tbuckley/cabot-search huggingface dataset:
Stable colony-stimulating factor 1 fusion protein treatment increases hematopoietic stem cell pool and enhances their mobilisation in mice
Authors: Simranpreet Kaur, Anuj Sehgal, Andy C. Wu, Susan M. Millard, Lena Batoon, Cheyenne J. Sandrock, Michelle Ferrari-Cestari, Jean-Pierre Levesque, David A. Hume, Liza J. Raggatt, Allison R. Pettit
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with modified recombinant colony-stimulating factor 1 (CSF1) to influence the HSC niche and expand the HSC pool for autologous transplantation. Methods We administered an acute treatment regimen of CSF1 Fc fusion protein (CSF1-Fc, daily injection for 4 consecutive days) to naive C57Bl/6 mice. Treatment impacts on macrophage and HSC number, HSC function and overall hematopoiesis were assessed at both the predicted peak drug action and during post-treatment recovery. A serial treatment strategy using CSF1-Fc followed by granulocyte colony-stimulating factor (G-CSF) was used to interrogate HSC mobilisation impacts. Outcomes were assessed by in situ imaging and ex vivo standard and imaging flow cytometry with functional validation by colony formation and competitive transplantation assay. Results CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of hematopoiesis was accompanied by an increase in the total available HSPC pool. Multiple approaches confirmed that CD48 − CD150 + HSC do not express the CSF1 receptor, ruling out direct action of CSF1-Fc on these cells. In the spleen, increased HSC was associated with expression of the BM HSC niche macrophage marker CD169 in red pulp macrophages, suggesting elevated spleen engraftment with CD48 − CD150 + HSC was secondary to CSF1-Fc macrophage impacts. Competitive transplant assays demonstrated that pre-treatment of donors with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of G-CSF treatment. Conclusion These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve HSC transplantation outcomes.
Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom
Authors: Belinda S. Lennerz, Andrew P. Koutnik, Svetlana Azova, Joseph I. Wolfsdorf, David S. Ludwig
Journal: Journal of Clinical Investigation (2021)

Carbohydrate restriction, used since the 1700s to prolong survival in people with diabetes, fell out of favor after the discovery of insulin. Despite costly pharmacological and technological developments in the last few decades, current therapies do not achieve optimal outcomes, and most people with diabetes remain at high risk for micro- and macrovascular complications. Recently, low-carbohydrate diets have regained popularity, with preliminary evidence of benefit for body weight, postprandial hyperglycemia, hyperinsulinemia, and other cardiometabolic risk factors in type 2 diabetes and, with more limited data, in type 1 diabetes. High-quality, long-term trials are needed to assess safety concerns and determine whether this old dietary approach might help people with diabetes attain clinical targets more effectively, and at a lower cost, than conventional treatment.
Integrating Mitochondrial Aerobic Metabolism into Ecology and Evolution
Authors: Rebecca E. Koch, Katherine L. Buchanan, Stefania Casagrande, Ondi Crino, Damian K. Dowling, Geoffrey E. Hill, Wendy R. Hood, Matthew McKenzie, Mylene M. Mariette, Daniel W.A. Noble, Alexandra Pavlova, Frank Seebacher, Paul Sunnucks, Eve Udino, Craig R. White, Karine Salin, Antoine Stier
Journal: Trends in Ecology & Evolution (2021)
Coronary Plaque Characterization by Computed Tomographic Angiography: Present Promise and Future Hope⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: James A. Goldstein
Journal: JACC. Cardiovascular imaging (2009)
Aberrant Activation of Notch1 Signaling in Glomerular Endothelium Induces Albuminuria
Authors: Liqun Li, Qiang Liu, Tongyao Shang, Wei Song, Dongmei Xu, Thaddeus D. Allen, Xia Wang, James Jeong, Corrinne G. Lobe, Ju Liu
Journal: Circulation Research (2021)

Glomerular capillaries are lined with a highly specialized fenestrated endothelium and contribute to the glomerular filtration barrier. The Notch signaling pathway is involved in regulation of glomerular filtration barrier, but its role in glomerular endothelium has not been investigated due to the embryonic lethality of animal models with genetic modification of Notch pathway components in the endothelium.To determine the effects of aberrant activation of the Notch signaling in glomerular endothelium and the underlying molecular mechanisms.We established the ZEG-NICD1 (notch1 intracellular domain)/Tie2-tTA/Tet-O-Cre transgenic mouse model to constitutively activate Notch1 signaling in endothelial cells of adult mice. The triple transgenic mice developed severe albuminuria with significantly decreased VE-cadherin (vascular endothelial cadherin) expression in the glomerular endothelium. In vitro studies showed that either NICD1 (Notch1 intracellular domain) lentiviral infection or treatment with Notch ligand DLL4 (delta-like ligand 4) markedly reduced VE-cadherin expression and increased monolayer permeability of human renal glomerular endothelial cells. In addition, Notch1 activation or gene knockdown of VE-cadherin reduced the glomerular endothelial glycocalyx. Further investigation demonstrated that activated Notch1 suppression of VE-cadherin was through the transcription factors SNAI1 (snail family transcriptional repressor 1) and ERG (Ets related gene), which bind to the -373 E-box and the -134/-118 ETS (E26 transformation-specific) element of the VE-cadherin promoter, respectively.Our results reveal novel regulatory mechanisms whereby endothelial Notch1 signaling dictates the level of VE-cadherin through the transcription factors SNAI1 and ERG, leading to dysfunction of glomerular filtration barrier and induction of albuminuria. Graphic Abstract: A graphic abstract is available for this article.
Patient Outcomes From Ground vs Helicopter Emergency Medical Services: The Challenges of an Accurate Comparison
Authors: Michael Abernethy
Journal: JAMA Network Open (2021)

Karen Alstrup, MD, PhD; Leif Rognås, MD, PhD; Stephen Sollid, MD, PhD; Søren Paaske Johnsen, MD, PhD; Jan Brink Valentin, MSc; Jens Aage Kølsen Petersen, MD, PhD
Multiomics Characterization of Low-Grade Serous Ovarian Carcinoma Identifies Potential Biomarkers of MEK Inhibitor Sensitivity and Therapeutic Vulnerability
Authors: Raunak Shrestha, Marta Llaurado Fernandez, Amy Dawson, Joshua Hoenisch, Stanislav Volik, Yen-Yi Lin, Shawn Anderson, Hannah Kim, Anne M. Haegert, Shane Colborne, Nelson K.Y. Wong, Brian McConeghy, Robert H. Bell, Sonal Brahmbhatt, Cheng-Han Lee, Gabriel E. DiMattia, Stephane Le Bihan, Gregg B. Morin, Colin C. Collins, Mark S. Carey
Journal: Cancer Research (2021)

Abstract Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates in patients with metastatic disease. There is a pressing need to develop effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use multiomics integration of whole-exome sequencing, RNA sequencing, and mass spectrometry–based proteomics on 14 LGSOC cell lines to elucidate novel biomarkers and therapeutic vulnerabilities. Comparison of LGSOC cell line data with LGSOC tumor data enabled predictive biomarker identification of MEK inhibitor (MEKi) efficacy, with KRAS mutations found exclusively in MEKi-sensitive cell lines and NRAS mutations found mostly in MEKi-resistant cell lines. Distinct patterns of Catalogue of Somatic Mutations in Cancer mutational signatures were identified in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes were more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. These LGSOC cell lines were representative models of the molecular aberrations found in LGSOC tumors. For prediction of in vitro MEKi efficacy, proteomic data provided better discrimination than gene expression data. Condensin, minichromosome maintenance, and replication factor C protein complexes were identified as potential treatment targets in MEKi-resistant cell lines. This study suggests that CDKN2A/B or MTAP deficiency may be exploited using synthetically lethal treatment strategies, highlighting the importance of using proteomic data as a tool for molecular drug prediction. Multiomics approaches are crucial to improving our understanding of the molecular underpinnings of LGSOC and applying this information to develop new therapies. Significance: These findings highlight the utility of global multiomics to characterize LGSOC cell lines as research models, to determine biomarkers of MEKi resistance, and to identify potential novel therapeutic targets.
Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study
Authors: Erica L Mayer, Amylou C Dueck, Miguel Martin, Gabor Rubovszky, Harold J Burstein, Meritxell Bellet-Ezquerra, Kathy D Miller, Nicholas Zdenkowski, Eric P Winer, Georg Pfeiler, Matthew Goetz, Manuel Ruiz-Borrego, Daniel Anderson, Zbigniew Nowecki, Sibylle Loibl, Stacy Moulder, Alistair Ring, Florian Fitzal, Tiffany Traina, Arlene Chan, Hope S Rugo, Julie Lemieux, Fernando Henao, Alan Lyss, Silvia Antolin Novoa, Antonio C Wolff, Marcus Vetter, Daniel Egle, Patrick G Morris, Eleftherios P Mamounas, Miguel J Gil-Gil, Aleix Prat, Hannes Fohler, Otto Metzger Filho, Magdalena Schwarz, Carter DuFrane, Debora Fumagalli, Kathy Puyana Theall, Dongrui Ray Lu, Cynthia Huang Bartlett, Maria Koehler, Christian Fesl, Angela DeMichele, Michael Gnant
Journal: The Lancet Oncology (2021)
New approaches to symptomatic treatments for Alzheimer’s disease
Authors: Jeffrey Cummings
Journal: Molecular Neurodegeneration (2021)

Successful development of agents that improve cognition and behavior in Alzheimer's disease (AD) is critical to improving the lives of patients manifesting the symptoms of this progressive disorder.There have been no recent approvals of cognitive enhancing agents for AD. There are currently 6 cognitive enhancers in Phase 2 trials and 4 in phase 3. They represent a variety of novel mechanisms. There has been progress in developing new treatments for neuropsychiatric symptoms in AD with advances in treatment of insomnia, psychosis, apathy, and agitation in AD. There are currently 4 AD-related psychotropic agents in Phase 2 trials and 7 in Phase 3 trials. Many novel mechanisms are being explored for the treatment of cognitive and behavioral targets. Progress in trial designs, outcomes measures, and population definitions are improving trial conduct for symptomatic treatment of AD.Advances in developing new agents for cognitive and behavioral symptoms of AD combined with enhanced trial methods promise to address the unmet needs of patients with AD for improved cognition and amelioration of neuropsychiatric symptoms.
MEK inhibitors for the treatment of non-small cell lung cancer
Authors: Jing Han, Yang Liu, Sen Yang, Xuan Wu, Hongle Li, Qiming Wang
Journal: Journal of Hematology & Oncology (2021)

Abstract BRAF and KRAS are two key oncogenes in the RAS/RAF/MEK/MAPK signaling pathway. Concomitant mutations in both KRAS and BRAF genes have been identified in non-small cell lung cancer (NSCLC). They lead to the proliferation, differentiation, and apoptosis of tumor cells by activating the RAS/RAF/MEK/ERK signaling pathway. To date, agents that target RAS/RAF/MEK/ERK signaling pathway have been investigated in NSCLC patients harboring BRAF mutations. BRAF and MEK inhibitors have gained approval for the treatment of patients with NSCLC. According to the reported findings, the combination of MEK inhibitors with chemotherapy, immune checkpoint inhibitors, epidermal growth factor receptor-tyrosine kinase inhibitors or BRAF inhibitors is highly significant for improving clinical efficacy and causing delay in the occurrence of drug resistance. This review summarized the existing experimental results and presented ongoing clinical studies as well. However, further researches need to be conducted to indicate how we can combine other drugs with MEK inhibitors to significantly increase therapeutic effects on patients with lung cancer.
AB0692 CLINICAL SIGNIFICANCE OF LIPID PROFILES IN PATIENTS WITH AXIAL SPONDYLOARTHRITIS
Authors: Y. Huang, M. Liu, Q. Huang, T. W. Li
Journal: Annals of the Rheumatic Diseases (2020)

Background: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease of the sacroiliac joints and spine. Lipid profiles, including total cholesterol(TC), high-density lipoprotein cholesterol(HDL-c), low-density lipoprotein cholesterol (LDL-c), TC/HDL-c, triglycerides(TG), have been reported to be changed regularly in axSpA patients. However, the clinical significance of lipid profiles in axSpA patients is controversial. Objectives: The study aims to determine the clinical significance of TC, HDL-c, LDL-c, TC/HDL-c, TG for axSpA patients. Methods: A total of 208 axSpA patients and 113 healthy subjects were enrolled in the study retrospectively. TC, HDL-c, LDL-c, TC/HDL-c, TG, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index(BASDAI) were collected. AxSpA patients were divided into remission axSpA group(BASDAI&lt;4, n=123) and active axSpA group(BASDAI≥4, n=85). Relationships between the parameters were assessed by the Sperman’ s correlations analysis. Receiver operation characteristic (ROC) curves were used to discriminate axSpA patients from healthy subjects and active axSpA group from remission axSpA group. Results: TC, HDL-c, and TG in axSpA group were lower than those of control group, while TC/HDL-c was higher (P&lt;0.05). ROC curve results showed that the AUC value of HDL-c for axSpA was 0.790 (CI95%: 0.740-0.839), yielding a highest AUC value. The optimal cutoff value of HDL-c for axSpA was 1.095, with the Youden index of 0.496, sensitivity of 65.5% and specificity of 84.1%. HDL-c was negatively correlated with BASDAI (r=-0.159, P=0.022). TC/HDL-c was positively correlated with BASDAI (r=0.183, P=0.008). Besides, TC/HDL-c, CRP, ESR in active axSpA group were higher than those of remission axSpA group, while HDL-c was lower (P&lt;0.05). ROC curve results showed that the AUC value of TC/HDL-c and CRP for active axSpA group were 0.621 (CI95%: 0.543-0.700) and 0.634 (CI95%: 0.556-0.712), yielding a higher AUC value than other parameters. The optimal cutoff value of TC/HDL-c for active axSpA group was 4.429, with the Youden index of 0.201, sensitivity of 40.2% and specificity of 79.9%. Conclusion: HDL-c was decreased in axSpA patients with a highest diagnostic value, compared with healthy control. TC/HDL-c was elevated in active axSpA patients, showing a significant correlation to the disease activity of axSpA. References: [1]Gluszko P, Bonek K, Rupinski R, et al. LIPID PROFILE AND ACTIVE SYSTEMIC INFLAMMATION MAY DIFFERENTLY AFFECT THE PATHOMECHANISM OF CARDIOVASCULAR DISORDERS IN ANKYLOSING SPONDYLITIS (AS) AND IN PSORIATIC ARTHRITIS (PSA)[J]. ANNALS OF THE RHEUMATIC DISEASES. 2016: 1146. Acknowledgments: This study was supported by Science and Technology Project of Guangzhou Haizhu District (Haike Business Infox 2018-89). Disclosure of Interests: None declared
Dietary interventions for obesity: clinical and mechanistic findings
Authors: Ariana M. Chao, Kerry M. Quigley, Thomas A. Wadden
Journal: Journal of Clinical Investigation (2021)

Dietary modification is central to obesity treatment. Weight loss diets are available that include various permutations of energy restriction, macronutrients, foods, and dietary intake patterns. Caloric restriction is the common pathway for weight reduction, but different diets may induce weight loss by varied additional mechanisms, including by facilitating dietary adherence. This narrative Review of meta-analyses and select clinical trials found that lower-calorie diets, compared with higher-calorie regimens, reliably induced larger short-term (<6 months) weight losses, with deterioration of this benefit over the long term (>12 months). Few significant long-term differences in weight loss were observed for diets of varying macronutrient composition, although some regimens were found to have short-term advantages (e.g., low carbohydrate versus low fat). Progress in improving dietary adherence, which is critical to both short- and long-term weight loss, could result from greater efforts to identify behavioral and metabolic phenotypes among dieters.
Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Early Triple-Negative Breast Cancer
Authors: Shalabh Arora, Akash Kumar, Atul Batra
Journal: JAMA Oncology (2021)

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PR01.05 Racial Differences in Eligibility for Low Dose CT Screening and Burden of Metastatic Disease at Diagnosis of Lung Cancer in the United States
Authors: M.P. Rai, P. Bedi, B. Ansari, S.S. Malleshappa, P. Neupane, C. Huang, J. Zhang, K. Mehta
Journal: Journal of Thoracic Oncology (2021)
CD30 function on normal human T cells
Authors: Kenichi Ito, Eckhard R. Podack
Journal: Cancer Research (2004)

4672  Background: CD30, a member of the TNF-receptor family, is expressed on many types of Lymphomas, germ cell tumors and multiple myeloma. Its ligand, CD30-L (CD153), a member of the TNF family, is expressed in chronic lymphocytic leukemia, follicular B cell lymphoma, T-cell lymphoblastic lymphoma, and adult T cell leukemia/lymphoma. CD30 may control apoptosis, cell activation, effector function, and proliferation. Despite its important clinical role, CD30 function is not well understood. The reason probably lies in a lack of good tools for analyzing CD30. In order to analyze human CD30 function in detail, we have tried to use human T cells. However, under unstimulated condition, few cells express CD30 in normal human T cells. We now report that CD45RO+ T (memory) cells when stimulated with OKT3 express high levels of CD30+ cells. Using CD45RO+ cells the functional role of CD30 is studied. Methods and Results: Normal human T cells from healthy volunteers were used to purify CD45RO+ T cells by magnetic sorting, at this stage they are CD30 negative. After stimulation with OKT3, anti-CD28, and IL-15 or IL-2, 40% of the cells expressed CD30. CD30+ and CD30- cells were separated by cell sorting or magnetic sorting and compared by phenotype and function. Phenotypically CD30+ cells expressed higher levels of CCR7, CD30-L, CD40, and CD40-L when compared to CD30- cells. When stimulated with the anti-CD30 agonistic antibody C10 and OKT3, CD30+ cells produced significantly more IL-5, IL-13, and IFN-γ compared to CD30- cells. There was no IL-4 production and no difference in IL-10. Regarding cytotoxicity activity, both CD30+ and CD30- cells had similar cytotoxic activity. We also found that CD30 expression was dynamic. After CD30 sorting, we re-stimulated CD30- cells with OKT3 and IL-15, and observed that a significant number of previously negative cells became CD30+. Comparison of gene expression patterns between the CD30+ YT lymphoma cell line and normal human T cells using cDNA microarray analysis will highlight changes in CD30 signaling that may be specific to lymphoma cells and may contribute to oncogenic transformation.
Abstract 10609: The Role of Routine Angiographic Follow-up Afte Percutaneous Coronary Intervention -a Meta Analysis Including 14199 Patients
Authors: Jin Xu, Yu Peng, Zheng Zhang, Yibo Wang
Journal: Circulation (2019)

Background: Numerous studies have repeatedly demonstrated that routine follow-up coronary angiography increases the incidence of target lesion revascularization or target vessel revascularization w...
Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects
Authors: Xiaofen Liu, Yuancheng Chen, Haijing Yang, Jian Li, Jicheng Yu, Zhenwei Yu, Guoying Cao, Xiaojie Wu, Yu Wang, Hailan Wu, Yaxin Fan, Jingjing Wang, Jufang Wu, Yi Jin, Beining Guo, Jiali Hu, Xingchen Bian, Xin Li, Jing Zhang
Journal: Journal of Infection (2021)
The effect of vitamin D supplementation on acute respiratory tract infection in older Australian adults: an analysis of data from the D-Health Trial
Authors: Hai Pham, Mary Waterhouse, Catherine Baxter, Briony Duarte Romero, Donald S A McLeod, Bruce K Armstrong, Peter R Ebeling, Dallas R English, Gunter Hartel, Michael G Kimlin, Adrian R Martineau, Rachel O'Connell, Jolieke C van der Pols, Alison J Venn, Penelope M Webb, David C Whiteman, Rachel E Neale
Journal: The Lancet Diabetes & Endocrinology (2021)