tbuckley/cabot-search huggingface dataset:
Memory T Cells Expressing an NKG2D-CAR Efficiently Target Osteosarcoma Cells
Authors: Lucía Fernández, Jean-Yves Metais, Adela Escudero, María Vela, Jaime Valentín, Isabel Vallcorba, Alejandra Leivas, Juan Torres, Antonio Valeri, Ana Patiño-García, Joaquín Martínez, Wing Leung, Antonio Pérez-Martínez
Journal: Clinical Cancer Research (2017)

Purpose: NKG2D ligands (NKG2DL) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. Various immune cells express NKG2D receptors, including natural killer (NK) cells and CD8+ T cells. Interactions between NKG2DL and NKG2D receptors are essential for NK-cell elimination of osteosarcoma tumor-initiating cells. In this report, we used NKG2D-NKG2DL interactions to optimize an immunotherapeutic strategy against osteosarcoma. We evaluated in vitro and in vivo the safety and cytotoxic capacity against osteosarcoma cells of CD45RA- memory T cells expressing an NKG2D-4-1BB-CD3z chimeric antigen receptor (CAR).Experimental Design: CD45RA- cells from healthy donors were transduced with NKG2D CARs containing 4-1BB and CD3z signaling domains. NKG2D CAR expression was analyzed by flow cytometry. In vitro cytotoxicity of NKG2D-CAR+ CD45RA- T cells against osteosarcoma was evaluated by performing conventional 4-hour europium-TDA release assays. For the in vivo orthotopic model, 531MII YFP-luc osteosarcoma cells were used as targets in NOD-scid IL2Rgnull mice.Results: Lentiviral transduction of NKG2D-4-1BB-CD3z markedly increased NKG2D surface expression in CD45RA- cells. Genetic stability was preserved in transduced cells. In vitro, NKG2D-CAR+ memory T cells showed significantly increased cytolytic activity than untransduced cells against osteosarcoma cell lines, while preserving the integrity of healthy cells. NKG2D-CAR+ memory T cells had considerable antitumor activity in a mouse model of osteosarcoma, whereas untransduced T cells were ineffective.Conclusions: Our results demonstrate NKG2D-4-1BB-CD3z CAR-redirected memory T cells target NKG2DL-expressing osteosarcoma cells in vivo and in vitro and could be a promising immunotherapeutic approach for patients with osteosarcoma. Clin Cancer Res; 23(19); 5824-35. ©2017 AACR.
Whole brain radiotherapy after stereotactic radiosurgery or surgical resection among patients with one to three brain metastases and favorable prognoses: a secondary analysis of EORTC 22952-26001
Authors: T.M. Churilla, E. Handorf, S. Collette, L. Collette, Y. Dong, A.A. Aizer, M. Kocher, R. Soffietti, B.M. Alexander, S.E. Weiss
Journal: Annals of Oncology (2017)
A TIM-3 Oligonucleotide Aptamer Enhances T Cell Functions and Potentiates Tumor Immunity in Mice
Authors: Tal Gefen, Iris Castro, Darija Muharemagic, Yvonne Puplampu-Dove, Shradha Patel, Eli Gilboa
Journal: Molecular Therapy (2017)

T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-γ (IFN-γ) secreting CD4+ T cells and CD8+ T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8+ T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check. Using a combined bead and cell-based systemic evolution of ligands by exponential enrichment (SELEX) protocol, we have isolated nuclease-resistant oligonucleotide aptamer ligands that bind to cell-associated TIM-3 with high affinity and specificity. A trimeric form of the TIM-3 aptamer blocked the interaction of TIM-3 with Galectin-9, reduced cell death, and enhanced survival, proliferation, and cytokine secretion in vitro. In tumor-bearing mice, the aptamer delayed tumor growth as monotherapy and synergized with PD-1 antibody in prolonging the survival of the tumor-bearing mice. Both in vitro and in vivo, the trimeric aptamer displayed superior activity compared to the currently used RMT3-23 monoclonal antibody. This study suggests that multi-valent aptamers could represent an alternative platform to generate potent ligands to manipulate the function of TIM-3 and other immune modulatory receptors. T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-γ (IFN-γ) secreting CD4+ T cells and CD8+ T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8+ T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check. Using a combined bead and cell-based systemic evolution of ligands by exponential enrichment (SELEX) protocol, we have isolated nuclease-resistant oligonucleotide aptamer ligands that bind to cell-associated TIM-3 with high affinity and specificity. A trimeric form of the TIM-3 aptamer blocked the interaction of TIM-3 with Galectin-9, reduced cell death, and enhanced survival, proliferation, and cytokine secretion in vitro. In tumor-bearing mice, the aptamer delayed tumor growth as monotherapy and synergized with PD-1 antibody in prolonging the survival of the tumor-bearing mice. Both in vitro and in vivo, the trimeric aptamer displayed superior activity compared to the currently used RMT3-23 monoclonal antibody. This study suggests that multi-valent aptamers could represent an alternative platform to generate potent ligands to manipulate the function of TIM-3 and other immune modulatory receptors.
Psychotherapies for depression in low‐ and middle‐income countries: a meta‐analysis
Authors: Pim Cuijpers, Eirini Karyotaki, Mirjam Reijnders, Marianna Purgato, Corrado Barbui
Journal: World Psychiatry (2018)

Most psychotherapies for depression have been developed in high‐income Western countries of North America, Europe and Australia. A growing number of randomized trials have examined the effects of these treatments in non‐Western countries. We conducted a meta‐analysis of these studies to examine whether these psychotherapies are effective and to compare their effects between studies from Western and non‐Western countries. We conducted systematic searches in bibliographical databases and included 253 randomized controlled trials, of which 32 were conducted in non‐Western countries. The effects of psychotherapies in non‐Western countries were large (g=1.10; 95% CI: 0.91‐1.30), with high heterogeneity (I 2 =90; 95% CI: 87‐92). After adjustment for publication bias, the effect size dropped to g=0.73 (95% CI: 0.51‐0.96). Subgroup analyses did not indicate that adaptation to the local situation was associated with the effect size. Comparisons with the studies in Western countries showed that the effects of the therapies were significantly larger in non‐Western countries, also after adjusting for characteristics of the participants, the treatments and the studies. These larger effect sizes in non‐Western countries may reflect true differences indicating that therapies are indeed more effective; or may be explained by the care‐as‐usual control conditions in non‐Western countries, often indicating that no care was available; or may be the result of the relative low quality of many trials in the field. This study suggests that psychotherapies that were developed in Western countries may or may not be more effective in non‐Western countries, but they are probably no less effective and can therefore also be used in these latter countries.
Prognostic significance of PD-L1 expression on circulating tumor cells in patients with head and neck squamous cell carcinoma
Authors: A. Strati, G. Koutsodontis, G. Papaxoinis, I. Angelidis, M. Zavridou, P. Economopoulou, I. Kotsantis, M. Avgeris, M. Mazel, C. Perisanidis, C. Sasaki, C. Alix-Panabières, E. Lianidou, A. Psyrri
Journal: Annals of Oncology (2017)

Successful application of programmed death 1 (PD1) checkpoint inhibitors in the clinic may ultimately benefit from appropriate patient selection based upon predictive biomarkers. Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular-targeted therapies while predictive biomarkers for response to PD1 checkpoint inhibitors are lacking. We sought to assess whether overexpression of PD-L1 in CTCs could be detected at baseline and at different timepoints during treatment in a prospective cohort of head and neck squamous cell carcinoma (HNSCC) patients and used to predict clinical outcome after treatment with curative intent.We developed a highly sensitive, specific and robust RT-qPCR assay for PD-L1 mRNA expression in EpCAM(+) CTCs. In a prospective cohort of 113 locally advanced HNSCC patients treated with curative intent we evaluated PD-L1 expression in the EpCAM(+) CTC fraction at baseline, after 2 cycles of induction chemotherapy (week 6) and at the end of concurrent chemoradiotherapy (week 15).PD-L1 overexpression was found in 24/94 (25.5%) patients at baseline, 8/34 (23.5%) after induction chemotherapy and 12/54 (22.2%) patients at the end of treatment. Patients with CTCs overexpressing PD-L1 at end of treatment had shorter progression-free survival (P = 0.001) and overall survival (P < 0.001). Multivariate analysis revealed that PD-L1 overexpression at end of treatment was independent prognostic factor for progression-free survival and overall survival. The absence of PD-L1 overexpression at the end of treatment was strongly associated with complete response with an odds ratio = 16.00 (95% CI = 2.76-92.72, P = 0.002).We demonstrate that detection of CTCs overexpressing PD-L1 is feasible and may provide important prognostic information in HNSCC. Our results suggest that adjuvant PD1 inhibitors deserve evaluation in HNSCC patients in whom PD-L1(+) CTCs are detected at the end of curative treatment.
Sugar intake in pregnancy is linked to child’s allergy and allergic asthma
Authors: Ingrid Torjesen
Journal: BMJ (2017)

Pregnant women who consume high levels of free sugars during pregnancy are more likely to give birth to a child with allergy or allergic asthma, a study published in the European Respiratory Journal suggests.1

The researchers used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), which looks at the offspring of predominantly white women living in Avon, UK, who were due to give birth from 1 April 1991 to 31 December 1992.

They analysed associations between maternal intake of free sugar (sugar that is added to foods or naturally present in honey, syrups, and fruit juice) during pregnancy and asthma diagnoses, wheezing, hay fever, eczema, atopy, serum total IgE, and lung …
BMA annual meeting: One in 10 doctors have European colleagues who have left the UK because of Brexit, says BMA
Authors: Abi Rimmer
Journal: BMJ (2017)

More than one in 10 doctors have European colleagues who have left the UK as a result of Brexit, a survey conducted by the BMA has found.

The BMA sent a survey to 1000 members and had 422 responses (a response rate of 42%).

The survey found that 11% of respondents said that they had colleagues who had left the UK because of Brexit, and 14% reported noticing a reduction in non-UK applicants for posts in their …
Abstract 155: Long-term Aortic Root Dilation in Kawasaki Disease with Coronary Aneurysm
Authors: Michael Carr, Caroline R Schuette, Elfriede Pahl
Journal: Circulation (2015)

Introduction: Aortic root dilation is a known finding in the acute/subacute phase of Kawasaki disease (KD). These changes may be inflammatory and related to the degree of coronary artery (CA) dilation, and may lag when compared to CA changes. Long-term changes in the aorta have not been previously reported. Methods: A retrospective review of patients with KD from our institution was conducted, identifying individuals with American Heart Association (AHA) Risk Level 3, 4 or 5 over a 20 year period (1994-2014). Aortic annular and root dimensions were measured at the most recent echocardiogram and converted to z-score measurements. When possible, ascending aorta dimensions were measured, and all studies were evaluated for the presence of aortic regurgitation. Time from KD diagnosis to the last echocardiogram was determined. Patients with disease processes predisposing to aortic dilation were excluded, as were those with duration of echocardiographic follow-up &lt;1 year. Results: Fifty-three patients were identified, with a median age at diagnosis of 29 months (SD 42, 1.2-162 months). Twenty-seven (51%) were AHA Risk Level 3, 20 (38%) Risk Level 4 and 6 (11%) Risk Level 5. The mean time from diagnosis to latest echocardiogram was 7.3 years (1.4-17.3 years). Aortic annular and root dimensions were obtained in all patients (mean aortic annular z-score -0.06, mean aortic root z-score 0.67). Four patients (8%) had a dilated (z-score &gt;2) aortic root, one also had a dilated annulus. Ten patients (19%) had borderline root dilation (z-score &gt;1.5). Ascending aorta dimension measurements were possible in 72% (38/53) of the cohort, of which only 1 (3%) had a z-score &gt;2 and 3 (8%) had a z-score &gt;1.5. Importantly, no patients demonstrated aortic regurgitation. Conclusion: In patients with history of KD and significant coronary artery involvement, borderline/mild dilation of the aortic root is not uncommon at intermediate to long- term follow-up, suggesting the possibility of a higher degree of aortic involvement in the acute and subacute phase of the disease process. The ascending aorta appears to be less affected and there was no evidence of functional derangements of the aortic valve. Accurate measurement of the aortic root dimension at all stages of KD is warranted.
A Phase 1 study to evaluate the safety, pharmacokinetics, immunogenicity, and antitumor activity of MEDI4276 in patients with select HER2-expressing advanced solid tumors.
Authors: Erika Paige Hamilton, Manish R. Patel, Mark D. Pegram, Antoinette R. Tan, Anna Maria Storniolo, John Li, Xiang-Qing Yu, Anita Scheuber
Journal: Journal of Clinical Oncology (2016)

TPS632 Background: Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor involved in regulating cell proliferation. HER2 is overexpressed in a subset of patients (pts) with breast or gastric cancer, and is generally associated with an unfavorable clinical outcome. There is a need to further improve the efficacy of available HER2-targeting agents, particularly in pts with HER2+ breast or gastric cancer that have progressed after standard available treatments. MEDI4276 is a HER2-targeting, bispecific antibody linked to a novel anti-microtubule inhibitor called tubulysin. Preclinically, MEDI4276 demonstrates broad antitumor activity as it induces tumor regression in primary xenograft models derived from either HER2+ or HER2- breast cancer pts, as well as a pt refractory to ado-trastuzumab emtansine. Methods: This is a first-in-human Phase 1, open-label, dose escalation and dose expansion study in pts with select HER2-expressing advanced solid tumors (NCT02576548). The primary objectives are to assess safety, describe dose-limiting toxicities, and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of single-agent MEDI4276. The secondary objectives are to evaluate antitumor activity (based on ORR, PFS, and OS endpoints), pharmacokinetics, and immunogenicity of MEDI4276. For the dose escalation phase, eligible pts ( ≥ 18 years) will have histologically or cytologically documented, HER2+, unresectable, locally advanced or metastatic breast or gastric cancer refractory to standard therapy or for which no standard therapy exists. The dose escalation phase will use a 3 + 3 design; sequential cohorts will receive 1 of 6 planned dose levels of MEDI4276 IV every 3 weeks until unacceptable toxicity or disease progression occurs. After determination of the MTD or MAD, the dose expansion phase may be initiated in HER2+ or HER2- pts with unresectable, locally advanced or metastatic breast cancer who have received prior treatment regimens. Recruitment is ongoing for this study, which has an estimated target enrollment of 120 pts. Clinical trial information: NCT02576548.
Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force
Authors: Josef S Smolen, Monika Schöls, Jürgen Braun, Maxime Dougados, Oliver FitzGerald, Dafna D Gladman, Arthur Kavanaugh, Robert Landewé, Philip Mease, Joachim Sieper, Tanja Stamm, Maarten de Wit, Daniel Aletaha, Xenofon Baraliakos, Neil Betteridge, Filip van den Bosch, Laura C Coates, Paul Emery, Lianne S Gensler, Laure Gossec, Philip Helliwell, Merryn Jongkees, Tore K Kvien, Robert D Inman, Iain B McInnes, Mara Maccarone, Pedro M Machado, Anna Molto, Alexis Ogdie, Denis Poddubnyy, Christopher Ritchlin, Martin Rudwaleit, Adrian Tanew, Bing Thio, Douglas Veale, Kurt de Vlam, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2017)

Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field.
The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain
Authors: Yan Jiang, Yong-Hwee Eddie Loh, Prashanth Rajarajan, Teruyoshi Hirayama, Will Liao, Bibi S Kassim, Behnam Javidfar, Brigham J Hartley, Lisa Kleofas, Royce B Park, Benoit Labonte, Seok-Man Ho, Sandhya Chandrasekaran, Catherine Do, Brianna R Ramirez, Cyril J Peter, Julia T C W, Brian M Safaie, Hirofumi Morishita, Panos Roussos, Eric J Nestler, Anne Schaefer, Benjamin Tycko, Kristen J Brennand, Takeshi Yagi, Li Shen, Schahram Akbarian
Journal: Nature Genetics (2017)
Evaluation of risk factors predicting delayed chemotherapy-induced nausea and vomiting in patients receiving low emetic risk chemotherapy (LEC): A prospective, observational, multicenter study
Authors: Toshinobu Hayashi, Mototsugu Shimokawa, Mikako Hiraike, Yoko Toriyama, Chiaki Yokota, Jun Taniguchi, Kiyonori Hanada, Kyouichi Tsumagari, Noriko Okubo, Yoshimichi Koutake, Kohei Sakata, Yosei Kawamata, Takashi Goto, Yasufumi Tsurusaki, Makiko Koyabu
Journal: Annals of Oncology (2017)
Real-world gastric cancer patients treated with at least three lines of chemotherapy: Outcomes and predictors for efficacy.
Authors: Valentina Fanotto, Mario Uccello, Irene Pecora, Lorenza Rimassa, Francesco Leone, Gerardo Rosati, Daniele Santini, Riccardo Giampieri, Samantha Di Donato, Gianluca Tomasello, Nicola Silvestris, Filippo Pietrantonio, Francesca Battaglin, Antonio Avallone, Mario Scartozzi, Stefania Lutrino, Davide Melisi, Lorenzo Antonuzzo, Antonio Pellegrino, Giuseppe Aprile
Journal: Annals of Oncology (2017)
Clinical Impact of the Quantitative Subclonal Architecture in Chronic Lymphocytic Leukemia
Authors: Ferran Nadeu, Julio Delgado, Guillem Clot, David Martín-García, Tycho Baumann, Magda Pinyol, Pedro Jares, Sílvia Beà, Itziar Salaverria, Alba Navarro, Helena Suárez-Cisneros, Marta Aymerich, Maria Rozman, Neus Villamor, Dolors Colomer, Marcos González, Miguel Alcoceba, María José Terol, Enrique Colado, Armando López-Guillermo, Xose S Puente, Carlos Lopez-Otin, Anna Enjuanes, Elias Campo
Journal: Blood (2016)
Cost-effectiveness of IDH testing in diffuse gliomas according to the 2016 WHO classification of tumors of the central nervous system recommendations
Authors: John C DeWitt, Justin T Jordan, Matthew P Frosch, Wesley R Samore, A John Iafrate, David N Louis, Jochen K Lennerz
Journal: Neuro-Oncology (2017)

Due to the decreasing prevalence of IDH1 mutations in older patients, the 2016 World Health Organization (WHO) classification of brain tumors proposed not to perform sequencing for isocitrate dehydrogenase (IDH) in glioblastoma patients ≥55 years old. We present a cost-effectiveness analysis to estimate the financial impact of these guidelines. From 2010 to 2015 we performed 1023 IDH tests in gliomas, amounting to ~$1.09 million in direct laboratory test costs. Samples were tested using R132H-specific immunohistochemistry, DNA sequencing validated for detection of noncanonical IDH1/2 mutations, or both methods. In cases tested by DNA sequencing, the fraction of non-R132H mutations was 5.4%, which included only 2 high-grade gliomas in patients ≥55 years (0.9%). When remodeling the optimal age cutoff in our patient population using 5-year age-binning, we found a 10-times higher pretest probability for the presence of a noncanonical IDH1 mutation in the setting of a negative IDH1-R132H immunohistochemistry result in patients <55 years. Applying the independently confirmed age cutoff of 55 years to glioblastoma patients (64%) would result in $403200 saved (43%). By not performing sequencing in patients ≥55 years, the turn-around time to final integrated neuropathological diagnosis is reduced by 53%, allowing these patients to gain earlier benefits from personalized genomic medicine. The negligible prevalence of noncanonical IDH mutations in glioblastoma patients ≥55 years argues against universal IDH sequencing in this population. We predict that adoption of this age-based sequencing cutoff recommendation from the 2016 WHO guidelines will result in significant cost and time savings throughout the global health care system.
Correction to Lancet HIV 2016; 3: e361–87
Journal: The Lancet HIV (2016)

© 2016 Elsevier Ltd GBD 2015 HIV Collaborators. Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2015: the Global Burden of Disease Study 2015. Lancet HIV 2016; 3: e361–87—In this Article, Kerrie E Doyle and David M Pereira have been added to the list of collaborators and Claudia C Pereira has been removed. These corrections have been made as of Aug 22, 2016.