bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of a vibrating mesh nebulizer for allergen challenge
Authors: Cockcroft Donald W. , Davis Beth E. , Blais Christianne M. , Boulet Louis-Philippe , Boulay Marie-Éve , Villeneuve Hélène , Gauvreau Gail M. , O’Byrne Paul M. , Howie Karen J. , Obminski Caitlin D. 
Published: November 2019

Abstract
Background
Allergen inhalation tests are a valuable research tool. The allergen dose producing an early asthmatic response (EAR) can be predicted from methacholine responsiveness and allergen skin test endpoint (STE). The Wright® jet nebulizer, which is both inefficient and increasingly difficult to obtain, has been used historically. We assessed the Solo® vibrating mesh nebulizer as an alternative for allergen and methacholine challenges.

Methods
Eighteen mild atopic asthmatics completed the study. Doubling concentration allergen prick skin tests were performed to determine the STE in allergen units/mL. The Wright® protocol was used to measure the methacholine provocation dose causing a 20% forced expired volume in one second (FEV1) fall (PD20) (μg) and the allergen PD20 (units). The Solo® protocol (0.5 mL nebulized to completion, tidal breathing inhalation) was used to determine both methacholine PD20 and allergen PD20. The nebulizer order was randomized and separated by ≥ 2 weeks.

Results
All data were log transformed. The allergen PD20, predicted from the methacholine PD20 and the STE, was within 2 doubling doses of the PD20 measured with the Wright® and 2.64 doubling doses of that measured with Solo®. The Wright® allergen PD20 correlated with the Wright® methacholine PD20 (r = 0.74) and the STE (r = 0.78) and more strongly with the product of the two (Wright® methacholine PD20 × STE, r = 0.91, p < 0.00001). The Solo® allergen PD20 showed similar relationships with the Solo® methacholine PD20 (r = 0.61), the STE (r = 0.75) and the product of the two (Solo® methacholine PD20 × STE, r = 0.83, p < 0.00002). The Wright® and the Solo® methacholine geometric mean PD20s were not significantly different (49.3 and 54.5 μg respectively, p = 0.62). The Wright® allergen PD20 was slightly but significantly lower than the Solo® allergen PD20 (geometric means 6.7 and 10.5 units respectively, p = 0.003).

Conclusion
The Solo® allergen PD20 showed the same relationship with methacholine responsiveness and STE as did the Wright®. The Solo® allergen PD20 was slightly but significantly higher than the Wright® allergen PD20. The Solo® vibrating mesh nebulizer was well tolerated and is an acceptable alternative for allergen challenge.
Trial registration clinicaltrials.gov: NCT03491358
Stem cell-derived extracellular vesicles: role in oncogenic processes, bioengineering potential, and technical challenges
Authors: Ullah Mujib , Qiao Yang , Concepcion Waldo , Thakor Avnesh S. 
Published: November 2019

AbstractExtracellular vesicles (EVs) are cellular-derived versatile transporters with a specialized property for trafficking a variety of cargo, including metabolites, growth factors, cytokines, proteins, lipids, and nucleic acids, throughout the microenvironment. EVs can act in a paracrine manner to facilitate communication between cells as well as modulate immune, inflammatory, regenerative, and remodeling processes. Of particular interest is the emerging association between EVs and stem cells, given their ability to integrate complex inputs for facilitating cellular migration to the sites of tissue injury. Additionally, stem cell-derived EVs can also act in an autocrine manner to influence stem cell proliferation, mobilization, differentiation, and self-renewal. Hence, it has been postulated that stem cells and EVs may work synergistically in the process of tissue repair and that dysregulation of EVs may cause a loss of homeostasis in the microenvironment leading to disease. By harnessing the property of EVs for delivery of small molecules, stem cell-derived EVs possess significant potential as a platform for developing bioengineering approaches for next-generation cancer therapies and targeted drug delivery methods. Although one of the main challenges of clinical cancer treatment remains a lack of specificity for the delivery of effective treatment options, EVs can be modified via genetic, biochemical, or synthetic methods for enhanced targeting ability of chemotherapeutic agents in promoting tumor regression. Here, we summarize recent research on the bioengineering potential of EV-based cancer therapies. A comprehensive understanding of EV modification may provide a novel strategy for cancer therapy and for the utilization of EVs in the targeting of oncogenic processes. Furthermore, innovative and emerging new technologies are shifting the paradigm and playing pivotal roles by continually expanding novel methods and materials for synthetic processes involved in the bioengineering of EVs for enhanced precision therapeutics.
The Parliamentary Scholar Scheme: a way to engage doctors in healthcare policy and politics
Authors: Perry Jen , Lomax Paul , Taylor Fiona , Howson Susan , McCurdy Kathleen 
Published: November 2019

SummaryThe Royal College of Psychiatrists’ Parliamentary Scholar Scheme gives higher trainees in psychiatry the opportunity to spend 1 day a week in the House of Lords working alongside a peer with an interest in health. This article describes the work of the House of Lords and Parliament using examples from the experiences of 2017–2018 scholars and outlines ways doctors can get more involved in policy and politics.
Mutational load (ML) and T-cell-inflamed microenvironment as predictors of response to pembrolizumab.
Authors: Cristescu Razvan , Mogg Robin , Ayers Mark , Albright Andrew , Murphy Erin , Yearley Jennifer , Sher Xinwei , Liu Xiaoqiao , Nebozhyn Michael , Lunceford Jared K. , Joe Andrew K. , Cheng Jonathan , Plimack Elizabeth R. , Ott Patrick Alexander , Seiwert Tanguy Y. , McClanahan Terrill K , Loboda Andrey , Kaufman David Ross 
Published: November 2019

1 Background: ML is associated with response to anti CTLA-4 and PD-1/L1 immunotherapies in some cancers, likely due to increased tumor antigenicity via generation of neoepitopes not subject to central immune tolerance. An IFNγ centric gene expression profile (GEP), characteristic of a T cell inflamed microenvironment, is also related to response to PD-1/PD-L1 therapies. The association between ML and outcome, and independent predictive values of ML and GEP in pembrolizumab treated patients across 21 tumor types were assessed. Methods: Whole exome and RNA sequencing were performed on FFPE specimens pooled from 2 multicohort advanced solid tumor trials (KEYNOTE 012 [n = 39] and 028 [n = 80]). The previously defined GEP score is a weighted sum of normalized expression values for 18 genes. ML and neoantigen analysis tools included GATK, MuTect and NetMHC. Statistical testing was adjusted for multiple testing. ML and GEP association was also explored in Moffitt and TCGA datasets. Results: ML and neoantigen load were significantly associated with objective response (OR) (AUROC = 0.76 and 0.78; p = 0.0036 and 0.0083, respectively). Median numbers of mutations were 180 in responders and 61 in nonresponders. The overall response rate (ORR) in all patients was 15%. At a ML cutoff of 102 (based on ROC Curve YoudenIndex), the ORR was 32.3% (prevalence 31.0%; NPV 92.8%). GEP was also significantly associated with OR (AUROC = 0.76; p = 0.0071). ML and GEP were modestly correlated (r = 0.28), consistent with associations between ML and GEP in Moffitt (r = 0.11) and TCGA databases (r = 0.29). When jointly modeled, ML was significantly associated with response (p = 0.0078) after adjusting for GEP (also significant; p = 0.0251). Data from additional patients will also be presented. Conclusions: These data show that ML and GEP are independently predictive biomarkers of response to pembrolizumab in multiple tumor types, suggesting that tumor antigenicity and T cell infiltration may provide complementary information for expected pembrolizumab activity. As measures of distinct, yet common features of a PD-1 checkpoint blockade responsive tumor, ML and GEP may have utility in characterizing responses to anti PD-1 and other cancer immunotherapies. Clinical trial information: NCT01848834; NCT02054806.
Trastuzumab versus MYL-1401O (a proposed trastuzumab biosimilar) in a phase I bioequivalence study: In vivo and in vitro immunomodulation.
Authors: Audran RÃÂ©gine , Chtioui Haithem , Thierry Anne-Christine , Mayor Carole , Vallotton Laure , Dao Kim , Rothuizen Laura , Maghraoui Ali , Pennella Eduardo J. , Brunner-Ferber Françoise , Buclin Thierry , Spertini Francois 
Published: November 2019

10 Background: Trastuzumab is a humanized monoclonal antibody targeting breast cancer cells overexpressing the HER2-oncoprotein. During a Phase-I single centre, single dose, randomized, double-blind, cross-over study assessing the bioequivalence of a proposed trastuzumab biosimilar (MYL-1401O) versus the initially marketed drug (Herceptin), we investigated in addition a large panel of pharmacodynamics parameters comparing the immunomodulatory activity of both drugs. Methods: 22 healthy males were included, 19 subjects receiving randomly a single intravenous infusion of MYL-1401O and 22 of Herceptin, separated by 16 to 22 week wash-out. Blood samples drawn pre- and post- infusion were assessed for in vivo serum cytokines induction (IL-1β, IL-2, IL-6, IL-10, IL-12, TNF-α, GM-CSF and IFN-γ) whereas the impact of treatment on mononuclear cell subsets and their level of activation was tested ex vivo. Volunteers’ PBMC (peripheral blood monocnuclear cells) were stimulated in vitro with recall antigens and mitogen for cytokine production. At baseline, we performed in addition a cytokine release assay on PBMC upon stimulation with trastuzumab as a preclinical safety test. Results: Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6h, and a modulation of mononuclear cell subset profile and level of activation. Notably CD16+ cells frequency decreased at 3h and peaked at 48h. Except for CD8+ T cells, there were no significant differences between Herceptin and its proposed biosimilar ex vivo. PBMC stimulated in vitro with trastuzumab secreted IL-6, TNF-a, IL-1β, GM-CSF, IFN-γ, and IL-10, but no IL-2. There was no significant difference between the two mAbs. Conclusions: Based on these in vivo, ex vivo and in vitro experiments, there is a strong assumption that MYL-1401O is biosimilar to the reference drug Herceptin for its immunomodulation properties as already proven for its bioequivalence. Clinical trial information: 2011-001406-94.
Activity of CBT-501, a novel humanized anti-PD-1 antibody, in a humanized genetically engineered mouse model of colon carcinoma.
Authors: Zhou Qing , Nian Weihong , Sun Ziyong , Qiu Junzhuan , Wang Zhun , Choy Gavin , Redkar Sanjeev 
Published: November 2019

108 Background: CBT-501 (Genolimzumab, GB-226) is a novel humanized mAb (IgG4k) against human Programmed Death-1 (PD-1). CBT-501 demonstrated highly specific binding to PD-1 of human (KD= 505 pM) and cynomolgus (KD= 7.2 nM). It did not completely block the binding of nivolumab or pembrolizumab, suggesting a novel epitope. CBT-501 efficiently inhibited the binding of PD-L1/L2 to PD-1 through a competitive action for both human and monkey. It enhanced human T-cell activation in the Mix Lymphocyte Reaction (MLR), as shown by increased release of IL-2 and INF-γ. The Fc-fragment bound to FcRn dose-dependently without any effector function. The PK/PD studies in cynomolgus showed a linear dose exposure, with a T1/2of 115-142 h for single and repeat dosing. The PD-1 receptor occupancy after a single dose was dose-dependent reaching 100% at peak, maintained after multiple dosing and continued for 6 wk after last dose. Single and repeat dose toxicology studies in cynomolgus showed weight gain of the thyroid and mild expansion of the thyroid follicles at the highest dose of 100 mg/kg which were reversible. No abnormal drug-related toxicity was found. In rhesus vaccinated with adenovirus-mediated Simian Immunodeficiency Virus, biweekly IV CBT-501 promoted the antigen-specific T-cell response, as shown by ELISPOT and intracellular staining of IL-2, INF-γ and TNF-α in PBMC and T-cell subpopulation. Due to lack of immunoselectivity to mouse PD-1, investigation of the in vivo anti-tumor activity in rodent model is challenging. Methods: Crown Bioscience has developed humanized genetically engineered mouse model expressing human PD-1 extracellular domain with a fully functional murine immune system. Subcutaneous colon adenocarcinoma MC38 syngeneic tumor draft was established in mice. Results: CBT-501 injected IP q2w×3wk demonstrated significant anti-tumor activity. The tumor growth reduction was dose dependent with comparable or improved activity over nivolumab, and with the highest inhibition rate at 83%. Conclusions: Based on the strong nonclinical data and differentiation, and an acceptable safety profile, a first in human Phase 1 trial is planned in the Asia-Pacific region.
Analysis of the newly defined immune checkpoints in pancreatic cancer.
Authors: Wada Satoshi 
Published: November 2019

109 Background: Pancreatic cancer has not been improved with the five-year survival rate for more than 10 years, which is a refractory cancer of poor prognosis. Development of novel therapeutic agents has been desired, because the standard chemotherapy has not been satisfied yet. Anti-tumor immunotherapy is expected for less burden on the patient in recent years. However, it is limited by multiple tolerogenic mechanisms related to the tumor, the host immune system, and the tumor microenvironment. Therefore satisfactory results are not obtained in the clinical trials for several vaccinations. In this experiment, we focused on negative co-signaling molecules, especially immune checkpoints. The purpose of the present study was to investigate the relationship between the expression of immune checkpoints and clinico-pathological findings, including prognosis in pancreatic cancer patients. Methods: We enrolled 81 patients (52 men and 29 women; age range: 36-84 years) with pancreatic cancer who underwent curative resection with lymphadenectomy at Gunma University Hospital and Saiseikai Maebashi Hospital (Maebashi, Japan) between 2000 and 2011. Patients who had undergone palliative resection, preoperative chemotherapy and radiation therapy were excluded from this study. Furthermore, none of the patients enrolled in this study had synchronous or metachronous cancer in other organs. Results: Immunohistochemical staining of immune checkpoints in primary pancreatic tissue was performed. Patients with high B7-H4 expression had a significantly poorer prognosis than those with low B7-H4 expression. It was also seen in B7-H3 expression in this experiment. Furthermore, in analysis for the expression of CD8, IFN-γ and FOXP3, patients with high FOXP3 expression had a significantly poorer prognosis than those with low FOXP3 expression. Conclusions: The B7-h3 and B7-H4 are negative co-stimulatory molecules and a novel prognostic marker related to the T-cell mediated immune response. It’s pathway may be a molecular target for controlling tumor progression in patients with pancreatic cancer.
Long-term follow-up of DNA engineered bi-shRNA furin GMCSF plasmid/autologous tumor induced immune response in patients with advanced solid tumors (phase I trial).
Authors: Nemunaitis John J. , Barve Minal A. , Melnyk Anton , Wallraven Gladice , Manning Luisa , Senzer Neil N. 
Published: November 2019

110 Background: Previously we described safety and evidence of activity to VigilÒ (FANGÒ) and identified relationship of survival advantage to ELISPOT “+” Vigil treated patients (Senzer N et al. Long Term Follow Up: Phase I Trial of “bi-shRNA furin/GMCSF DNA/Autologous Tumor Cell” Immunotherapy (FANG) in Advanced Cancer. J Vaccines Vaccine 2013; 4: 209. doi: 10.4172/2157-7560.1000209). We have updated survival and long-term ELISPOT assessment of this same group of patients. Methods: A non-randomized phase 1 trial of patient treated with Vigil immunotherapy (n=39) compared to a similar matched comparator (MC) group not treated with Vigil (n=35). Results: Trial results suggest survival benefit without evidence of Vigil related toxicity (no ≥ grade 3). γ-IFN ELISPOT served as a biomarker for response and shows correlation with survival. 22/30 evaluable Vigil-treated patients showed ELISPOT conversion (73%) from negative to positive (threshold of ≥10 spots from baseline) during treatment. Durable evidence of γIFN-secreting circulating cytotoxic T cells was observed (up to 30months from treatment start), suggesting induction of memory T effector cells. Survival correlation demonstrated significant benefit of ELISPOT “+” Vigil treated patients (median OS of 784 days, 26.1 months) compared to ELISPOT “-“ patients (median OS of 353 days, 11.77 moths), and supports immune-related survival benefit compared to MC (median OS of 122 days, 4 months), (Table). Conclusions: Vigil immunotherapy induces a significant immune response. Detailed analysis of the immune effector population phenotype is underway to determine optimal correlation with survival. Clinical trial information: NCT01061840. [Table: see text]
Effects of TTI-621 (SIRPαFc) on CD47 and serum cytokines associated with phagocytosis in subjects with relapsed, refractory hematologic malignancies: Pharmacodynamic findings from a first-in-human clinical trial.
Authors: Johnson Lisa , Pillai Raju K. , King Rebecca L. , Ansell Stephen Maxted , Chen Robert W. , Flinn Ian , Maris Michael B. , Irwin Meghan , Sievers Eric L. , Petrova Penka S. , Uger Robert A. 
Published: November 2019

112 Background: CD47 delivers an anti-phagocytic (“do not eat”) signal by binding SIRPα on macrophages and is overexpressed on many cancers enabling immune surveillance evasion. TTI-621 is a decoy receptor that promotes phagocytosis of tumors by blocking CD47 and engaging activating FcR on macrophages. A first-in-human, phase 1a, open label, multicenter study (NCT02663518) evaluating safety and tolerability of weekly, intravenous infusions of TTI-621 was conducted. As of October 12, 2016, 18 subjects were treated with TTI-621 with doses of 0.05-0.3 mg/kg. Multiple pharmacodynamic and hematologic assessments were performed to characterize the effects of TTI-621 and better understand the mechanism of action. Methods: Serial blood draws were analyzed for CD47 receptor occupancy (RO), complete blood counts, cytokines, T cell repertoire changes and CD47, SIRPα and FcR sequences. CD47 expression, macrophage and T cell infiltration was assessed on biopsies by IHC. Results: Peripheral CD47 levels varied considerably between subjects and were inversely correlated with RO. A maximum of 80% RO was achieved on peripheral leukocytes. Circulating monocytes, neutrophils, and lymphocytes were transiently decreased at the end of the TTI-621 infusion and generally returned to baseline levels by 24 to 72 hours. Platelet counts decreased immediately after TTI-621 infusions, typically recovering to baseline levels prior to the subsequent treatment cycle. Hemoglobin levels did not meaningfully change during treatment. Cytokines associated with macrophage activation or phagocytosis, notably MIP-1α, MIP-1β, TNF-α and IP-10 were elevated in a dose dependent manner. Conclusions: Systemic administration of TTI-621 leads to CD47 blockade and dose dependent increases in cytokines associated with phagocytosis, temporally associated with reversible thrombocytopenia, suggesting enhanced macrophage mediated clearance of circulating platelets followed by a robust marrow regenerative response. Enrollment into multiple expansion cohorts addressing a wide range of hematopoietic cancers is ongoing. Clinical trial information: NCT02663518.
Conversion of CCL18-recruited naïve CD4+ T cells to tumor-infiltrating regulatory T cells in breast cancer and suppression of antitumor immunity.
Authors: Su Shicheng , Liao Jianyou , Liu Jiang , Liu Qiang , Song Erwei 
Published: November 2019

114 Background: Tumor-infiltrating regulatory T cells (Tregs) play a central role in tumor immunosuppression. However, it remains unclear whether they are directly recruited from peripheral blood or converted from infiltrating naive T cells. Methods: We use full-length TCR ¦Á/¦Â repertoire to analyse the difference of T cell subsets from peripheral blood, primary tumors and draining lymph nodes in patents. Results: Infiltration of naive CD4+ T cells and Tregs are closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells in the tumors are recruited by tumor-associated macrophages (TAMs) via CCL18. In addition, naive T cells and memory T cells exhibit distinctive chemotactic response due to different expression of regulator of G-protein signaling 1(RGS1). Specific silencing CCL18 receptor-PITPNM3 in naive CD4+ T cells using CD4 aptamer-siRNA blocks their chemotaxis, and thus reduces infiltrating Tregs and inhibits tumor progression in humanized mice. By comparison, silencing RGS1 in memory CD8+ T cells using CD8 aptamer-siRNA enhance their recruitment to tumors and anti-tumor immune response in vivo. Conclusions: These findings provide mechanistic insights for Treg enrichment in breast cancer and suggest that modification of the CCL18-PITPNM3-RGS1 signaling pathway may be an attractive strategy for anticancer immunotherapy.
Toll like receptors as a risk factor for early death in elderly cancer patients.
Authors: Telles O Lima Jurema , Mello Maria Julia Gonçalves , Thuler Luiz Claudio Santos , Telles Sales Letícia , Santaliz de Godoy Moreno Marina , Bergmann Anke , Jatahy Kleber , Resende Lira Clara Cinthia , Bezerra Cintra Evandro , Delgado Soriano Gabriela , Torres Leuridan 
Published: November 2019

133 Background: the elderly cancer group is a heterogeneous and growing one. In the elderly, the genes of toll-like receptors (TLR) have been described as related to the immunosenescence process and carcinogenesis. The relationship of this gene family with carcinogenesis and immunoregulatory responses seems a promising field. Methods: Between 2015 and 2016, a prospective cohort study in 445 elderly patients with incident cancer ( ≥ 60 years) at the time of admission, assessed and collected sociodemographic and clinical variables and collected analysis of peripheral blood in translational exploratory study. Determination of TLR2 and TLR9 was performed by flow cytometry with monoclonal antibodies anti-TLR2 and TLR9 in the peripheral blood at the beginning of anti-cancer therapy in older patients with cancer. Results: 445 elderly patients were included with incident cancer, age of 71.13 years (SD 7.41) means. Most were male (50.9%) and self-reported black or brown skin color (71.4%). The topography of prostate cancer was more frequent (29.4%), followed by the digestive system (24.3%). They were mostly patients with advanced stage (III and IV) at nutritional risk (52.6%) and reported using up to 5 medications (77.2%). Patients were followed for an average of 128 days (SD 54.37). During this period, there were 62 deaths (13.9 %) with a mean overall survival of 165 days (95% CI 161.25 to 170.02). There are significant differences in the percentage values of TLR9 (p = 0.0009) and TLR2 (p = 0.04) in monocytes between the groups of patients who died in less than 6 months of treatment and those who survived. Conclusions: Overexpression of TLR9 and TLR2 may be a protective factor for the occurrence of early death in elderly patients with cancer.