tbuckley/cabot-search huggingface dataset:
A MyD88/IL1R Axis Regulates PD-1 Expression on Tumor-Associated Macrophages and Sustains Their Immunosuppressive Function in Melanoma
Authors: Sarang Tartey, Geoffrey Neale, Peter Vogel, R.K. Subbarao Malireddi, Thirumala-Devi Kanneganti
Journal: Cancer Research (2021)

Abstract Macrophages are critical mediators of tissue homeostasis, cell proliferation, and tumor metastasis. Tumor-associated macrophages (TAM) are generally associated with tumor-promoting immunosuppressive functions in solid tumors. Here, we examined the transcriptional landscape of adaptor molecules downstream of Toll-like receptors in human cancers and found that higher expression of MYD88 correlated with tumor progression. In murine melanoma, MyD88, but not Trif, was essential for tumor progression, angiogenesis, and maintaining the immunosuppressive phenotype of TAMs. In addition, MyD88 expression in myeloid cells drove melanoma progression. The MyD88/IL1 receptor (IL1R) axis regulated programmed cell death (PD)-1 expression on TAMs by promoting recruitment of NF-κBp65 to the Pdcd1 promoter. Furthermore, a combinatorial immunotherapy approach combining the MyD88 inhibitor with anti–PD-1 blockade elicited strong antitumor effects. Thus, the MyD88/IL1R axis maintains the immunosuppressive function of TAMs and promotes tumor growth by regulating PD-1 expression. Significance: These findings indicate that MyD88 regulates TAM-immunosuppressive activity, suggesting that macrophage-mediated immunotherapy combining MYD88 inhibitors with PD-1 blockade could result in better treatment outcomes in a wide variety of cancers.
Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons
Authors: Jacob A. Blum, Sandy Klemm, Jennifer L. Shadrach, Kevin A. Guttenplan, Lisa Nakayama, Arwa Kathiria, Phuong T. Hoang, Olivia Gautier, Julia A. Kaltschmidt, William J. Greenleaf, Aaron D. Gitler
Journal: Nature Neuroscience (2021)
Regular exercise and patterns of response across multiple cardiometabolic traits: the HERITAGE family study
Authors: Jacob L Barber, Jonathan J Ruiz-Ramie, Jeremy M Robbins, Robert E Gerszten, Arthur S Leon, DC Rao, James S Skinner, Claude Bouchard, Mark A Sarzynski
Journal: British Journal of Sports Medicine (2021)

Objectives We investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits. Methods A total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%–75% of participants’ maximal oxygen uptake (VO 2 max)) with VO 2 max, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses. Results Only one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits. Conclusions Interindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve.
Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology
Authors: Berna C Özdemir
Journal: Journal for ImmunoTherapy of Cancer (2021)

Despite a significant amount of data on incidence and therapy of immune-related adverse events affecting virtually all organ systems, the potential impact of immune checkpoint inhibitors (ICIs) on gonadal function has not been sufficiently studied. The limited evidence available suggests that ICI-related primary hypogonadism due to orchitis as well as secondary hypogonadism due to hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted given the increasing application of ICIs in the adjuvant setting, among young adults and children and the possible influence of sex hormone levels on the efficacy and toxicity of ICIs.
Epithelial Cells in 2D and 3D Cultures Exhibit Large Differences in Higher-Order Genomic Interactions
Authors: Xin Liu, Qiu Sun, Qi Wang, Chuansheng Hu, Xuecheng Chen, Hua Li, Daniel M. Czajkowsky, Zhifeng Shao
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Recent studies have characterized the genomic structures of many eukaryotic cells, often focusing on their relation to gene expression. However, these studies have largely investigated cells grown in 2D cultures, although the transcriptomes of 3D-cultured cells are generally closer to their in vivo phenotypes. To examine the effects of spatial constraints on chromosome conformation, we investigated the genomic architecture of mouse hepatocytes grown in 2D and 3D cultures using in situ Hi-C. Our results reveal significant differences in higher-order genomic interactions, notably in compartment identity and strength as well as in topologically associating domain (TAD)–TAD interactions, but only minor differences are found at the TAD level. Our RNA-seq analysis reveals an up-regulated expression of genes involved in physiological hepatocyte functions in the 3D-cultured cells. These genes are associated with a subset of structural changes, suggesting that differences in genomic structure are critically important for transcriptional regulation. However, there are also many structural differences that are not directly associated with changes in gene expression, whose cause remains to be determined. Overall, our results indicate that growth in 3D significantly alters higher-order genomic interactions, which may be consequential for a subset of genes that are important for the physiological functioning of the cell.
Identification of clinically relevant biomarkers of epileptogenesis — a strategic roadmap
Authors: Michele Simonato, Denes V. Agoston, Amy Brooks-Kayal, Chris Dulla, Brandy Fureman, David C. Henshall, Asla Pitkänen, William H. Theodore, Roy E. Twyman, Firas H. Kobeissy, Kevin K. Wang, Vicky Whittemore, Karen S. Wilcox
Journal: Nature Reviews Neurology (2021)
Psychology of cleansing through the prism of intersecting object histories
Authors: Zachary Ekves, Yanina Prystauka, Charles P. Davis, Eiling Yee, Gerry T. M. Altmann
Journal: Behavioral and Brain Sciences (2021)

Abstract We link cleansing effects to contemporary cognitive theories via an account of event representation (intersecting object histories) that provides an explicit, neurally plausible mechanism for encoding objects (e.g., the self) and their associations (with other entities) across time. It explains separation as resulting from weakening associations between the self in the present and the self in the past.
Clinical Translation of Cardiovascular Outcome Trials in Type 2 Diabetes: Is There More or Is There Less Than Meets the Eye?
Authors: Ele Ferrannini, Julio Rosenstock
Journal: Diabetes Care (2021)

Randomized controlled trials (RCTs) have become the gold standard of clinical evidence and the staple of guided clinical practice. RCTs are based on a complex set of principles and procedures heavily strung by statistical analysis, primarily designed to answer a specific question in a clinical experiment. Readers of clinical trials need to apply critical appraisal skills before blindly accepting the results and conclusions of trials, lest they misinterpret and misapply the findings. We introduce the fundamentals of an RCT and discuss the relationship between relative risk (RR) and absolute risk (AR) in terms of the different information each conveys. The top results of some recent cardiovascular outcome trials using sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes are used to exemplify the merit of assessing both RR and AR changes for a balanced translation of findings into shrewd clinical judgment. We also suggest practical points to assist with a clinically useful interpretation of both within-trial and across-trial reports. Finally, we mention an alternative approach, namely, the restricted mean survival time, to obtaining unbiased estimates of the mean time of missed events in the treatment versus placebo arm for the duration of the trial.
Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes
Authors: Minjung Lee, Jianfang Li, Jia Li, Shaohai Fang, Joanna Zhang, Anh Tran Tram Vo, Wei Han, Hongxiang Zeng, Sevinj Isgandarova, Margarita Martinez-Moczygemba, Yubin Zhou, Deqiang Sun, Yun Huang
Journal: Cancer Research (2021)

Abstract Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that Tet2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8+ T-cell activation. Furthermore, the ETS family of transcription factors contributed to augmented CD8+ T-cell function following Tet2 depletion. Overall, our study establishes that Tet2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that Tet2 inactivation could promote antitumor immunity to suppress tumor growth. Significance: This study suggests that ablation of TET2+ from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.
Platelet Programmed Cell Death Ligand 1 (pPDL-1) Is a Prognostic Marker in Advanced Lung Cancer
Authors: Clemens Hinterleitner, Jasmin Strähle, Stefan Wirths, Stefanie Bugl, Elke Malenke, Martin R. Mueller, Lothar Kanz, Hans-Georg Kopp
Journal: Blood (2017)
Central Venous Catheters, a Major Culprit for Pediatric Venous Thrombosis: A Report from the Children's Hospital Acquired Thrombosis (CHAT) Project
Authors: Julie Jaffray, Arash Mahajerin, Stacy E. Croteau, Michael Silvey, Emily Krava, Amy Stillings, Guy Young, Brian R. Branchford
Journal: Blood (2017)
Incremental Prognostic Utility of Adverse Right Ventricular Remodeling in Patients With Covid-19 Infection: A Multicenter Cohort Study
Authors: A. Volodarskiy, R. Sultana, M. P. Pollie, B. Yum, A. RoyChoudhury, R. Tafreshi, H. Mitlak, L. J. Shaw, E. M. Horn, P. Goyal, M. M. Safford, R. B. Devereux, J. W. Weinsaft, J. Kim
Journal: Circulation (2020)
Loss-of-Function Variants in the Tumor-Suppressor Gene <i>PTPN14</i> Confer Increased Cancer Risk
Authors: Thorhildur Olafsdottir, Simon N. Stacey, Gardar Sveinbjornsson, Gudmar Thorleifsson, Kristjan Norland, Bardur Sigurgeirsson, Kristin Thorisdottir, Arni Kjalar Kristjansson, Laufey Tryggvadottir, Kavita Y. Sarin, Rafn Benediktsson, Jon G. Jonasson, Asgeir Sigurdsson, Aslaug Jonasdottir, Snaedis Kristmundsdottir, Hakon Jonsson, Arnaldur Gylfason, Asmundur Oddsson, Run Fridriksdottir, Sigurjon A. Gudjonsson, Florian Zink, Sigrun H. Lund, Solvi Rognvaldsson, Pall Melsted, Valgerdur Steinthorsdottir, Julius Gudmundsson, Evgenia Mikaelsdottir, Pall I. Olason, Lilja Stefansdottir, Hannes P. Eggertsson, Bjarni V. Halldorsson, Unnur Thorsteinsdottir, Tomas T. Agustsson, Karl Olafsson, Jon H. Olafsson, Patrick Sulem, Thorunn Rafnar, Daniel F. Gudbjartsson, Kari Stefansson
Journal: Cancer Research (2021)

Abstract The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10−12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10−4) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. Significance: This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.
mRNA vaccine for cancer immunotherapy
Authors: Lei Miao, Yu Zhang, Leaf Huang
Journal: Molecular Cancer (2021)

Abstract mRNA vaccines have become a promising platform for cancer immunotherapy. During vaccination, naked or vehicle loaded mRNA vaccines efficiently express tumor antigens in antigen-presenting cells (APCs), facilitate APC activation and innate/adaptive immune stimulation. mRNA cancer vaccine precedes other conventional vaccine platforms due to high potency, safe administration, rapid development potentials, and cost-effective manufacturing. However, mRNA vaccine applications have been limited by instability, innate immunogenicity, and inefficient in vivo delivery. Appropriate mRNA structure modifications (i.e., codon optimizations, nucleotide modifications, self-amplifying mRNAs, etc.) and formulation methods (i.e., lipid nanoparticles (LNPs), polymers, peptides, etc.) have been investigated to overcome these issues. Tuning the administration routes and co-delivery of multiple mRNA vaccines with other immunotherapeutic agents (e.g., checkpoint inhibitors) have further boosted the host anti-tumor immunity and increased the likelihood of tumor cell eradication. With the recent U.S. Food and Drug Administration (FDA) approvals of LNP-loaded mRNA vaccines for the prevention of COVID-19 and the promising therapeutic outcomes of mRNA cancer vaccines achieved in several clinical trials against multiple aggressive solid tumors, we envision the rapid advancing of mRNA vaccines for cancer immunotherapy in the near future. This review provides a detailed overview of the recent progress and existing challenges of mRNA cancer vaccines and future considerations of applying mRNA vaccine for cancer immunotherapies.
Handling missing MRI sequences in deep learning segmentation of brain metastases: a multicenter study
Authors: Endre Grøvik, Darvin Yi, Michael Iv, Elizabeth Tong, Line Brennhaug Nilsen, Anna Latysheva, Cathrine Saxhaug, Kari Dolven Jacobsen, Åslaug Helland, Kyrre Eeg Emblem, Daniel L. Rubin, Greg Zaharchuk
Journal: npj Digital Medicine (2021)

Abstract The purpose of this study was to assess the clinical value of a deep learning (DL) model for automatic detection and segmentation of brain metastases, in which a neural network is trained on four distinct MRI sequences using an input-level dropout layer, thus simulating the scenario of missing MRI sequences by training on the full set and all possible subsets of the input data. This retrospective, multicenter study, evaluated 165 patients with brain metastases. The proposed input-level dropout (ILD) model was trained on multisequence MRI from 100 patients and validated/tested on 10/55 patients, in which the test set was missing one of the four MRI sequences used for training. The segmentation results were compared with the performance of a state-of-the-art DeepLab V3 model. The MR sequences in the training set included pre-gadolinium and post-gadolinium (Gd) T1-weighted 3D fast spin echo, post-Gd T1-weighted inversion recovery (IR) prepped fast spoiled gradient echo, and 3D fluid attenuated inversion recovery (FLAIR), whereas the test set did not include the IR prepped image-series. The ground truth segmentations were established by experienced neuroradiologists. The results were evaluated using precision, recall, Intersection over union (IoU)-score and Dice score, and receiver operating characteristics (ROC) curve statistics, while the Wilcoxon rank sum test was used to compare the performance of the two neural networks. The area under the ROC curve (AUC), averaged across all test cases, was 0.989 ± 0.029 for the ILD-model and 0.989 ± 0.023 for the DeepLab V3 model ( p = 0.62). The ILD-model showed a significantly higher Dice score (0.795 ± 0.104 vs. 0.774 ± 0.104, p = 0.017), and IoU-score (0.561 ± 0.225 vs. 0.492 ± 0.186, p &lt; 0.001) compared to the DeepLab V3 model, and a significantly lower average false positive rate of 3.6/patient vs. 7.0/patient ( p &lt; 0.001) using a 10 mm 3 lesion-size limit. The ILD-model, trained on all possible combinations of four MRI sequences, may facilitate accurate detection and segmentation of brain metastases on a multicenter basis, even when the test cohort is missing input MRI sequences.
Left Posterior Fascicular Block and Increased Risk of Sudden Cardiac Death in Young People
Authors: Leonardo Calò, Roberta Della Bona, Annamaria Martino, Cinzia Crescenzi, Germana Panattoni, Giulia d’Amati, Fiorenzo Gaita, Ruggiero Mango, Luigi Sciarra, Mikael Laredo
Journal: Journal of the American College of Cardiology (2021)
Bacterial-Driven Inflammation and Mutant <i>BRAF</i> Expression Combine to Promote Murine Colon Tumorigenesis That Is Sensitive to Immune Checkpoint Therapy
Authors: Christina E. DeStefano Shields, James R. White, Liam Chung, Alyssa Wenzel, Jessica L. Hicks, Ada J. Tam, June L. Chan, Christine M. Dejea, Hongni Fan, John Michel, Ashley R. Maiuri, Shruthi Sriramkumar, Ram Podicheti, Douglas B. Rusch, Hao Wang, Angelo M. De Marzo, Sepideh Besharati, Robert A. Anders, Stephen B. Baylin, Heather M. O'Hagan, Franck Housseau, Cynthia L. Sears
Journal: Cancer Discovery (2021)

Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, mutagens, and/or microbiota. Colorectal cancers with activating mutations in BRAF are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (MinApcΔ716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAF V600E mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAF V600E Lgr5 CreMin (BLM) mice, tumors have similarities to human BRAF V600E tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8+ T cells, express IFNγ signatures, and are sensitive to anti-PD-L1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in colorectal cancer pathogenesis and sensitivity to immunotherapy. SIGNIFICANCE: Colorectal cancers with BRAF mutations have distinct characteristics. We present evidence of specific colorectal cancer gene-microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in BRAF V600E Lgr5 CreMin mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.This article is highlighted in the In This Issue feature, p. 1601.
Abstract PS16-16: B-catenin-ccl2 axis regulates breast cancer stem cells via crosstalk between cancer cells and tumor-associated macrophages
Authors: Hao Liu, Bolin Liu
Journal: Cancer Research (2021)

Abstract Breast cancer is most frequently diagnosed cancer among women worldwide. Though advance in diagnosis and treatment strategies have prolonged disease-free survival (DFS) and overall survival (OS) for different molecular types of breast cancer patients, many patients initially benefit from chemotherapy but experience recurrence, metastasis, and ultimately death. Breast cancer stem cells (BCSCs) are tumor initiating cells with self-renewal, low differentiation, and high tumorigenicity and metastasis abilities. The ineffectiveness of conventional chemotherapy to eradicate BCSCs frequently results in therapy failure. Therefore, understanding the molecular pathways sustaining BCSC characteristics and targeting BCSCs will ultimately improve breast cancer treatments. Here, we found that activation of β-Catenin directly regulated CCL2 expression at the transcriptional level, and in turn, promoted tumor-associated macrophage (TAM) infiltration and M2 polarization. Moreover, crosstalk between the TAM and breast cancer cells increased secretion of CCL2, which promoted cancer progression by regulating BCSCs characteristics through feedback activation of β-Catenin. The combined inhibition of CCR2 and β-catenin synergistically suppressed breast cancer growth. The results described herein provide novel insights into our understanding how the β-Catenin-CCL2 feedback loop mediates the crosstalk between cancer stem cells and tumor-associated macrophages. They may also facilitate the development of useful therapeutic targets against BCSCs for breast cancer therapy. Citation Format: Hao Liu, Bolin Liu. B-catenin-ccl2 axis regulates breast cancer stem cells via crosstalk between cancer cells and tumor-associated macrophages [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-16.
Abstract 17175: Cardioprotective Effects of Beta Blockers in Duchenne Muscular Dystophy
Authors: Satyabrata Das, Forum Kamdar, Wuming Gong, Andre Klaassen Kamdar, Tatyana Meyers, Dewayne Townsend, James M Ervasti, Timothy J Kamp, Joseph C Wu, Jianyi Zhang, Daniel J Garry
Journal: Circulation (2019)

Background: Cardiomyopathy has emerged as a leading cause of death in DMD although limited therapies have been developed for dystrophic heart failure. Methods: We used DMD patient-specific hiPSC-de...