bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myd88/CD40 Costimulation to Enhance the Antitumor Activity of CD123-ENG T-Cells for the Immunotherapy of AML
Authors: Doherty Erin , Vaidya Abishek , Wu Xiya , Bonifant Challice L. , Mata Melinda , Leen Ann M. , Gottschalk Stephen , Velasquez Mireya P. 
Published: October 2019

Abstract
Background: Acute myeloid leukemia (AML) represents a treatment challenge due to its poor prognosis and high associated morbidity and mortality rates. Thus, new therapies are needed. CD123-ENG T-cells are cells genetically modified to secrete bispecific antibodies that recognize CD3 (T-cells) and CD123 (AML). Preclinical studies show that these cells recruit bystander T-cells to kill CD123+ blasts in vitro and in vivo. However, CD123-ENGs are unable to maintain sequential killing capability of CD123+ targets. To overcome this limitation, we have devised an approach that provides inducible Myd88/CD40 costimulation activated by a chemical inducer of dimerization (CID). This strategy should increase the persistence, expansion and anti-AML activity of CD123-ENG T-cells.
Methods: We generated a retroviral vector encoding a CD20 safety switch, CD123-ENG, and the inducible costimulatory molecule MyD88.CD40 (iMC) linked by 2A sequences (CD20.2A.CD123-ENG.2A.iMC). We used a vector specific for CD19 (CD20.2A.CD19-ENG.2A.iMC) and non-transduced (NT) cells as controls for non-specific effects of the iMC construct. We genetically modified T-cells using a retroviral transduction protocol and evaluated their effector function +/- CID. We assessed the effector function of transduced T-cells using standard immunological assays and a flow cytometry based sequential killing assay.
Results: We successfully generated CD20.CD123-ENG.iMC T-cells, which maintained a transduction efficiency above 50% throughout our study period. We performed coculture and cytotoxicity assays using NT, CD20.CD123-ENG, CD20.CD19-ENG.iMC and CD20.CD123-ENG.iMC T-cells +/-CID as effectors and MOLM13 (CD123+), Kg1a (CD123+) and K562 (CD123-) as targets. Cocultures were performed +/- CID. CD20.CD123-ENG.iMC T-cells maintained CD123 antigen specificity, as evidenced by cytotoxicity and cytokine assays. CD20.CD123-ENG.iMC T-cells + CID secreted increased IL-2 and IFN-γ in the presence of CD123+ targets (KG1a and MOLM13) when compared to baseline and to CD20.CD123-ENG T-cells. In addition, CD20.CD123-ENG.iMC T-cells + CID displayed enhanced sequential killing capabilities at a 1:1 ratio, compared to CD20.CD123-ENG T-cells.
Conclusion: CD20.CD123-ENG.iMC T-cells recognize and kill CD123+ AML blasts in an antigen dependent manner. In addition, control ENG.iMC T-cells have no antitumor activity, indicating that activation of Myd88/CD40 does not induce nonspecific AML blast killing. CD20.CD123-ENG.iMC T-cells have improved effector function in the presence of CID as judged by increased cytokine production and their ability to sequentially kill CD123+ target cells in vitro. Based on our promising in vitro experiments, we have initiated in vivo studies in AML xenograft models, which are currently in progress.

Disclosures
Leen: Marker: Equity Ownership.
The Fate of Patients with Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Authors: Otahal Pavel , Janikova Andrea , Belada David , Prochazka Vit , Mocikova Heidi , Pirnos Jan , Ďuraš Juraj , Kopečková Kateřina , Campr Vit , Pytlik Robert , Blahovcova Petra , Trneny Marek 
Published: October 2019

Abstract
Background:
The outcome of DLBCL patients is improving, it however seems to be very poor for those who are refractory to the therapy. We have decided to analyze this group of patients.
Methodology:
As part of an observational clinical study NiHiL (GovTrial No NCT03199066) we identified the patients treated in the first line by R-CHOP like immunochemotherapy who met at least one criterium: 1. refractory (stable disease - SD or progression) on 1st line therapy (1st l- R), 2. refractory (SD or progression) on salvage (platinum based regimen) (Salv-R), 3. refractory to or relapse/progression within 12 months after ASCT (ASCT-R/R). There were 210 patients diagnosed in the period 2001-2017 who fulfilled the criteria. Progression-free survival (PSF) and overall survival (OS) were estimated from the time of determination of a refractory disease.
Results:
The cohort consisted of 163 patients primarily resistant to the first-line therapy, 31 patients were resistant to the salvage therapy and 16 patients progressed within 12 months after ASCT . At the time of the diagnosis, the median age was 65 years (22-91) (the same as at the refractory disease), 54% were males, 74% had advanced clinical stage (III+IV), 68% had IPI >3, 77% had above-normal LDH, and 45% had a tumor mass >10cm.
The OS from the time of determination of refractory disease was 0.53 years, median PFS was 0.29 years. Patients under 65 years had median survival 0.8 years compared to 0.4 years in the group of patients above 65 years of age. The median PFS for 1st l-R, Salv-R and ASCT-R/R resp. was 0.3, 0.26 and 0.35 years resp. and 5y survival 22%, 0% and 6% resp. The median OS for 1st l-R, Salv-R and ASCT-R/R resp. was 0.55, 0.39 and 0.65 y resp. and 5y survival was 28%, 0% and 13% resp.
Our results demonstrate that resistant DLBCL has an extremely poor prognosis, clearly new effective therapeutic strategies such as CAR-based therapies or others are required.
This work was supported by a research program Progres Q28-9.

Disclosures
Belada: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Target of Erythropoietin, Fam210b, Regulates Erythroid Heme Synthesis By Control of Mitochondrial Iron Import and Regulation of Fech Activity
Authors: Yien Yvette Y , Shi Jiahai , Chen Caiyong , Cheung Jesmine , Grillo Anthony , Shrestha Rishna , Li Liangtao , Zhang Xuedi , Kafina Martin Daniel , Kingsley Paul D. , King Matthew , Ablain Julien , Zon Leonard I. , Palis James , Burke Martin , Bauer Daniel E. , Orkin Stuart H. , Koehler Carla , Phillips John D. , Kaplan Jerry , Ward Diane , Lodish Harvey 
Published: October 2019

Abstract
Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well understood. To better understand these regulatory mechanisms, we profiled gene expression in EPO-treated fetal liver cells to identify novel iron regulatory genes (Figure A). We determined that FAM210B, a mitochondrial inner membrane protein, was essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation (Figure B). Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation (Figure C). These defects were corrected with a lipid-soluble small molecule iron transporter in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter, but is required for optimal mitochondrial iron import during erythroid differentiation (Figure D). FAM210B is also required for optimal FECH activity in differentiating erythroid cells. As FAM210B interacts with the terminal enzymes of the heme synthesis pathway, we propose that FAM210B functions as an adaptor protein to facilitate the formation of an oligomeric mitochondrial iron transport complex, which is required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis (Figure E). Collectively, our data reveal a novel mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.
Figure. Figure.

Disclosures
Palis: Rubies Therapeutics: Consultancy.
Lung clearance index in detection of post-transplant bronchiolitis obliterans syndrome
Authors: Driskel Madeleine , Horsley Alex , Fretwell Laurice , Clayton Nigel , Al-Aloul Mohamed 
Published: October 2019

BackgroundLong-term outcomes after lung transplantation are often limited by the development of obliterative bronchiolitis (OB), which is clinically defined using spirometry as bronchiolitis obliterans syndrome (BOS). Lung clearance index (LCI), derived from multiple breath washout (MBW) testing, is a global measure of ventilation heterogeneity that has previously been shown to be a more sensitive measure of obstructive small airway diseases than spirometry. We aimed to assess the feasibility of LCI in adult lung transplant patients and to compare LCI to BOS grade.Methods51 stable adult double-lung transplant recipients performed sulfur hexafluoride MBW in triplicate on a single occasion, using a closed-circuit Innocor device. BOS grades were derived from serial spirometry according to International Society for Heart and Lung Transplantation criteria and, where available, high-resolution computed tomography (HRCT) evidence of OB was recorded.ResultsLCI was successfully performed in 98% of patients. The within-visit coefficient of variation for repeat LCI measurements was 3.1%. Mean LCI increased significantly with BOS grades: no BOS (n=15), LCI 7.6; BOS-0p (n=16), LCI 8.3; BOS-1 (n=11), LCI 9.3; BOS-2–3 (n=9), LCI 13.2 (p<0.001). 27 patients had HRCT within 12 months. LCI in those with HRCT evidence of OB was higher than those without OB (11.1versus8.2, p=0.006). 47% patients displayed abnormal LCI (>7) despite a normal forced expiratory volume in 1 s (FEV1) (>80% of baseline).ConclusionsLCI measurement in lung transplant recipients is feasible and reproducible. LCI increased with increasing BOS grade. A significant proportion of this cohort had abnormal LCI with preserved FEV1, suggesting early subclinical small airway dysfunction, and supporting a role for MBW in the early identification of BOS.
Small RNA and degradome deep sequencing reveal respective roles of cold-related microRNAs across Chinese wild grapevine and cultivated grapevine
Authors: Wang Pengfei , Yang Yang , Shi Hongmei , Wang Yongmei , Ren Fengshan 
Published: October 2019

Abstract

Background
Chinese wild grapevine (Vitis amurensis) has remarkable cold stress tolerance, exceeding that of the common cultivated grapevine (Vitis vinifera L.).

Result
Here, we surveyed the expression dynamics of microRNAs (miRNAs) across Chinese wild grapevine (cv. Beibinghong) and cultivated grapevine (cv. Cabernet Sauvignon) under cold stress using high-throughput sequencing. We identified 186 known miRNAs in cultivated grape and 427 known miRNAs in Beibinghong. Of the identified miRNAs, 59 are conserved miRNAs orthologous in Cabernet Sauvignon and Beibinghong. In addition, 105 and 129 novel miRNAs were identified in Cabernet Sauvignon and Beibinghong, respectively. The expression of some miRNAs was related to cold stress both in Cabernet Sauvignon and Beibinghong. Many cold-related miRNAs in Cabernet Sauvignon and Beibinghong were predicted to target stress response-related genes such as MYB, WRKY, bHLH transcription factor genes, and heat shock protein genes. However, the expression tendency under cold treatment of many of these miRNAs was different between Cabernet Sauvignon and Beibinghong. Different modes of expression of cultivated and Chinese wild grape miRNAs were indicated in key pathways under cold stress by degradome, target prediction, GO, and KEGG analyses.

Conclusion
Our study indicated three likely reasons that led to the different cold stress tolerance levels of Cabernet Sauvignon and Beibinghong. Specifically, there may be (1) differential expression of orthologous miRNAs between cultivated grapevine and Chinese wild grape; (2) species-specific miRNAs or target genes; or (3) different regulatory models of miRNAs in cultivated and Chinese wild grape in some key pathways.
Ataxia as the main manifestation of tumor-like primary angiitis of the central nervous system: a case report and literature review
Authors: Huang Yu-Jing , Zhang Li , Mao Ying , Nan Guang-Xian 
Published: October 2019

Abstract

Background
Primary angiitis of the central nervous system (PACNS) is a rare disease, and tumor-like primary angiitis of the central nervous system is even rarer. Histopathology is the gold standard for tumor-mimicking PACNS. However, pathological diagnosis is relatively limited due to fewer biopsy opportunities.

Case presentation
A 68-year-old male presented with ataxia, and was diagnosed with tumor-like primary angiitis of the central nervous system. The patient underwent Intravenous drip glucocorticoid therapy (10 mg of dexamethasone, daily). After 10 days, the symptoms of the patient were completely relieved. Radiology revealed that the low density lesion in the right cerebellar hemisphere obviously narrowed. Cyclophosphamide therapy was not initiated.

Conclusion
It is crucial for clinicians to be aware of changes in radiology that indicate PACNS, since the diagnosis of tumor-like PACNS remains quite challenging. Glucocorticoid therapy is an effective therapy in this condition, and the prognosis can be favorable.
A risk factor for early wheezing in infants: rapid weight gain
Authors: Yin Lijuan , Song Ye , Liu Yongfang , Ye Zehui 
Published: October 2019

Abstract

Background
The aim of this study was to investigate the correlation between rapid weight gain and early wheezing.

Methods
This study screened 701 infants with lower respiratory tract infection who were no more than 4 months from Jan 1st to Dec 31st in 2018. According to weight-for-age Z-value (WAZ), these infants were divided into the considerably slow weight gain group (group I), the normal weight gain group (group II) and the excessively rapid weight gain group (group III), respectively. The clinical characteristics, weight growth speeds and serum lipid levels were analyzed, and multivariable Logistic model was conducted to select significant variables.

Results
Our results showed that male (OR = 1.841, 95%CI: 1.233–2.751), family wheezing (OR = 5.118, 95%CI: 2.118–12.365), age (OR = 1.273, 95%CI: 1.155–1.403), eczema (OR = 2.769, 95%CI: 1.793–4.275), respiratory syncytial virus (RSV) infection (OR = 1.790, 95%CI: 1.230–2.604), birth weight (OR = 1.746, 95%CI: 1.110–2.746) and total cholesterol (TC) (OR = 1.027, 95%CI: 1.019–1.036) and ΔWAZ (OR = 1.182, 95%CI: 1.022–1.368) were associated with early wheezing. Results indicated that serum TC (P = 0.018) and ΔWAZ (P = 0.023) were positive correlation with wheezing days.

Conclusion
Besides male, family wheezing, age, eczema, RSV infection, birth weight and TC, the rapid weight growth as a risk factor should be concerned in the early wheezing infants.
Immunosuppressive effect of hispidulin in allergic contact dermatitis
Authors: Thitilertdecha Premrutai , Pluangnooch Panwadee , Timalsena Sunita , Soontrapa Kitipong 
Published: October 2019

Abstract

Background
Long-term use of most immunosuppressants to treat allergic contact dermatitis (ACD) generates unavoidable severe side effects, warranting discovery or development of new immunosuppressants with good efficacy and low toxicity is urgently needed to treat this condition. Hispidulin, a flavonoid compound that can be delivered topically due to its favorable skin penetrability properties, has recently been reported to possess anti-inflammatory and immunosuppressive properties. However, no studies have investigated the effect of hispidulin on Th1 cell activities in an ACD setting.

Methods
A contact hypersensitivity (CHS) mouse model was designed to simulate human ACD. The immunosuppressive effect of hispidulin was investigated via ear thickness, histologic changes (i.e., edema and spongiosis), and interferon-gamma (IFN-γ) gene expression in 1-fluoro-2,4-dinitrobenzene (DNFB)-sensitized mice. Cytotoxicity, total number of CD4+ T cells, and percentage of IFN-γ-producing CD4+ T cells were also investigated in vitro using isolated CD4+ T cells from murine spleens.

Results
Topically applied hispidulin effectively inhibited ear swelling (as measured by reduction in ear thickness), and reduced spongiosis, IFN-γ gene expression, and the number of infiltrated immune cells. The inhibitory effect of hispidulin was observed within 6 h after the challenge, and the observed effects were similar to those effectuated after dexamethasone administration. Hispidulin at a concentration up to 50 μM also suppressed IFN-γ-producing CD4+ T cells in a dose-dependent manner without inducing cell death, and without a change in total frequencies of CD4+ T cells among different concentration groups.

Conclusion
The results of this study, therefore, suggest hispidulin as a novel compound for the treatment of ACD via the suppression of IFN-γ production in Th1 cells.
Evaluating treatment modalities in chronic pain treatment by the multi-criteria decision making procedure
Authors: Sir Ender , Batur Sir Gül Didem 
Published: October 2019

Abstract

Background
Chronic pain is one of the most common complaints of cancer patients. There are many pharmacological and non-pharmacological treatment modalities used for the treatment of pain. Nonetheless, non-pharmacological interventions are preferred because of potential side effects in cases resistant to medical therapy that require a dose increase or potent drug use. In most real-life situations, the decision on which technique to choose is based on the clinical but subjective decisions of the practitioners. This study aimed to find out the best non-pharmacological treatment option for patients with chronic cancer pain by following a rational and reasonable approach.

Methods
Since the evaluation of treatment options requires to make a comparison between a number of alternatives in the light of certain criteria, we utilize the order relation analysis (G1-method) which is a method for determining the weights based on the improved Analytic Hierarchy Process (AHP). The method uses the relative importances on prioritizing the four criteria and eight sub-criteria defined by the experts of three pain physicians, one oncologist, and one oncologic surgeon. Four alternatives are then compared according to the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) using the verbal subjective judgments of the practitioners.

Results
Obtained results indicate that the general medical condition of the patient and the stage of the cancer are the essential factors in the selection of the treatment method. It is followed by the extent of the pain and the level of evidence, respectively. According to the evaluations performed, spinal port and splanchnic nerve radiofrequency thermocoagulation treatments are the first and second priority methods for pain treatment, respectively, compared to lumbar epidural catheter and celiac plexus block.

Conclusions
The results of this study emphasize the need to integrate critical criteria into the decision-making process objectively. This is the first study in which multi-criteria decision-making tools are used in the evaluation and selection of pain management methods in cancer patients.
A novel endothelial damage inhibitor for the treatment of vascular conduits in coronary artery bypass grafting: protocol and rationale for the European, multicentre, prospective, observational DuraGraft registry
Authors: Caliskan Etem , Sandner Sigrid , Misfeld Martin , Aramendi Jose , Salzberg Sacha P. , Choi Yeong-Hoon , Satishchandran Vilas , Iyer Geeta , Perrault Louis P. , Böning Andreas , Emmert Maximilian Y. 
Published: October 2019

Abstract

Background
Vein graft disease (VGD) impairs graft patency rates and long-term outcomes after coronary artery bypass grafting (CABG). DuraGraft is a novel endothelial-damage inhibitor developed to efficiently protect the structural and functional integrity of the vascular endothelium. The DuraGraft registry will evaluate the long-term clinical outcomes of DuraGraft in patients undergoing CABG procedures.

Methods
This ongoing multicentre, prospective observational registry will enrol 3000 patients undergoing an isolated CABG procedure or a combined procedure (ie, CABG plus valve surgery or other surgery) with at least one saphenous vein grafts or one free arterial graft (ie, radial artery or mammary artery). If a patient is enrolled, all free grafts (SVG and arterial will be treated with DuraGraft. Data on baseline, clinical, and angiographic characteristics as well as procedural and clinical events will be collected.
The primary outcome measure is the occurrence of a major adverse cardiac event (MACE; defined as death, non-fatal myocardial-infarction, or need for repeat-revascularisation). Secondary outcome measures are the occurrence of major adverse cardiac and cerebrovascular events (MACCE; defined as death, non-fatal myocardial-infarction, repeat-revascularisation, or stroke), patient-reported quality of life, and health-economic data. Patient assessments will be performed during hospitalisation, at 1-month, 1-year, and annually thereafter to 5 years post-CABG. Events will be adjudicated by an independent clinical events committee. This European, multi-institutional registry will provide detailed insights into clinical outcome associated with DuraGraft.

Discussion
This European, multi-institutional registry will provide detailed insights into clinical outcome associated with the use of DuraGraft. Beyond that, and given the comprehensive data sets comprising of patient, procedural, and graft parameters that are being collected, the registry will enable for multiple subgroup analyses targeting focus groups or specific clinical questions. These may include analysis of subpopulations such as patients with diabetes or multimorbid high-risk patients (patient level), evaluation of relevance of harvesting technique including endoscopic versus open conduit harvesting (procedural level), or particular graft-specific aspects (conduit level).

Trial registration
ClinicalTrials.gov NCT02922088. Registered October 3, 2016.

Ethics and dissemination
The regional ethics committees have approved the registry. Results will be submitted for publication.