tbuckley/cabot-search huggingface dataset:
Abstract P4-04-12: Macrophage migration inhibitory factor regulates triple-negative breast cancer progression by enhancing the recruitment of immune suppressive cells
Authors: Manish Charan, Subhadip Das, Sanjay Mishra, Sanjay Varikuti, Abhay R Satoskar, Ramesh K Ganju
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and lacks the expression of estrogen, progesterone, and Her2 receptors. TNBC is a highly aggressive subtype of breast cancer that has been associated with poorer prognosis and worse overall survival rate. Macrophage migration inhibitory factor (MIF) is a multipotent pro-inflammatory cytokine, highly expressed in various cancers and reported to enhance tumor growth and metastasis. However, its role in influencing the anti-tumor immunity is unexplored. We have previously shown that MIF promotes TNBC growth and metastasis. In addition, CPSI-1306 (MIF inhibitor), reduces its oncogenic effects. Here, we have shown that MIF downregulation in human TNBC xenografts correlate with reduced infiltration of myeloid derived suppressor cells (MDSCs). Furthermore, using a MIF knockout mouse model, we detected reduced MDSC population in the tumor microenvironment. In addition, we observed higher recruitment and increased proliferation of CD3+ T cells. Furthermore, we utilized a syngeneic mouse model to study the effect of MIF inhibition on infiltration of different immune cells in-vivo. CPSI-1306 treatment decreased the recruitment of MDSCs in both the tumor and spleen. In addition, CPSI-1306 treatment promotes the infiltration of CD8+ T cells in both the tumor and spleen. However, CPSI-1306 treatment did not influence the recruitment of CD4+ T cells. We further analyzed the expression of various cytokines and chemokines in blood sera of control and CPSI-1306 treated mice groups using a cytokine array kit. We observed that CPSI-1306 treatment group showed reduced levels of GCSF, GMCSF, IL-2 and IL-4 levels compared to vehicle control groups. Overall, our data strongly suggests that small molecular weight MIF inhibitors could be a potential strategy against TNBC. Citation Format: Manish Charan, Subhadip Das, Sanjay Mishra, Sanjay Varikuti, Abhay R Satoskar, Ramesh K Ganju. Macrophage migration inhibitory factor regulates triple-negative breast cancer progression by enhancing the recruitment of immune suppressive cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-12.
Conservative Care for Kidney Failure—The Other Side of the Coin
Authors: Christine K. Liu, Manjula Kurella Tamura
Journal: JAMA Network Open (2022)

Susan P. Y. Wong, MD, MS; Tamara Rubenzik, MD; Leila Zelnick, PhD; Sara N. Davison, MD; Diana Louden, MLib; Taryn Oestreich, MPH, MCHES; Ann L. Jennerich, MD, MS
COMBINED PROGNOSTIC IMPACT OF PHENOTYPE AND GENOTYPE ON 5-YEAR CLINICAL OUTCOMES IN PATIENTS ON CLOPIDOGREL AFTER PERCUTANEOUS CORONARY INTERVENTION: RESULTS FROM THE PTRG-DES REGISTRY
Authors: Seung Hwan Lee, Sung Gyun Ahn, Ho-Sung Jeon, Young In Kim, Tae-Hwa Go, Dae Ryong Kang, Jun-Won Lee, Young Jin Youn, Junghan Peter Yoon
Journal: Journal of the American College of Cardiology (2022)
Malignant progression of liver cancer progenitors requires lysine acetyltransferase 7–acetylated and cytoplasm‐translocated G protein GαS
Authors: Ye Zhou, Kaiwei Jia, Suyuan Wang, Zhenyang Li, Yunhui Li, Shan Lu, Yingyun Yang, Liyuan Zhang, Mu Wang, Yue Dong, Luxin Zhang, Wannian Zhang, Nan Li, Yizhi Yu, Xuetao Cao, Jin Hou
Journal: Hepatology (2022)

Background and Aims: Hepatocarcinogenesis goes through HCC progenitor cells (HcPCs) to fully established HCC, and the mechanisms driving the development of HcPCs are still largely unknown. Approach and Results: Proteomic analysis in nonaggregated hepatocytes and aggregates containing HcPCs from a diethylnitrosamine‐induced HCC mouse model was screened using a quantitative mass spectrometry–based approach to elucidate the dysregulated proteins in HcPCs. The heterotrimeric G stimulating protein α subunit (GαS) protein level was significantly increased in liver cancer progenitor HcPCs, which promotes their response to oncogenic and proinflammatory cytokine IL‐6 and drives premalignant HcPCs to fully established HCC. Mechanistically, GαS was located at the membrane inside of hepatocytes and acetylated at K28 by acetyltransferase lysine acetyltransferase 7 (KAT7) under IL‐6 in HcPCs, causing the acyl protein thioesterase 1–mediated depalmitoylation of GαS and its cytoplasmic translocation, which were determined by GαS K28A mimicking deacetylation or K28Q mimicking acetylation mutant mice and hepatic Kat7 knockout mouse. Then, cytoplasmic acetylated GαS associated with signal transducer and activator of transcription 3 (STAT3) to impede its interaction with suppressor of cytokine signaling 3, thus promoting in a feedforward manner STAT3 phosphorylation and the response to IL‐6 in HcPCs. Clinically, GαS, especially K28‐acetylated GαS, was determined to be increased in human hepatic premalignant dysplastic nodules and positively correlated with the enhanced STAT3 phosphorylation, which were in accordance with the data obtained in mouse models. Conclusions: Malignant progression of HcPCs requires increased K28‐acetylated and cytoplasm‐translocated GαS, causing enhanced response to IL‐6 and driving premalignant HcPCs to fully established HCC, which provides mechanistic insight and a potential target for preventing hepatocarcinogenesis.
Ifnar gene variants influence gut microbial production of palmitoleic acid and host immune responses to tuberculosis
Authors: Lingming Chen, Guoliang Zhang, Guobao Li, Wei Wang, Zhenhuang Ge, Yi Yang, Xing He, Zhi Liu, Zhiyi Zhang, Qiongdan Mai, Yiwei Chen, Zixu Chen, Jiang Pi, Shuai Yang, Jun Cui, Haipeng Liu, Ling Shen, Lingchan Zeng, Lin Zhou, Xinchun Chen, Baoxue Ge, Zheng W. Chen, Gucheng Zeng
Journal: Nature Metabolism (2022)
Abstract P5-12-11: NSDHL knockdown decreases tightly cohesive tumorsphere formation and breast cancer stem cell population
Authors: So-Hyun Yoon, Hoe Suk Kim, Junhyuk Song, Sunkyu Kwon, Seungyeon Ryu, Moonjou Baek, Sangeun Lee, Han-Byoel Lee, Hyeong-Gon Moon, Dong-Young Noh, Sangyong Jon, Wonshik Han
Journal: Cancer Research (2022)

Abstract Background: Cholesterol biosynthesis pathway is commonly elevated or dysregulated in cancer cells and high cholesterol levels are associated with cancer progression. NAD(P)-dependent steroid dehydrogenase-like (NSDHL), an enzyme involved in cholesterol biosynthesis, has been implicated in maintaining cancer stem cell, but its role in regulating breast cancer stem cells (BCSC) remains unclear. This study aimed to uncover the molecular mechanisms by which NSDHL regulates BCSC properties.Methods: The knockdown of NSDHL was induced by an introduction of siRNA/shRNA into MCF-7 cells. A non-adherent 3D culture method based on polymer-X coating was applied for growing tumorspheres under serum-free condition. 3’ quant mRNA-sequencing, qRT-PCR, western blot, immunofluorescent staining, ELISA, flow cytometry and ALDEFLUOR assay were carried out. Immunodeficient NSG mice were used for orthotropic xenograft tumor models by injecting tumorspheres.Result: NSDHL knockdown reduced a tightly cohesive sphere formation. RNA-seq data revealed a significant upregulation of 253 DEGs and downregulation of 364 DEGs with &amp;gt;2-fold change in NSDHL knockdown tumorsphere. The KEGG pathway analysis showed that DEGs were mainly enriched in TGF-β signaling pathway and cell cycle. NSDHL knockdown reduced the population of BCSCs with CD44+/CD24- phenotype and high ALDH activity as well as luminal progenitors with CD49f+/EpCAM+ phenotype along with decrease in TGF-β 1 and 3 and GLI1 in tumorsphere. In orthotropic xenograft tumor models, NSDHL knockdown strongly suppressed the tumor initiation and growth.Conclusions: Our findings reveal that NSDHL has an important role in maintaining BCSC population and tumor initiating capacity, suggesting NSDHL as an attractive therapeutic target to eliminate BCSCs, and thus preventing breast cancer initiation and progression. Citation Format: So-Hyun Yoon, Hoe Suk Kim, Junhyuk Song, Sunkyu Kwon, Seungyeon Ryu, Moonjou Baek, Sangeun Lee, Han-Byoel Lee, Hyeong-Gon Moon, Dong-Young Noh, Sangyong Jon, Wonshik Han. NSDHL knockdown decreases tightly cohesive tumorsphere formation and breast cancer stem cell population [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-11.
Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics
Authors: Emanuel Wyler, Julia M. Adler, Kathrin Eschke, G. Teixeira Alves, Stefan Peidli, Fabian Pott, Julia Kazmierski, Laura Michalick, Olivia Kershaw, Judith Bushe, Sandro Andreotti, Peter Pennitz, Azza Abdelgawad, Dylan Postmus, Christine Goffinet, Jakob Kreye, S Momsen Reincke, Harald Prüss, Nils Blüthgen, Achim D. Gruber, Wolfgang M. Kuebler, Martin Witzenrath, Markus Landthaler, Geraldine Nouailles, Jakob Trimpert
Journal: Molecular Therapy (2022)

For coronavirus disease 2019 (COVID-19), effective and well-understood treatment options are still scarce. Since vaccine efficacy is challenged by novel variants, short-lasting immunity, and vaccine hesitancy, understanding and optimizing therapeutic options remains essential. We aimed at better understanding the effects of two standard-of-care drugs, dexamethasone and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, on infection and host responses. By using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of single or combinatorial treatments. Pulmonary viral burden was reduced by anti-SARS-CoV-2 antibody treatment and unaltered or increased by dexamethasone alone. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment and identified a specifically responsive subpopulation of neutrophils, thereby indicating a potential mechanism of action. Our analyses confirm the anti-inflammatory properties of dexamethasone and suggest possible mechanisms, validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and reveal synergistic effects of a combination therapy, thus informing more effective COVID-19 therapies.
ARTIFICIAL INTELLIGENCE-ENABLED PREDICTION OF ATRIAL FIBRILLATION EVENTS USING MOBILE ELECTROCARDIOGRAMS
Authors: Dan Nguyen, Ananditha Raghunath, Matthew Schram, Dave Albert, Shyamnath Gollakota, Linda Shapiro, Arun Raghav Mahankali Sridhar
Journal: Journal of the American College of Cardiology (2022)
RESECTION MITRAL VALVE REPAIR WITH SMALL ANNULOPLASTY IS AT HIGHER RISK OF FUNCTIONAL MITRAL STENOSIS
Authors: Makoto Hibino, Arjun K. Pandey, Nitish Dhingra, Vincent Chan, C David Mazer, Hwee Teoh, Adrian Quan, Howard M. Leong-Poi, Kim A. Connelly, Subodh Verma
Journal: Journal of the American College of Cardiology (2022)
How to Treat Breast Cancer After Childhood Cancer
Authors: Anne H. Blaes, Suma Konety, Jane Hui, Kathryn Dusenbery, Jianling Yuan, Susan Dent, Kevin C. Oeffinger, Lucie M. Turcotte
Journal: JACC CardioOncology (2022)

• Childhood cancer survivors are at higher risk for the development of breast cancer necessitating early breast cancer screening, often with both breast MRI and mammography. • Risk-stratify breast cancer treatment, taking into account prior radiation fields, surgical procedures, use of anthracyclines, and current comorbidities is essential. • Aggressive management of CV risk factors in collaboration with cardiologists, oncologists, primary care providers, and allied health care providers is needed to provide the best cancer treatment while optimizing CV health.
Enhancement of Impaired Olfactory Neural Activation and Cognitive Capacity by Liraglutide, but Not Dapagliflozin or Acarbose, in Patients With Type 2 Diabetes: A 16-Week Randomized Parallel Comparative Study
Authors: Haiyan Cheng, Zhou Zhang, Bing Zhang, Wen Zhang, Jin Wang, Wenyu Ni, Yingwen Miao, Jiani Liu, Yan Bi
Journal: Diabetes Care (2022)

OBJECTIVE The comparative neuroprotective effects of different antidiabetes drugs have not been characterized in randomized controlled trials. Here, we investigated the therapeutic effects of liraglutide, dapagliflozin, or acarbose treatment on brain functional alterations and cognitive changes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Thirty-six patients with type 2 diabetes inadequately controlled with metformin monotherapy were randomized to receive liraglutide, dapagliflozin, or acarbose treatment for 16 weeks. Brain functional MRI (fMRI) scan and a battery of cognitive assessments were evaluated pre- and postintervention in all subjects. RESULTS The 16-week treatment with liraglutide significantly enhanced the impaired odor-induced left hippocampal activation with Gaussian random field correction and improved cognitive subdomains of delayed memory, attention, and executive function (all P &amp;lt; 0.05), whereas dapagliflozin or acarbose did not. Structural equation modeling analysis demonstrated that such improvements of brain health and cognitive function could be partly ascribed to a direct effect of liraglutide on left hippocampal activation (β = 0.330, P = 0.022) and delayed memory (β = 0.410, P = 0.004) as well as to the metabolic ameliorations of reduced waist circumference, decreased body fat ratio, and elevated fasting insulin (all P &amp;lt; 0.05). CONCLUSIONS Our head-to-head study demonstrated that liraglutide enhanced impaired brain activation and restored impaired cognitive domains in patients with type 2 diabetes, whereas dapagliflozin and acarbose did not. The results expand the clinical application of liraglutide and provide a novel treatment strategy for individuals with diabetes and a high risk of cognitive decline.
NORMAL AGE- AND SEX-BASED VALUES OF RIGHT VENTRICULAR FREE WALL LONGITUDINAL STRAIN BY SPECKLE-TRACKING ECHOCARDIOGRAPHY: THE COPENHAGEN CITY HEART STUDY
Authors: Caroline Espersen, Raphael Hauser, Kristoffer Grundtvig Skaarup, Mats Højbjerg Lassen, Niklas Dyrby Johansen, Flemming Javier Olsen, Gorm B. Jensen, Peter Schnohr, Rasmus Mogelvang
Journal: Journal of the American College of Cardiology (2022)
Multi-landmark environment analysis with reinforcement learning for pelvic abnormality detection and quantification
Authors: Imad Eddine Ibrahim Bekkouch, Bulat Maksudov, Semen Kiselev, Tamerlan Mustafaev, Tomaž Vrtovec, Bulat Ibragimov
Journal: Medical Image Analysis (2022)

Morphological abnormalities of the femoroacetabular (hip) joint are among the most common human musculoskeletal disorders and often develop asymptomatically at early easily treatable stages. In this paper, we propose an automated framework for landmark-based detection and quantification of hip abnormalities from magnetic resonance (MR) images. The framework relies on a novel idea of multi-landmark environment analysis with reinforcement learning. In particular, we merge the concepts of the graphical lasso and Morris sensitivity analysis with deep neural networks to quantitatively estimate the contribution of individual landmark and landmark subgroup locations to the other landmark locations. Convolutional neural networks for image segmentation are utilized to propose the initial landmark locations, and landmark detection is then formulated as a reinforcement learning (RL) problem, where each landmark-agent can adjust its position by observing the local MR image neighborhood and the locations of the most-contributive landmarks. The framework was validated on T1-, T2- and proton density-weighted MR images of 260 patients with the aim to measure the lateral center-edge angle (LCEA), femoral neck-shaft angle (NSA), and the anterior and posterior acetabular sector angles (AASA and PASA) of the hip, and derive the quantitative abnormality metrics from these angles. The framework was successfully tested using the UNet and feature pyramid network (FPN) segmentation architectures for landmark proposal generation, and the deep Q-network (DeepQN), deep deterministic policy gradient (DDPG), twin delayed deep deterministic policy gradient (TD3), and actor-critic policy gradient (A2C) RL networks for landmark position optimization. The resulting overall landmark detection error of 1.5 mm and angle measurement error of 1.4° indicates a superior performance in comparison to existing methods. Moreover, the automatically estimated abnormality labels were in 95% agreement with those generated by an expert radiologist.
Fine Particulate Matter Exposure From Secondhand Cannabis Bong Smoking
Authors: Patton Khuu Nguyen, S. Katharine Hammond
Journal: JAMA Network Open (2022)

This cohort study suggests that, contrary to popular beliefs, bong smoking is not safe.Decades ago, many people thought SHTS presented no health risk to nonsmokers.Scientific research since then changed this perception and led to smoke-free environments. 3Incorrect beliefs about SHCS safety promote indoor cannabis smoking. 1,2Nonsmokers are exposed to even higher concentrations of SHCS materials during "hot-boxing," the popular practice in which cannabis smokers produce high volumes of smoke in an enclosed environment.This study's findings suggest SHCS in the home is not safe and that public perceptions of SHCS safety must be addressed.
Nose-to-brain/spinal cord delivery kinetics of liposomes with different surface properties
Authors: Takumi Kurano, Takanori Kanazawa, Aoi Ooba, Yudai Masuyama, Nao Maruhana, Mayu Yamada, Shingo Iioka, Hisako Ibaraki, Yasuhiro Kosuge, Hiromu Kondo, Toyofumi Suzuki
Journal: Journal of Controlled Release (2022)
Adding Base-Excision Repair Inhibitor TRC102 to Standard Pemetrexed–Platinum–Radiation in Patients with Advanced Nonsquamous Non–Small Cell Lung Cancer: Results of a Phase I Trial
Authors: Tithi Biswas, Afshin Dowlati, Charles A. Kunos, John J. Pink, Nancy L. Oleinick, Shakun Malik, Pingfu Fu, Shufen Cao, Debora S. Bruno, David L. Bajor, Monaliben Patel, Stanton L. Gerson, Mitchell Machtay
Journal: Clinical Cancer Research (2021)

Abstract Purpose: TRC102, a small-molecule base-excision repair inhibitor, potentiates the cytotoxicity of pemetrexed and reverses resistance by binding to chemotherapy-induced abasic sites in DNA. We conducted a phase I clinical trial combining pemetrexed and TRC102 with cisplatin–radiation in stage III nonsquamous non–small cell lung cancer (NS-NSCLC). Patients and Methods: Fifteen patients were enrolled from 2015 to 2019. The primary objective was to determine the dose-limiting toxicity and maximum tolerated dose of TRC102 in combination with pemetrexed, cisplatin, and radiotherapy. Secondary objectives were to assess toxicity, tumor response, and progression-free survival at 6 months. Based on our preclinical experiments, pemetrexed–TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated in the second cycle. After completion, two additional cycles of pemetrexed–cisplatin were given. Toxicities were assessed using NCI CTACAE versions 4/5. Results: The median age was 69 years (45–79) with the median follow-up of 25.7 months (range, 7.9–47.4). No dose-limiting toxicities and no grade 5 toxicity were seen. Hematologic and gastrointestinal toxicities were the most common side effects. No clinical radiation pneumonitis was seen. Of 15 evaluable patients, three had complete response (20%), and 12 had partial response (80%). The 6-month progression-free survival was 80%, and the 2-year overall survival was 83%. Conclusions: Pemetrexed–TRC102 combined with cisplatin/radiotherapy in NS-NSCLC is safe and well tolerated. The recommended phase II dose is 200 mg TRC102 along with cisplatin–pemetrexed. No additional safety signal was seen beyond the expected CRT risks. A phase II trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen, is warranted.
Spatially mapping the immune landscape of melanoma using imaging mass cytometry
Authors: Dan Moldoveanu, LeeAnn Ramsay, Mathieu Lajoie, Luke Anderson-Trocme, Marine Lingrand, Diana Berry, Lucas J.M. Perus, Yuhong Wei, Cleber Moraes, Rached Alkallas, Shivshankari Rajkumar, Dongmei Zuo, Matthew Dankner, Eric Hongbo Xu, Nicholas R. Bertos, Hamed S. Najafabadi, Simon Gravel, Santiago Costantino, Martin J. Richer, Amanda W. Lund, Sonia V. Del Rincon, Alan Spatz, Wilson H. Miller, Rahima Jamal, Réjean Lapointe, Anne-Marie Mes-Masson, Simon Turcotte, Kevin Petrecca, Sinziana Dumitra, Ari-Nareg Meguerditchian, Keith Richardson, Francine Tremblay, Beatrice Wang, May Chergui, Marie-Christine Guiot, Kevin Watters, John Stagg, Daniela F. Quail, Catalin Mihalcioiu, Sarkis Meterissian, Ian R. Watson
Journal: Science Immunology (2022)

Melanoma is an immunogenic cancer with a high response rate to immune checkpoint inhibitors (ICIs). It harbors a high mutation burden compared with other cancers and, as a result, has abundant tumor-infiltrating lymphocytes (TILs) within its microenvironment. However, understanding the complex interplay between the stroma, tumor cells, and distinct TIL subsets remains a substantial challenge in immune oncology. To properly study this interplay, quantifying spatial relationships of multiple cell types within the tumor microenvironment is crucial. To address this, we used cytometry time-of-flight (CyTOF) imaging mass cytometry (IMC) to simultaneously quantify the expression of 35 protein markers, characterizing the microenvironment of 5 benign nevi and 67 melanomas. We profiled more than 220,000 individual cells to identify melanoma, lymphocyte subsets, macrophage/monocyte, and stromal cell populations, allowing for in-depth spatial quantification of the melanoma microenvironment. We found that within pretreatment melanomas, the abundance of proliferating antigen-experienced cytotoxic T cells (CD8+CD45RO+Ki67+) and the proximity of antigen-experienced cytotoxic T cells to melanoma cells were associated with positive response to ICIs. Our study highlights the potential of multiplexed single-cell technology to quantify spatial cell-cell interactions within the tumor microenvironment to understand immune therapy responses.
Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directions
Authors: Daniele Lavacchi, Enrico Caliman, Gemma Rossi, Eleonora Buttitta, Cristina Botteri, Sara Fancelli, Elisa Pellegrini, Giandomenico Roviello, Serena Pillozzi, Lorenzo Antonuzzo
Journal: Pharmacology & Therapeutics (2022)