 toxicities included ANC (n=2), fatigue (n=4), rash (n=2), arthritis (n=1), diarrhea (n=1), dehydration (n=2). One patient developed variceal bleeding which precipitated encephalopathy and death. Of the 32 patients with elevated baseline AFP, nine (28%) had a &gt;50% reduction including one patient with a reduction in AFP from 56,900ng/ml to 5 ng/ml. Six of the first 37 patients (16%) had a radiographic partial response. Two patients achieved a complete response and have not progressed at 36 and 32 months. Conclusions: Lenalidomide can be administered to patients with advanced HCC and significant hepatic dysfunction. Promising, and in a small percentage of patients, dramatic and durable activity has been demonstrated. Investigations are underway to explore the mechanism of action of lenalidomide in HCC.
Engineered tendon-fibrocartilage-bone composite and bone marrow-derived mesenchymal stem cell sheet augmentation promotes rotator cuff healing in a non-weight-bearing canine model
Authors: Qian Liu, Yinxian Yu, Ramona L. Reisdorf, Jun Qi, Chun-Kuan Lu, Lawrence J. Berglund, Peter C. Amadio, Steven L. Moran, Scott P. Steinmann, Kai-Nan An, Anne Gingery, Chunfeng Zhao
Journal: Biomaterials (2018)
Abstract 17698: Will Access to Timely Primary Care Influence the Success of the American Heart Association’s 2020 Strategic Impact Goals? A Report From the 2012 National Health Interview Survey
Authors: Lakshmi Venkitachalam, Mary M Gerkovich, Jenifer E Allsworth, Janet N Ross, Mark Hoffman, Karen B Williams
Journal: Circulation (2014)

Background: The AHA’s 2020 Strategic Impact Goals are to improve cardiovascular (CV) health and reduce related deaths by 20% by 2020. Our objective is to examine the association between perceived barriers to timely primary care and CV metrics relevant to these goals for the US population. Methods: We examined data on key CV metrics (aspirin, blood pressure, cholesterol and smoking) from 34,525 respondents (estimated 234.9 million adults) to the 2012 National Health Interview Survey. Barriers to primary care included: unable to get through on telephone, unable to obtain appointment soon enough, long wait in the physician’s office, limited clinic hours, and lack of transportation. National estimates were obtained using appropriate sampling weights. Odd ratios for CV metrics for adults with ≥ 1 vs. no barriers were obtained from logistic regression models. Results: The majority of respondents were 18-64 years of age (82%), non-Hispanic white (66%) and currently employed (62%); 52% were female and 16% reported no insurance. An estimated 24.7 million (10.7%) adults reported ≥ 1 barriers in the past year. Of the 46.3 million (32%) who were advised to take aspirin, 17% reported no aspirin use. Of the 60 million (26%) with documented hypertension, 85% had high BP in the last year. Of the 62 million (26%) with high cholesterol, 70% reported high rates in the last year. Of the 42 million (18%) who were current smokers, only 46% attempted to quit in the last year. Compared to those without barriers, adults with ≥ 1 barriers were more likely to be advised to take aspirin but less likely to follow the recommendation, were more likely to report diagnoses of CV risk factors and attempts to quit smoking (table). Conclusion: Barriers to timely primary care are likely markers of CV burden and are associated with key metrics that impact CV health and mortality among adults. These patient-centered factors merit further exploration when designing strategies to achieve the AHA’s 2020 Strategic Impact goals.
Mass media campaigns are needed to counter misconceptions about back pain and promote higher value care
Authors: Mary O’Keeffe, Chris G Maher, Tasha R Stanton, Neil E O’Connell, Sameer Deshpande, Douglas P Gross, Kieran O’Sullivan
Journal: British Journal of Sports Medicine (2018)

Back pain is saddled by misconceptions that contribute to low-value care and poor outcomes. Many patients and clinicians mistakenly view the spine as fragile, believe that pain equates to damage and overemphasise the role and value of rest, imaging, medication and surgery.1 Guideline-based care will not be embraced if such misconceptions are not countered. Here, we provide four arguments for accessible, engaging and convincing education to the public and health professionals.

The ‘Back Pain: Don’t Take it Lying Down’ media campaign in Victoria, Australia, aired in the late 1990s and aimed to shift public attitudes about what to do when you experience back pain.2 Television (TV) advertisements were aired for the first 12 months and again for the final 3 months of the 3-year period. There were substantial improvements in workers’ compensation costs (15% reduction in the number of claims), as well as back pain beliefs, disability and medical management by the end of the campaign. Variants of this campaign have been repeated elsewhere, with observed improvements in pain beliefs.3 …
MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance
Authors: Jinping Lu, Yuejin Li, Yuanzhong Wu, Shan Zhou, Chaojun Duan, Zigang Dong, Tiebang Kang, Faqing Tang
Journal: Theranostics (2018)

Molecule interacting with CasL2 (MICAL2), a microtubule-associated monooxygenase, is highly expressed in various cancers and is involved in cancer pathogenesis, but the mechanisms underlying its regulation in carcinogenesis are unclear. In this study, we aim to clarify the mechanism by which MICAL2 participates in colorectal cancer (CRC) and identify novel markers for predicting prognosis of CRC patients. Methods: The value of MICAL2 in CRC prognosis was determined by immunohistochemical analysis of a CRC biopsy array. A short hairpin RNA target MICAL2 (shMICAL2) was designed to knock down MICAL2 expression and observe MICAL2's function on CRC cell growth. mRNA expression array was used to screen target molecules of MICAL2. HCT116 p53+/+ and HCT116 p53-/- cells were used to confirm whether MICAL2 exerts its oncogenic effect through p53. The in vivo effect of MICAL2 on CRC growth was assessed by subcutaneously injecting MICAL2-knockout CRC cells into the dorsal flank of each mouse. Immunofluorescence was used to observe the effect of MICAL2 on p53 cellular location. Reverse-phase nano ESI-LCMS analysis was used to investigate if MICAL2 mediates p53 oxidation. Results: MICAL2 was found to be highly expressed in CRC tissues, and its expression was associated with CRC carcinogenesis and poor patient outcome. MICAL2-knockdown decreased growth and colony formation of CRC cells, which was linked with cell cycle arrest and apoptosis. MICAL2 physically interacted with p53 and retained p53 in the cytoplasm. MICAL2 shortened the half-life of p53, and ectopic MICAL2 expression decreased p53 protein stability through ubiquitin degradation. MICAL2 was also found to oxidize p53 at methionine 40 and 160, which mediated p53 ubiquitin degradation. MICAL2-promoted CRC growth in vivo was confirmed in nude mice. Conclusion: MICAL2 binds to p53, retains p53 in the cytoplasm and oxidizes it at Met 40 and 160, promotes p53 ubiquitination, and decreases p53 function. MICAL2-reduced p53 promotes CRC development.
NHS staff get new measures to tackle violence in the workplace
Authors: Abi Rimmer
Journal: BMJ (2018)

NHS staff in England will be better protected from attacks and abuse under a new NHS violence reduction strategy, the health and social care secretary has announced.

Matt Hancock said that he had made it his “personal mission” to ensure that NHS staff feel safe and secure at work and that the new violence reduction strategy would be a “key strand” of that.

The Department of Health and Social Care said that the most recent NHS staff survey showed that over 15% of …
Chronic diarrhoea: the indications for lower GI endoscopy when functional bowel disease is suspected
Authors: John Ong, Carla Swift, Ian Allwood, Roger Norman, Yasseen Al-Naeeb, Arun Shankar
Journal: Gut (2018)

We read with interest the ‘Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, third Edition’ by Arasaradnam et al .1 Compared with the second edition, the new guidance provides more detailed and specific content which will undoubtedly aid the investigation of chronic diarrhoea both in primary and secondary care. However, we would like to clarify the authors’ position …
Brentuximab Vedotin with Chemotherapy in Adolescents and Young Adults (AYA) with Stage III or IV Hodgkin Lymphoma: A Subgroup Analysis from the Phase 3 Echelon-1 Study
Authors: Howland E. Crosswell, Ann S. LaCasce, Nancy L. Bartlett, David J. Straus, Kerry J Savage, Keenan Fenton, Gerald Engley, Hina Jolin, Rachael Liu, Pier Luigi Zinzani, Graham P. Collins, Andrew P. Grigg
Journal: Blood (2018)
Maternal-fetal transmission and adverse perinatal outcomes in pregnant women infected with Zika virus: prospective cohort study in French Guiana
Authors: Léo Pomar, Manon Vouga, Véronique Lambert, Céline Pomar, Najeh Hcini, Anne Jolivet, Guillaume Benoist, Dominique Rousset, Séverine Matheus, Gustavo Malinger, Alice Panchaud, Gabriel Carles, David Baud
Journal: BMJ (2018)

To estimate the rates of maternal-fetal transmission of Zika virus, adverse fetal/neonatal outcomes, and subsequent rates of asymptomatic/symptomatic congenital Zika virus infections up to the first week of life.Cohort study with prospective data collection and subsequent review of fetal/neonatal outcomes.Referral centre for prenatal diagnosis of the French Guiana Western Hospital.Pregnant women at any stage of pregnancy with a laboratory confirmed symptomatic or asymptomatic Zika virus infection during the epidemic period in western French Guiana. The cohort enrolled 300 participants and prospectively followed their 305 fetuses/newborns.Rate of maternal-fetal transmission of Zika virus (amniotic fluid, fetal and neonatal blood, urine, cerebrospinal fluid, and placentas); clinical, biological, and radiological outcomes (blindly reviewed); and adverse outcomes defined as moderate signs potentially related to congenital Zika syndrome (CZS), severe complications compatible with CZS, or fetal loss. Associations between a laboratory confirmed congenital Zika virus infection and adverse fetal/neonatal outcomes were evaluated.Maternal-fetal transmission was documented in 26% (76/291) of fetuses/newborns with complete data. Among the Zika virus positive fetuses/newborns, 45% (34/76) presented with no signs/complications at birth, 20% (15/76) with moderate signs potentially related to CZS, 21% (16/76) with severe complications compatible with CZS, and 14% (11/76) with fetal loss. Compared with the Zika virus positive fetuses/neonates, those that were identified as negative for Zika virus (215/291) were less likely to present with severe complications (5%; 10/215) or fetal loss (0.5%; 1/215; relative risk 6.9, 95% confidence interval 3.6 to 13.3). Association between a positive Zika virus test and any adverse fetal/neonatal outcome was also significant (relative risk 4.4, 2.9 to 6.6). The population attributable fraction estimates that a confirmed congenital Zika virus infection contributes to 47% of adverse outcomes and 61% of severe adverse outcomes observed.In cases of a known maternal Zika virus infection, approximately a quarter of fetuses will become congenitally infected, of which a third will have severe complications at birth or fetal loss. The burden of CZS might be lower than initially described in South America and may not differ from other congenital infections.
CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma
Authors: Ranjana Advani, Ian Flinn, Leslie Popplewell, Andres Forero, Nancy L. Bartlett, Nilanjan Ghosh, Justin Kline, Mark Roschewski, Ann LaCasce, Graham P. Collins, Thu Tran, Judith Lynn, James Y. Chen, Jens-Peter Volkmer, Balaji Agoram, Jie Huang, Ravindra Majeti, Irving L. Weissman, Chris H. Takimoto, Mark P. Chao, Sonali M. Smith
Journal: New England Journal of Medicine (2018)

The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically.
Microbiome–microglia connections via the gut–brain axis
Authors: Reem Abdel-Haq, Johannes C.M. Schlachetzki, Christopher K. Glass, Sarkis K. Mazmanian
Journal: The Journal of Experimental Medicine (2018)

Microglia, the resident immune cells in the brain, are essential for modulating neurogenesis, influencing synaptic remodeling, and regulating neuroinflammation by surveying the brain microenvironment. Microglial dysfunction has been implicated in the onset and progression of several neurodevelopmental and neurodegenerative diseases; however, the multitude of factors and signals influencing microglial activity have not been fully elucidated. Microglia not only respond to local signals within the brain but also receive input from the periphery, including the gastrointestinal (GI) tract. Recent preclinical findings suggest that the gut microbiome plays a pivotal role in regulating microglial maturation and function, and altered microbial community composition has been reported in neurological disorders with known microglial involvement in humans. Collectively, these findings suggest that bidirectional crosstalk between the gut and the brain may influence disease pathogenesis. Herein, we discuss recent studies showing a role for the gut microbiome in modulating microglial development and function in homeostatic and disease conditions and highlight possible future research to develop novel microbial treatments for disorders of the brain.
Patient Treatment Preferences for Relapsed/Refractory Multiple Myeloma: Are Patients Willing to Trade Off Efficacy for Tolerability?
Authors: Daniel Auclair, Carol Mansfield, Ajai Chari, Craig E. Cole, Mark A. Fiala, Jonathan L Kaufman, Gregory Orloff, David S Siegel, Jeffrey A Zonder, Brennan Mange, Jennifer Yesil, Mehul Dalal, Joseph Mikhael
Journal: Blood (2018)
A thorough analysis of the effect of surfactant/s on the solubility and pharmacokinetics of (S)-zaltoprofen
Authors: Cuong Viet Pham, Jong-Suep Baek, Jong-Hun Park, Sang-Hun Jung, Jong-Seong Kang, Cheong-Weon Cho
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Until now, there are no publications about the preformulation studies on (S)-zaltoprofen ((S)-ZPF). Hence, we first investigated the solubility of (S)-ZPF, screened solubilizers and performed the pharmacokinetic study of (S)-ZPF in the presence of the solubilizers. The measurement of the solubility of (S)-ZPF in 26 different solvents was carried out, including d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), 2-hydroxypropyl-β-cyclodextrin (HPCD), and mixtures of individual solvent. The plasma concentration of (S)-ZPF and the amount of (S)-ZPF retained in stomach were determined after oral (35.0 mg/kg) and intravenous (5.0 mg/kg) administration. The solubility of (S)-ZPF showed an increase of 484-fold in TPGS compared to its aqueous solubility. There was a significant increase of AUC0-24 h for pure (S)-ZPF in the TPGS group (813.59 ± 64.17 µg⋅h/ml) in comparison with AUC0-24 h in the HPCD group (595.57 ± 71.76 µg⋅h/ml) and water group (465.57 ± 90.89 µg⋅h/ml). In addition, the Tmax of (S)-ZPF in the TPGS group was 2 h, much faster than that in the HPCD or water groups (5.50 or 5.67 h, respectively). This suggested that TPGS played a significant role in the increase of solubility and bioavailability of (S)-ZPF.
Phase I evaluation of OXi4503, a vascular disrupting agent, in patients with advanced solid tumours
Authors: D. M. Patterson, P. Ross, B. Koetz, A. Saleem, M. Stratford, J. Stirling, A. Padhani, M. Asselin, P. Price, G. J. Rustin
Journal: Journal of Clinical Oncology (2007)

14146 Background: OXi4500, the active product of OXi4503, is a vascular disrupting agent acting at the colchicine binding site on the β subunit of tubulin. OXi4503 has greater anti-tumour activity in human cancer cell lines, causes a greater reduction in tumour blood flow than combretastatin A4P and has single agent activity in human tumour xenograft models. A phase I trial has commenced to examine the safety, tolerability and pharmacokinetics of OXi4503, with the primary objective being determination of MTD. FDG-PET scans were performed prior to and 28 days after the first infusion of OXi4503. Several other pharmacodynamic endpoints are also being assessed including DCE &amp; BOLD MRI, circulating endothelial progenitor cells and cytokeratin 18. Methods: OXi4503 is administered by 3 weekly iv infusions to a maximum of 6 cycles. Starting dose was 0.06mg/m 2 . 100% dose escalation in single patient cohorts proceeded to 3.84mg/m 2 , when cohorts were expanded to three patients and 30% escalation due to emergence of grade 2 drug-related toxicity (thrombocytopaenia). Results: 11 patients have so far received OXi4503 (5F 6M, median age 54, range 33–68); median cycles received was 2 (range 1–4). Common AE’s include hypertension, pyrexia and anaemia. PK profiles show a dose-dependent linear increase in peak plasma concentrations and AUC of both OXi4503 and OXi4500. OXi4500 concentrations at current dosing (5 mg/m 2 ) are close to that seen at the MTD in rats and dogs. DCE-MRI showed significant reduction in K trans in one patient (0.24mg/m 2 ). In the 2 patients studied to date, PET images showed a decrease in the standardised uptake value (SUV) in 3 out of 4 metastases for one subject (1.92mg/m 2 ) and in 5 out of 7 metastases for the other subject (3.84mg/m 2 ) demonstrating a reduction in FDG uptake following drug treatment. Of 10 patients assessed, 2 have stable disease and 8 disease progression. Conclusions: OXi4503 has been tolerated at doses up to 5mg/m 2 with no DLT observed, but changes in functional activity have been seen in 3 patients. MTD has not been reached and recruitment is ongoing. [Table: see text]