tbuckley/cabot-search huggingface dataset:
Inhibition of the angiopoietin/Tie2 axis induces immunogenic modulation, which sensitizes human tumor cells to immune attack
Authors: Italia Grenga, Anna R. Kwilas, Renee N. Donahue, Benedetto Farsaci, James W. Hodge
Journal: Journal for ImmunoTherapy of Cancer (2015)

The angiopoietin/Tie2 pathway is an attractive target for cancer therapy due to its well-known role in regulating angiogenesis. Trebananib, a recombinant peptide-Fc fusion protein, or peptibody, that binds to angiopoietin-1 (Ang1) and Ang2 to block their interaction with the Tie2 receptor, is under active clinical investigation. We investigated whether suppressing the angiopoietin/Tie2 pathway, using the preclinical version of Trebananib (mL4-3 and L1-7(N)), could increase the sensitivity of human tumor cells to immune-mediated lysis through immunogenic modulation, which would make Trebananib a promising candidate for combination with immunotherapy.We assessed human carcinoma cells for expression and activation of Ang1 and Ang2 and their receptor tyrosine kinase Tie2. In vitro, we exposed tumor cell lines expressing Tie2 to the peptibodies mL4-3 and L1-7(N), which inhibit the binding of Ang1 and Ang2 to Tie2, and assessed the cells for changes in viability, proliferation, surface phenotype, and sensitivity to attack by antigen-specific cytotoxic T lymphocytes (CTLs).Suppression of the angiopoietin/Tie2 pathway using mL4-3 and L1-7(N) had no effect on the proliferation or viability of tumor cells. However, these inhibitors markedly altered tumor cell phenotype, rendering tumor cells significantly more sensitive to antigen-specific CTL killing. ICAM-1 was shown to be mechanistically involved in these inhibitors' ability to sensitize tumor cells to immune-mediated attack by functional blocking studies.Our findings provide a rationale for the combination of agents targeting the angiopoietin/Tie2 pathway with cancer immunotherapies.
Enumerating β-Cells in Whole Human Islets: Sex Differences and Associations With Clinical Outcomes After Islet Transplantation
Authors: Enza Marchese, Caitlin Rodeghier, Rebecca S. Monson, Benjamin McCracken, Tingqi Shi, Wesley Schrock, Joan Martellotto, Jose Oberholzer, Kirstie K. Danielson
Journal: Diabetes Care (2015)

Islet transplantation is an experimental therapy for type 1 diabetes. Though it is increasingly successful, limitations include unpredictable declines in islet graft function (1). There is still inadequate knowledge of specific human islet characteristics that predispose to successful and durable islet graft function and what types of donors are more likely to have islets with these beneficial traits. The relationship between the composition of dissociated human islets (as opposed to whole islets) and transplant outcomes has been studied (2), with a positive association between recipients’ acute insulin response to glucose (AIRg) posttransplant and number of pancreatic ductal cells in the preparation (a positive association with number of β-cells approached significance). However, as dissociation inherently damages islets, β-cells enumerated after dissociation may no longer reflect the number of β-cells within whole islets ultimately transplanted. Using an epidemiological approach, we therefore investigated 1 ) the independent association of the β-cell composition of transplanted whole human islets with recipient outcomes and 2 ) the donor …
Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models
Authors: David M. Francis, Shyhmin Huang, Eric A. Armstrong, Lauryn R. Werner, Craig Hullett, Chunrong Li, Zachary S. Morris, Adam D. Swick, Michael Kragh, Johan Lantto, Randall J. Kimple, Paul M. Harari
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Aberrant regulation of the EGF receptor family (EGFR, HER2, HER3, HER4) contributes to tumorigenesis and metastasis in epithelial cancers. Pan-HER represents a novel molecular targeted therapeutic composed of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3. Experimental Design: In the current study, we examine the capacity of Pan-HER to augment radiation response across a series of human lung and head and neck cancers, including EGFR inhibitor–resistant cell lines and xenografts. Results: Pan-HER demonstrates superior antiproliferative and radiosensitizing impact when compared with cetuximab. The mechanisms underlying these effects appear to involve attenuation of DNA damage repair, enhancement of programmed cell death, cell-cycle redistribution, and induction of cellular senescence. Combined treatment of Pan-HER with single or fractionated radiation in human tumor xenografts reveals a potent antitumor and regrowth delay impact compared with Pan-HER or radiation treatment alone. Conclusions: These data highlight the capacity of Pan-HER to augment radiation response in lung and head and neck cancer models and support investigation of Pan-HER combined with radiation as a promising clinical therapeutic strategy. Clin Cancer Res; 22(3); 633–43. ©2015 AACR.
Identification of an anti-inflammatory protein from<i>Faecalibacterium prausnitzii</i>, a commensal bacterium deficient in Crohn’s disease
Authors: E Quévrain, M A Maubert, C Michon, F Chain, R Marquant, J Tailhades, S Miquel, L Carlier, L G Bermúdez-Humarán, B Pigneur, O Lequin, P Kharrat, G Thomas, D Rainteau, C Aubry, N Breyner, C Afonso, S Lavielle, J-P Grill, G Chassaing, J M Chatel, G Trugnan, R Xavier, P Langella, H Sokol, P Seksik
Journal: Gut (2015)

Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined.Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Anti-inflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice.The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-κB pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice.A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.
Systematic review hacks for the sports and exercise clinician: five essential methodological elements
Authors: Clare L Ardern
Journal: British Journal of Sports Medicine (2015)

Karen is a keen middle-aged tennis player who presents at your busy practice after her family physician told her she has chronic lateral elbow tendinopathy. Karen is anxious to be back playing at her best for a big regional tournament in 6-weeks time. She has consulted with Dr Google and read about a promising treatment called ‘PRP’ (platelet-rich plasma). She asks you what you know about this treatment and whether you think it could help her get back on court.

You recall an abstract you scanned some months ago; patients who received PRP injections for chronic lateral epicondylitis ( sic ) had less pain at 6 months than those who received an active control treatment (needling under local anaesthetic).1 Promising. However, you know that evidence from more than one study is needed to help you and Karen make an optimal treatment decision. Searching PubMed that evening, you find a randomised, double-blind and placebo-controlled study. Injections of PRP were no better than injections of saline for reducing pain in patients with lateral elbow tendinopathy.2 So what now? How do you resolve this conflict? Are these the only two relevant articles or is there additional evidence either for or against PRP?

PubMed identifies 87 articles reporting on PRP and lateral elbow tendinopathy. Nightmare. However, hooray! There is a recent systematic review!3 Owing to the structured methodological approach to collating all available evidence that fits a specific and predefined research question, systematic reviews are an attractive and practical way for busy clinicians to keep abreast of new developments. However, not all systematic reviews are equal; a systematic review is only as good as the quality of the studies included in it—if those included studies are open to a large amount of bias, the systematic review might be at risk too.4 

This editorial …
Effects of visual adaptation on perception of and satisfaction with own body size: two randomised studies
Authors: Helen Bould, Rebecca Carnegie, Heather Allward, Emily Bacon, Emily Lambe, Megan Sapseid, Katherine Button, Glyn Lewis, Andy Skinner, Matthew Broome, Rebecca Park, Catherine Harmer, Ian Penton-Voak, Marcus Munafò
Journal: The Lancet (2015)
Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study
Authors: Julian H Elliott, James H McMahon, Christina C Chang, Sulggi A Lee, Wendy Hartogensis, Namandje Bumpus, Rada Savic, Janine Roney, Rebecca Hoh, Ajantha Solomon, Michael Piatak, Robert J Gorelick, Jeff Lifson, Peter Bacchetti, Steven G Deeks, Sharon R Lewin
Journal: The Lancet HIV (2015)
Unconscious bias harms patients and staff
Authors: Narinder Kapur
Journal: BMJ (2015)

<h3>ABSTRACT</h3> <h3>Background:</h3> Community health workers (CHWs) are increasingly deployed to support mothers’ adoption of healthy home practices in low- and middle-income countries. However, little is known regarding how best to train them for the capabilities and cultural competencies needed to support maternal health behavior change. We tested a CHW training method, Sharing Histories (SH), in which CHWs recount their own childbearing and childrearing experiences on which to build new learning. <h3>Methods:</h3> We conducted an embedded cluster-randomized trial in rural Peru in 18 matched clusters. Each cluster was a primary health facility catchment area. Government health staff trained female CHWs using SH (experimental clusters) or standard training methods (control clusters). All other training and system-strengthening interventions were equal between study arms. All CHWs conducted home visits with pregnant women and children aged 0–23 months to teach, monitor health practices and danger signs, and refer. The primary outcome was height-for-age (HAZ)&lt;−2 Z-scores (stunting) in children aged 0–23 months. Household surveys were conducted at baseline (606 cases) and 4-year follow-up (606 cases). <h3>Results:</h3> Maternal and child characteristics were similar in both study arms at baseline and follow-up. Difference-in-differences analysis showed mean HAZ changes were not significantly different in experimental versus control clusters from baseline to endline (<i>P</i>=.469). However, in the subgroup of literate mothers, mean HAZ improved by 1.03 on the Z-score scale in experimental clusters compared to control clusters from baseline to endline (<i>P</i>=.059). Using generalized estimating equations, we demonstrated that stunting in children of mothers who were literate was significantly reduced (Beta=0.77; 95% confidence interval=0.23, 1.31; <i>P</i>&lt;.01), adjusting for covariates. <h3>Conclusion:</h3> Compared with standard training methods, SH may have improved the effectiveness of CHWs as change agents among literate mothers to reduce child stunting. Stunting experienced by the children of illiterate mothers may have involved unaddressed determinants of stunting.
Association between day of delivery and obstetric outcomes: observational study
Authors: William L Palmer, A Bottle, P Aylin
Journal: BMJ (2015)

<b>Study question</b> What is the association between day of delivery and measures of quality and safety of maternity services, particularly comparing weekend with weekday performance? <b>Methods</b> This observational study examined outcomes for maternal and neonatal records (1 332 835 deliveries and 1 349 599 births between 1 April 2010 and 31 March 2012) within the nationwide administrative dataset for English National Health Service hospitals by day of the week. Groups were defined by day of admission (for maternal indicators) or delivery (for neonatal indicators) rather than by day of complication. Logistic regression was used to adjust for case mix factors including gestational age, birth weight, and maternal age. Staffing factors were also investigated using multilevel models to evaluate the association between outcomes and level of consultant presence. The primary outcomes were perinatal mortality and—for both neonate and mother—infections, emergency readmissions, and injuries. <b>Study answer and limitations</b> Performance across four of the seven measures was significantly worse for women admitted, and babies born, at weekends. In particular, the perinatal mortality rate was 7.3 per 1000 babies delivered at weekends, 0.9 per 1000 higher than for weekdays (adjusted odds ratio 1.07, 95% confidence interval 1.02 to 1.13). No consistent association between outcomes and staffing was identified, although trusts that complied with recommended levels of consultant presence had a perineal tear rate of 3.0% compared with 3.3% for non-compliant services (adjusted odds ratio 1.21, 1.00 to 1.45). Limitations of the analysis include the method of categorising performance temporally, which was mitigated by using a midweek reference day (Tuesday). Further research is needed to investigate possible bias from unmeasured confounders and explore the nature of the causal relationship. <b>What this study adds</b> This study provides an evaluation of the "weekend effect" in obstetric care, covering a range of outcomes. The results would suggest approximately 770 perinatal deaths and 470 maternal infections per year above what might be expected if performance was consistent across women admitted, and babies born, on different days of the week. <b>Funding, competing interests, data sharing</b> The research was partially funded by Dr Foster Intelligence and the National Institute for Health Research (NIHR) Imperial Patient Safety Translational Research Centre in partnership with the Health Protection Research Unit (HPRU) in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London. WLP was supported by the National Audit Office.
Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma.
Authors: E C Holmes, M Gail
Journal: Journal of Clinical Oncology (1986)

The Lung Cancer Study Group randomized 141 patients with resected stage II and III adenocarcinoma and large-cell undifferentiated carcinoma to receive postoperative Cytoxan (Bristol-Meyers, Syracuse, NY), Adriamycin (Adria Laboratories, Columbus, Ohio), and cisplatin (CAP) chemotherapy or bacillus Calmette-Guerin (BCG) and levamisole immunotherapy. Careful intraoperative staging was performed on all patients. Before randomization, patients were stratified by stage, weight loss, cardiac arrhythmia, and institution. Prognostic variables such as stage, age, weight loss, and nodal involvement were equally distributed between the two groups. Disease-free survival was significantly prolonged in the group receiving chemotherapy. There was no evidence of a deleterious effect of the immunotherapy. This study indicates that postoperative CAP chemotherapy is effective in prolonging disease-free survival in these patients.
In Vitro Analysis of Murine B-Cell Development
Authors: Cheryl Whitlock, Kathleen Denis, Debra Robertson, Owen Witte
Journal: Annual Review of Immunology (1985)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Ageing and the telomere connection: An intimate relationship with inflammation
Authors: Jingwen Zhang, Grishma Rane, Xiaoyun Dai, Muthu K. Shanmugam, Frank Arfuso, Ramar Perumal Samy, Mitchell Kim Peng Lai, Dennis Kappei, Alan Prem Kumar, Gautam Sethi
Journal: Ageing Research Reviews (2015)
Widen criteria for vaccination
Authors: S Reilly, A G Prentice, J A Copplestone, M D Hamon, J Sarangi
Journal: BMJ (1994)

EDITOR, - In common with other districts we are seeking to increase awareness among our general practitioners, hospital doctors, and local residents of sepsis after splenectomy and the need for adequate prophylaxis.*RF 1-3* Each year Plymouth Public Health Laboratory (which serves a population of about 425 000 in south west Devon and east Cornwall) diagnoses 40 cases of pneumococcal septicaemia. To the end of November there were 54 …
Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin, and total-body irradiation.
Authors: G B McCowage, M R Vowels, P J Shaw, L Lockwood, H Mameghan
Journal: Journal of Clinical Oncology (1995)

Disseminated neuroblastoma after infancy has a dismal prognosis; long-term survival with conventional therapy occurs in approximately 10% of cases.Between 1985 and 1992, we followed a strategy aimed to achieve remission with an induction combination of intensive chemotherapy, primary resection, and tumor-bed radiotherapy (TBRT). Patients who achieved remission proceeded to myeloablative chemoradiotherapy and unpurged autologous bone marrow transplant (ABMT). Twenty-eight patients older than 1 year presented with stage IV disease during the study period; six died of progressive disease and three died of complications of therapy. Nineteen patients achieved remission, two of whom did not receive ABMT. Seventeen patients proceeded to ABMT. Conditioning was with teniposide 130 mg/m2, doxorubicin 30 mg/m2, melphalan 120 mg/m2, cisplatin 80 mg/m2, and total-body irradiation 12 Gy in six fractions (modified VAMP-TBI).Principal nonhematologic toxicities were mucositis and diarrhea. There were no ABMT-related deaths. Two patients relapsed at 8 and 26 months post-ABMT, respectively. Fifteen patients remain in complete remission (CR) at 24 to 102 months (median, 71) from ABMT and 30 to 114 months (median, 78) from diagnosis. Survival rates of all 28 patients are 61% and 50% at 2 and 5 years, respectively, and the disease-free survival (DFS) of the ABMT group is 94% and 87% at 2 and 5 years, respectively.Modified VAMP-TBI appears to be an effective conditioning regimen, with 15 of 17 patients remaining disease-free, with no toxic deaths. This result compares favorably with that of other groups. Larger numbers of patients need to be treated to confirm the efficacy of this therapy.
Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model
Authors: K. A. Staines, K. Madi, S. M. Mirczuk, S. Parker, A. Burleigh, B. Poulet, M. Hopkinson, A. J. Bodey, R. C. Fowkes, C. Farquharson, P. D. Lee, A. A. Pitsillides
Journal: Arthritis & Rheumatology (2015)

To explore whether aberrant transient chondrocyte behaviors occur in the joints of STR/Ort mice (which spontaneously develop osteoarthritis [OA]) and whether they are attributable to an endochondral growth defect.Knee joints from STR/Ort mice with advanced OA and age-matched CBA (control) mice were examined by Affymetrix microarray profiling, multiplex polymerase chain reaction (PCR) analysis, and immunohistochemical labeling of endochondral markers, including sclerostin and MEPE. The endochondral phenotype of STR/Ort mice was analyzed by histologic examination, micro-computed tomography, and ex vivo organ culture. A novel protocol for quantifying bony bridges across the murine epiphysis (growth plate fusion) using synchrotron x-ray computed microtomography was developed and applied.Meta-analysis of transcription profiles showed significant elevation in functions linked with endochondral ossification in STR/Ort mice (compared to CBA mice; P < 0.05). Consistent with this, immunolabeling revealed increased matrix metalloproteinase 13 (MMP-13) and type X collagen expression in STR/Ort mouse joints, and multiplex quantitative reverse transcriptase-PCR showed differential expression of known mineralization regulators, suggesting an inherent chondrocyte defect. Support for the notion of an endochondral defect included accelerated growth, increased zone of growth plate proliferative chondrocytes (P < 0.05), and widespread type X collagen/MMP-13 labeling beyond the expected hypertrophic zone distribution. OA development involved concomitant focal suppression of sclerostin/MEPE in STR/Ort mice. Our novel synchrotron radiation microtomography method showed increased numbers (P < 0.001) and mean areal growth plate bridge densities (P < 0.01) in young and aged STR/Ort mice compared to age-matched CBA mice.Taken together, our data support the notion of an inherent endochondral defect that is linked to growth dynamics and subject to regulation by the MEPE/sclerostin axis and may represent an underlying mechanism of pathologic ossification in OA.