tbuckley/cabot-search huggingface dataset:
Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models
Authors: Kyeongdae Kim, Dahee Shim, Jun Seong Lee, Konstantin Zaitsev, Jesse W. Williams, Ki-Wook Kim, Man-Young Jang, Hyung Seok Jang, Tae Jin Yun, Seung Hyun Lee, Won Kee Yoon, Annik Prat, Nabil G. Seidah, Jungsoon Choi, Seung-Pyo Lee, Sang-Ho Yoon, Jin Wu Nam, Je Kyung Seong, Goo Taeg Oh, Gwendalyn J. Randolph, Maxim N. Artyomov, Cheolho Cheong, Jae-Hoon Choi
Journal: Circulation Research (2018)

Rationale: Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis. Objective: We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima. Methods and Results: Single-cell RNA sequencing analysis of CD45 + leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining–based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPY hi SSC hi foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1β and many other inflammatory transcripts in atherosclerotic aorta. Conclusions: RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.
Sox12 promotes T reg differentiation in the periphery during colitis
Authors: Shigeru Tanaka, Akira Suto, Taro Iwamoto, Takahiro Kageyama, Tomohiro Tamachi, Hiroaki Takatori, Kotaro Suzuki, Koichi Hirose, Osamu Ohara, Véronique Lefebvre, Hiroshi Nakajima
Journal: The Journal of Experimental Medicine (2018)

Peripherally induced regulatory T (pT reg) cells play indispensable roles in regulating gut inflammation; however, the mechanism underling the differentiation of pT reg cells under inflammatory conditions remains largely unknown. Here, we show that the expression of Sox12, a member of SoxC family, is significantly induced in T reg cells in colitic mice. We also show that TCR–NFAT signaling induces Sox12 expression in CD4+ T cells. Although Sox12 is not required for the development of thymus-derived T reg (tT reg) cells, Sox12 is involved in the development of pT reg cells under inflammatory conditions in an adoptive transfer colitis model. Moreover, we found that enforced expression of Sox12 is sufficient to promote Foxp3 expression in CD4+ T cells even in the absence of TGF-β or IL-2 and that Sox12 binds to Foxp3 promoter and drives its transcription. These results suggest that TCR-NFAT signaling induces the development of pT reg cells in colitic mice partly through Sox12 induction.
Impact of additional cytogenetic abnormalities on clinical outcomes in chronic myeloid leukemia: First report in a Latin American population.
Authors: Christianne Bourlon, Katherinee Morales-Chacon, Aldo Adrian Medina-Acosta, Alvaro Aguayo, Victor Manuel Anguiano-Alvarez, Maria Teresa Bourlon, Antonio Olivas-Martinez, Elena Tuna-Aguilar
Journal: Journal of Clinical Oncology (2018)

e19023 Background: Additional cytogenetic abnormalities (ACAs) that arise within Philadelphia-positive cells in patients with chronic myeloid leukemia (CML), have been reported in 10%, 30%, and 90% of chronic, accelerated, and blastic phase, respectively. Their presence is related to an increased risk of treatment failure, leukemic progression, and decreased survival. However, there is no data in the Latin American population. The aim of this study, was to outline the impact of ACAs emergence in Mexican patients with CML. Methods: We retrospectively analyzed clinical data of adult patients with CML treated with upfront imatinib with assessable diagnostic and follow-up cytogenetics at our institution, within 2001 and 2016. Two groups were defined for comparison according to the presence of ACAs: ACAs and non-ACAs. Results: A total of 97 CML patients were included. In 30 patients (30.1%) ACAs were found, 20% at diagnosis, and 80% during follow-up. The emergence was detected in chronic phase in 90%. Baseline characteristics between ACAs and non-ACAs groups had no significant differences. Regarding clinical outcomes: rate of CCyR at last follow-up (16.5% vs 59.8%; p < .001), PFS at 10-years (76% vs 95%; p = .009), and FFS at 10-years (16% vs 73%; p < .001) were significantly inferior in the ACAs patients. Multivariate analysis confirmed that ACAs emergence was a deleterious independent prognostic factor for PFS (HR 8.9; 95% CI 1.35-58.4; p = .023) and FFS (HR 3.7; 95% CI 1.54-8.58; p = .003). Other cytogenetic abnormalities found in Philadelphia-negative cells were observed in 24.7%. When compared with ACAs and non-ACAs groups, their presence was not related to worse clinical outcome. Conclusions: To our knowledge, this is the first study to demonstrate the adverse impact of ACAs emergence in a Latin American population. We must urge multicenter collaboration to validate our results and establish more efficient diagnostic and management strategies to improve outcomes in this group of patients with unfavorable prognosis.
The delivery of value-based healthcare for children with osteosarcoma at Children’s Cancer Hospital Egypt.
Authors: Ranin Soliman, Wael Eweida, Manal Zamzam, Alaa Elhaddad, Sherif Abouelnaga
Journal: Journal of Clinical Oncology (2017)

e18310 Background: Aim of the study was to develop a system to measure the value of health care services delivered to osteosarcoma patients, through developing a standardized set of patient-centered outcomes for Osteosarcoma and using a consistent approach to measure the costs of Osteosarcoma care throughout all care cycles. Methods: The Porter’s Outcomes Measurement Hierarchy was used to define the domains of outcomes reporting for Osteosarcoma, which included three levels of measuring outcomes; health status achieved or retained, process of recovery, and sustainability of health. Time-driven activity-based costing (TDABC) approach was used a guide to determine the actual costs of healthcare services delivered to Osteosarcoma patients throughout their journey of cure. Results: Osteosarcoma outcome measurement tools and questionnaires were standardized based on the following domains: survival, degree of health or recovery, time to recovery and return to normal activities, disutility of care and treatment processes, sustainability of health and nature of recurrences, and the long-term consequences of therapy. The standardized outcome reporting tools under each domain included: toxicity reporting using NCI-Common Toxicity Criteria version 4.0, Pediatric Quality of Life Inventory (PedsQL) Cancer module, Musculoskeletal Tumour Society Score (MSTS) for functional outcome assessment, Palliative Care Outcomes Scale (POS). Process mapping was done for each step involved in the delivery of health care services to children with Osteosarcoma at Children’s Cancer hospital Egypt (57357 Hospital). Conclusions: Developing a standardized system for measuring the health outcomes of Osteosarcoma and the total costs for delivering the health care services is fundamental to measure and improve the value of health care delivered to Osteosarcoma patients.
Aggressiveness of care at the end of life in patients with localized and advanced bladder cancer.
Authors: Olivier Huillard, Francois Goldwasser, Lucas Morin
Journal: Journal of Clinical Oncology (2016)

10029 Background: Metastatic or locally advanced bladder cancer is a severe non-curable disease and patients may benefit from early and integrated palliative care. Localized bladder cancer is a curable disease but patients’ comorbidities may limit their ability to receive and tolerate optimal care. We hypothesized that in this setting the goals of care may be difficult to determine and that inadequate aggressiveness exists. Methods: Retrospective cohort study of electronic records of all hospitalized adults ( ≥ 20 years) who died from bladder cancer between 2010 and 2013 in France. Individuals with co-occurring primary malignancies affecting other organs were excluded. Results: A total of 17,306 patients died from bladder cancer and were included. Among them 8,766 (50,1%) had a metastatic or locally advanced (i.e. with lymph nodes involvement) disease and 8,540 (49,9%) had a local disease. At least one comorbidity existed for 69.2% of patients with local disease compared to 53.2% of patients with advanced disease (p < 0.001). In the last month before death, 13,4% of patients with advanced cancer received chemotherapy, 6,9% artificial nutrition, 2,4% invasive ventilation, 2,6% dialysis, 4,0% hemodynamic support. 20,6% were admitted in ICU. Palliative care needs were first identified more than 30 days before death for 17,6% of patients with local disease and for 24,8% of patients with advanced disease (p < 0.001). 48,9% of patients with local disease and 26,6% of patients with advanced cancer died without any prior identification of their palliative care needs (p < 0.001). Conclusions: In the study, prognosis and palliative care needs are often underestimated in advanced bladder cancer patients resulting in important aggressiveness of care at the end of life. Furthermore, a high proportion of the patients died from localized bladder cancer and had a high burden of comorbidity. Our results suggest some individuals of this frail population may not be eligible for the standard of care of localized disease resulting in inadequate aggressiveness of care.
Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer
Authors: Jason M. Redman, Seth M. Steinberg, James L. Gulley
Journal: Journal for ImmunoTherapy of Cancer (2018)

Advances in immunotherapy utilizing immune checkpoint inhibitors (ICIs) have transformed the treatment landscapes of several malignancies in recent years. Oncologists are now tasked with extending these benefits to a greater number of patients and tumor types. Metastatic castration-resistant prostate cancer (mCRPC) infrequently responds to ICIs, while the cellular vaccine approved for mCRPC, sipuleucel-T, provides a 4-month survival benefit but does not produce clinical responses as monotherapy. However, many novel and generally well-tolerated immune oncology agents with potential for immune synergy and/or additive effects are undergoing clinical development. This availability presents opportunities to develop adaptive-design combination clinical trials aimed to generate, expand, and facilitate antitumor immune responses. Here we describe a currently accruing phase I/II trial (NCT03493945) testing a brachyury-targeted antitumor vaccine, TGF-β TRAP/anti-PD-L1 antibody, an IL-15 agonist, and an IDO1 inhibitor in mCRPC.This trial ( NCT03493945 ) was registered in National Clinical Trials on April 11th 2018.
Abstract 14571: Prospective Randomized Comparisonof Miniaturized Extracorporeal Circulation System (MECC) versus Conventional Extracorporeal Circulation System (cecc) in the Prevention of Postoperative Atrial Fibrillation (FA) and Other Clinical Results in Cardiac Surgery Patients
Authors: Sten Ellam, Pekka Korvenoja, Juha Hartikainen, Antti Valtola, Mikko Hippelainen, Otto Pitkanen, Jari Halonen
Journal: Circulation (2015)

Introduction: Postoperative atrial fibrillation (AF) is the most common arrhythmia to occur after cardic surgery with an incidence between 20-45 %. It is associated with increased morbidity, including increased risk of stroke and need for additional treatment and costs. The pathophysiology of postoperative AF is not fully understood.cardiac surgery with extracorporeal circulation is known to be associated with a systemic inflammatory response,which may be in part responsible for postoperative AF. furthermore,foreign surface contact,blood-air contact,abnormal blood flow and hemodilution are broblems related to extracorporeal circulation. Hypothesis and Methods: In this prospective,randomized,open labelled clinical study,240 cardiac surgery patients were randomized either miniaturized extracorporeal circulation (MECC) group or conventional extracorporeal circulation (CECC) group before the surgery. The main outcome measure was the incidence of postoperative atrial fibrillation (AF) during the hospital stay after surgery. Other end points were use of blood products and vasoactive agents and the first (CKMBm) value postoperatively. Results: The incidence of postoperative atrial fibrillation was 43/120 (35.8 %) in the conventional extracorporeal circulation group (CECC) compared with 42/120 (35.0%) in the miniaturized extracorporeal circulation group (MECC) (p=0.893). The use of perioperative vasoactive agents was significantly lower in the (MECC) group compared with (CECC) group . Furthermore, the first postoperative CKMBm value was significantly lower in (MECC) patient group than in (CECC) patient group. There were no difference in the use of blood products between the groups. Conclusion: The clinical use of MECC with cardiac operative patients is safe and results are optimal when this procedure is performed by experienced teams. There were no difference in the incidence of postoperatrive atrial fibrillation (AF) between the groups, but the use of vasoactive agents was lower in (MECC) patient group, than in (CECC) patient group and also the first postoperative (CKMBm) value was lower in the (MECC) group than in (CECC) group.
P05.19 Hippocampal N - acetylaspartate concentration correlates to verbal memory before radiotherapy for brain metastases
Authors: R Jancalek, P Solar, P Pospisil, M Bulik, P Burkon, L Hynkova, P Slampa, J Sana, O Slaby, T Kazda
Journal: Neuro-Oncology (2018)

Changes of quality of life and cognitive function (especially verbal memory) after brain radiotherapy is currently widely discussed in neurooncology with substantial change in the paradigm of treatment of patients with brain metastases. In our previous prospective study, we described a decrease in the hippocampal concentration of N-acetylaspartate (NAA, marker of neuronal density and viability) in response to whole brain radiotherapy (WBRT). These changes may be at least partially responsible for subsequent memory impairment. The aim of presented secondary analysis is to evaluate the baseline NAA concentration (ie, before radiotherapy) in all enrolled patients and to describe the relation to the baseline verbal memory. Patients with brain metastases indicated to WBRT underwent hippocampal MR spectroscopy (MRS) along with neuropsychological examinations focused among others to verbal memory. The areas of interest in MRS were temporal lobes, the voxel layer was adapted to the area of hippocampus. A specialized java Spectroscopic Imaging Processing Software (jSIPRO) was used to calculate the absolute [mM] NAA concentrations in individual voxels. Verbal memory was evaluated using the Auditory Verbal Learning Test with the main subtest being total recall (AVLT_TR). Absolute NAA concentrations for right and left hippocampus and the sum of absolute NAA concentrations in both hippocampi were correlated to results of AVLT_TR. The examination was performed in 26 patients. Patients were divided into two groups based on median NAA concentration (8.56 mM). The median AVLT_TR was 37 points in the group with hippocampal NAA concentration ˂8.56 mM. In the group of patients with baseline NAA concentration ≥ 8.56 mM, the median AVLT_TR was higher with 43 points (Mann-Whitney U Test, p = 0.02). Non-invasive examination by hippocampal MRS can predict the baseline preradiotherapy cognitive functions (the most important domain in relation to radiotherapy of brain metastases is verbal memory), which are normally tested by time-consuming and difficult for patients psychological tests. Patients in our cohort who had lower baseline NAA hippocampal concentrations had a significantly lower baseline verbal memory. NAA hippocampal concentrations may be a useful biomarker for selecting patients who would benefit most from the subsequent special radiotherapy techniques such as hippocampal sparing WBRT or other procedures reducing the risk of iatrogenic deterioration of quality of life in patients treated with a palliative intent, especially in cases where local brain stereotactic radiotherapy is not applicable or available.
Targeted Alpha Therapy, an Emerging Class of Cancer Agents
Authors: Christopher Parker, Valerie Lewington, Neal Shore, Clemens Kratochwil, Moshe Levy, Ola Lindén, Walter Noordzij, Jae Park, Fred Saad
Journal: JAMA Oncology (2018)

Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types.Theoretically, the high-energy emission of short-range alpha particles causes complex double-stranded DNA breaks, eliciting cell death. No known resistance mechanism to alpha particles has been reported or scientifically established. The short-range emission of alpha particle radiation confines its cytotoxic effect to cancerous lesions and the surrounding tumor microenvironment while limiting toxic effects to noncancerous tissues. The high level of radiobiological effectiveness of alpha particles, in comparison with beta emissions, requires fewer particle tracks to induce cell death. Clinically effective alpha particle-emitting isotopes for cancer therapy should have a short half-life, which will limit long-term radiation exposure and allow for the production, preparation, and administration of these isotopes for clinical use and application. Radium 223 dichloride is the first-in-class, commercially available targeted alpha therapy approved for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases. Given the established overall survival benefit conferred by radium 223 for patients with metastatic castration-resistant prostate cancer, several other targeted alpha therapies are being investigated in clinical trials across many tumor types.Targeted alpha therapy represents an emerging treatment approach and provides for the possibility to bypass mechanisms of acquired resistance in selected tumors. In addition, developing novel radionuclide conjugation strategies may overcome targeting limitations. So far, the clinical success of radium 223 has demonstrated the proof of concept for targeted alpha therapy, and future studies may lead to additional treatment options for many cancer types.
P04.61 Effects of TRAP1 on expression of glycolytic enzymes in glioblastoma stem cells
Authors: J Wu, S Zhao
Journal: Neuro-Oncology (2018)

Tumor necrosis factor receptor-associated protein 1 (TRAP1) belongs to the HSP90 family, mainly presents in mitochondria.TRAP1 is highly expressed in many cancer cells, and it controls a variety of physiological functions, including cell survival, passage and differentiation. TRAP1 protects mitochondrial integrity, regulates the amount of oxygen free radicals and prevents apoptosis. Moreover, TRAP1 is critical to the Warburg effect in tumor cells. Tumor stem cells have long been considered the cause of tumor recurrence, TRAP1 may be involved in the stemness maintenance and metabolic reprogramming of cancer stem cells, which makes it possible to be a therapeutic target for tumor disease. In this study, we studied the effect of TRAP1 on the expression of glycolytic enzymes in glioblastoma stem cells, and laid the foundation for the future treatment of glioblastoma. Induced the tumor stem cell enrich and the format into the tumor ball by cell suspension culture with the serum-free DMEM-F12 medium supplemented which contains bFGF and EGF. The expression of TRAP1 and glioblastoma stem cell marker CD133 in glioblastoma cancer cell line siRNA-TRAP1 and NC group was detected by immunofluorescence. Western blotting technique was used to detect the expression of TRAP1 and phosphofructokinase, lactate dehydrogenase A, hexokinase I, pyruvate kinase 1/2, hexokinase II, Pyruvate kinase 2, pyruvate dehydrogenase in the shRNA-TRAP1 and NC groups of glioblastoma stem cells, and glyceraldehyde-3-phosphate dehydrogenase was used as internal reference. In cultured glioblastoma stem cell spheres, immunofluorescence results verified the tumor surface of the tumor stem cell markers CD133 was positive. Immunofluorescence results showed that the expression of CD133 in tumor stem cells was decreased after the silencing of TRAP1 gene expression in glioblastoma stem cells. Western blotting results showed that the expression of Glycolysis related enzymes like phosphoglycans kinase, hexokinase I, hexokinase II, pyruvate kinase 1/2, pyruvate kinase 2 and pyruvate dehydrogenase was decreased and the lactate dehydrogenase A was increased after the silencing of TRAP1 gene expression in glioblastoma stem cells. TRAP1 may be involved in the stemness maintenance of glioblastoma stem cells. TRAP1 is involved in the regulation of metabolic reprogramming of glioblastoma stem cells by regulating the expression of glycolytic enzymes.