tbuckley/cabot-search huggingface dataset:
Reorganization of the 3D Genome Pinpoints Noncoding Drivers of Primary Prostate Tumors
Authors: James R. Hawley, Stanley Zhou, Christopher Arlidge, Giacomo Grillo, Ken J. Kron, Rupert Hugh-White, Theodorus H. van der Kwast, Michael Fraser, Paul C. Boutros, Robert G. Bristow, Mathieu Lupien
Journal: Cancer Research (2021)

Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the noncoding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher-order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. Nonetheless, we identified changes in focal chromatin interactions, typical of loops bridging noncoding cis-regulatory elements, and showed how structural variants can induce these changes to guide cis-regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher-order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer. SIGNIFICANCE: This work showcases how the noncoding genome can be hijacked by focal insults to its three-dimensional organization that contribute to prostate cancer oncogenesis.
A transcription factor is the target of propranolol treatment in infantile hemangioma
Authors: Sandra Schrenk, Elisa Boscolo
Journal: Journal of Clinical Investigation (2022)

Propranolol is a nonselective β-adrenergic receptor (AR) blocker that has been the first-line therapy for problematic infantile hemangioma (IH), the most frequent childhood vascular tumor. Although IHs are benign and eventually regress spontaneously, at least 15% of patients require treatment. Despite the extensive use of propranolol for IH treatment, its mode of action remains unclear. In this issue of the JCI, Seebauer et al. investigated the cellular and molecular consequences of propranolol treatment on IH vascular tumor formation in a murine model of IH. The efficacy of propranolol was independent of its β-AR blocker activity and was attributable to the direct targeting of the transcription factor SOX18, which, in turn, reduced hemangioma blood vessel formation. We believe these results will guide clinical translation for the use of more efficient and safer therapies for IH and possibly for other vascular anomalies in which SOX18 plays a role.
Release of IFNγ by Acute Myeloid Leukemia Cells Remodels Bone Marrow Immune Microenvironment by Inducing Regulatory T Cells
Authors: Giulia Corradi, Barbara Bassani, Giorgia Simonetti, Sabina Sangaletti, Jayakumar Vadakekolathu, Maria Chiara Fontana, Martina Pazzaglia, Alessandro Gulino, Claudio Tripodo, Gianluca Cristiano, Lorenza Bandini, Emanuela Ottaviani, Darina Ocadlikova, Milena Piccioli, Giovanni Martinelli, Mario Paolo Colombo, Sergio Rutella, Michele Cavo, Marilena Ciciarello, Antonio Curti
Journal: Clinical Cancer Research (2022)

The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Treg) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFNγ released by AML cells in BM Treg induction and its impact on AML prognosis.BM aspirates from patients with AML were subdivided according to IFNG expression. Gene expression profiles in INFγhigh and IFNγlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFNγ release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell cocultures. In mice, AML cells silenced for ifng expression were injected intrabone.IFNγhigh AML samples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. In contrast, in patients with AML, high IFNG expression was associated with poor overall survival. Notably, IFNγ release by AML cells positively correlated with a higher BM suppressive Treg frequency. In coculture experiments, IFNγhigh AML cells modified MSC transcriptome by upregulating IFNγ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFNγ release by AML cells on MSC-derived Treg induction. In vivo, the genetic ablation of IFNγ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment.IFNγ release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunologic landscape toward Treg induction, contributing to an immunotolerant microenvironment. See related commentary by Ferrell and Kordasti, p. 2986.
Adjuvant Hormone Therapy–Related Hot Flashes Predict Treatment Discontinuation and Worse Breast Cancer Prognosis
Authors: Erwei Zeng, Wei He, Karin E. Smedby, Kamila Czene
Journal: Journal of the National Comprehensive Cancer Network (2022)

Clinical trials have shown that adjuvant hormone therapy (AHT)-related hot flashes can predict better breast cancer outcomes. This population-based cohort study investigated whether this result can be generalized to a real-world setting.By linking the National Quality Registry for Breast Cancer, Prescribed Drug Register, and Cause-of-Death Register, we identified 7,152 chemotherapy-free patients with breast cancer who initiated AHT in Stockholm from 2006 through 2019, and followed them until 2020. Hot flashes were defined as new use of drugs for hot flashes within 6 months after initiating AHT. We used Cox models to compare disease-free survival and treatment discontinuation among patients with and without hot flashes.Patients who newly used drugs for hot flashes shortly after AHT initiation had worse disease-free survival (adjusted hazard ratio [HR], 1.67; 95% CI, 1.11-2.52) and a higher treatment discontinuation rate (adjusted HR, 1.47; 95% CI, 1.21-1.78). The association between drugs for hot flashes and discontinuation of AHT differed by patient characteristics, with stronger associations among low-income patients (HR, 1.91; 95% CI, 1.41-2.59) and those without first-degree relatives who had cancer (HR, 1.81; 95% CI, 1.39-2.35) or died from cancer (HR, 1.71; 95% CI, 1.37-2.12).AHT-related hot flashes predict worse, rather than better, breast cancer outcomes among patients in clinical routine practice. The identification of adverse effects by the initiation of hot flash medications may identify a subset of patients with more severe hot flashes who are more likely to discontinue AHT and need more support for treatment adherence.
Abstract EP50: Implementation Of A Cloud-Connected Remote Blood Pressure Monitoring Program During The Postpartum Period Improves Ascertainment
Authors: Ema Mujic, Samantha Parker, Christina Yarrington
Journal: Circulation (2022)

Introduction: Postpartum hypertension is a leading cause of postpartum hospital readmissions and severe maternal morbidity. Monitoring postpartum blood pressure (BP) through office visits is challenging due to barriers in accessing care, which disproportionately affect people of color. Remote BP monitoring programs are promising but many require cellular data plans or smartphones. The aim of this study is to examine the impact of a cloud-connected remote BP monitoring program in BP ascertainment during the six weeks postpartum in a diverse, safety-net hospital population. Methods: Eligible patients were those delivering between April 2020 through September 2021 at Boston Medical Center and at high-risk of postpartum hypertension, including those with hypertensive disorders of pregnancy, chronic hypertension, or hypertension during hospitalization for delivery. Patients were given a cell-enabled cuff and provided instructions in either English, Spanish, or Haitian Creole to take their BP daily for six weeks. BP measurements are transmitted to a web-based portal via the local cellular network. Data collected through the portal were merged with clinical information from the medical record. Metrics of compliance included frequency, defined as number of daily measurements ascertained, and duration, or day of last measurement, within the six-week period were examined using means and standard deviations (SD). We examined compliance by self-reported race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic). We calculated the prevalence of postpartum hypertension, defined as ≥ 2 BP measures with systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg. Severe hypertension was defined as SBP ≥160 and/or DPB ≥110. Results: Among the 3,525 deliveries during the study period, 1,008 (28.6%) were eligible for the program. Of the eligible participants, 40.5% identified as Black (n=409), 36.3% as Hispanic (n=366), and 14.4% as White (n=145). Participation was high; only 15 patients (1.5%) did not take any BP measures. Among the 993 participants, the average number of daily BP measures was 17.1 (SD: 10.4), which was similar across racial/ethnic groups (Black: 17.3, Hispanic: 16.5, White: 17.1). Furthermore, the mean duration of participation was 31.7 days (SD: 12.2), which was also similar by race/ethnicity. In this high-risk cohort, the prevalence of postpartum hypertension was 64.3% (n=638), with 9.6% (n=61) meeting severe criteria. Conclusion: In conclusion, implementation of a cloud-connected BP monitoring program among a diverse, safety-net population was successful at ascertaining multiple BP measures in the postpartum period. Furthermore, similar patterns of use across racial and ethnic groups suggest that this program could reduce disparities with respect to postpartum BP ascertainment.
Incidental Detection of Viral Conjunctivitis on 68Ga-DOTANOC PET/CT in a Patient Suspected With Von Hippel–Lindau Syndrome
Authors: Yamini Mathur, Venkata Subramanian Krishnaraju, Harmandeep Singh, Rajender Kumar, Pinaki Dutta
Journal: Clinical Nuclear Medicine (2022)

Von Hippel-Lindau syndrome is an autosomal dominant disorder. It is associated with a spectrum of benign and malignant tumors, including pancreatic and adrenal neuroendocrine tumors, renal cell carcinoma, and hemangioblastomas of the central nervous system and retina. 68Ga-DOTANOC PET/CT has shown somatostatin receptor expression in inflammatory conditions. In the present case, we report that 68Ga-DOTANOC PET/CT demonstrates the tracer avidity in the bilateral swollen eyelids in a patient with clinical suspicion of Von Hippel-Lindau syndrome, which was confirmed as viral conjunctivitis on clinical examination.
Particle uptake driven phagocytosis in macrophages and neutrophils enhances bacterial clearance
Authors: Preeti Sharma, Anjali Vijaykumar, Jayashree Vijaya Raghavan, Supriya Rajendra Rananaware, Alakesh Alakesh, Janhavi Bodele, Junaid Ur Rehman, Shivani Shukla, Virta Wagde, Savitha Nadig, Sveta Chakrabarti, Sandhya S. Visweswariah, Dipankar Nandi, Balasubramanian Gopal, Siddharth Jhunjhunwala
Journal: Journal of Controlled Release (2022)
Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex
Authors: Cyril Djari, Isabelle Sahut-Barnola, Amandine Septier, Ingrid Plotton, Nathanaëlle Montanier, Damien Dufour, Adrien Levasseur, James Wilmouth, Jean-Christophe Pointud, Fabio R. Faucz, Crystal Kamilaris, Antoine-Guy Lopez, Florian Guillou, Amanda Swain, Seppo J. Vainio, Igor Tauveron, Pierre Val, Hervé Lefebvre, Constantine A. Stratakis, Antoine Martinez, Anne-Marie Lefrançois-Martinez
Journal: Journal of Clinical Investigation (2021)

Large-cell calcifying Sertoli cell tumors (LCCSCTs) are among the most frequent lesions occurring in male Carney complex (CNC) patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A, leading to unrepressed PKA activity, LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the induction of CNC testis lesions. We demonstrate that the Prkar1a mutation was required in both stromal and Sertoli cells for the occurrence of LCCSCTs. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to the understanding of human LCCSCT pathogenesis and demonstrated PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in a mouse model and in human CNC testes.
CTX-712, a Novel Clk Inhibitor Targeting Myeloid Neoplasms with <i>SRSF2</i> Mutation
Authors: Akinori Yoda, Daisuke Morishita, Yotaro Ochi, Akio Mizutani, June Takeda, Hirokazu Tozaki, Yoshihiko Satoh, Yasuhito Nannya, Hideki Makishima, Hiroshi Miyake, Seishi Ogawa
Journal: Blood (2021)
18F-FDG PET/CT of Malignant Presacral Masses in Currarino Syndrome
Authors: Ba D. Nguyen
Journal: Clinical Nuclear Medicine (2021)

The Currarino syndrome is characterized by 3 main features: anorectal malformation, presacral lesion, and dysgenesis of the sacrum and coccyx. The presacral lesion is usually benign with a rare occurrence of malignant degeneration. The author presents 2 cases of Currarino syndrome with presacral mucinous adenocarcinoma and neuroendocrine tumor depicted by 18F FDG PET/CT.
The unintended contribution of clinical microbiology laboratories to climate change and mitigation strategies: a combination of descriptive study, short survey, literature review and opinion
Authors: Erlangga Yusuf, Ad Luijendijk, Geesje Roo-Brand, Alexander W. Friedrich
Journal: Clinical Microbiology and Infection (2022)

ObjectiveClimate change poses a significant threat to humanity and human activity is largely responsible for it. Clinical microbiology laboratories have their unintended shares in carbon dioxide (CO2) emissions. The aim of this study is to estimate CO2 emission of a clinical microbiology laboratory and to propose initiatives to reduce the emissions.MethodsCO2 emission of instruments was estimated based on their electricity consumption. CO2 emitted in producing consumables was estimated by weighing the consumables needed to perform major tests in a large academic hospital. A systematic literature review was performed to identify studies on the impact of clinical microbiology laboratories on the environment. A short survey was sent to four major manufacturers of agar plates on initiatives to reduce the environmental impact of their products. Opinion was given on activities that can reduce CO2 emission in laboratories.ResultsThe study shows that the largest amount of CO2 emission in the microbiological laboratories comes from consumables and personnel commuting. For example, the production and transportation of agar plates needed to culture samples for a year in a hospital with 1320 beds result in 16 590 kg CO2 is emitted. All survey participants mentioned that they were committed to reduce environmental impact of their products. The initiatives to reduce CO2 emission can be performed at the laboratory and at policy level, such as reducing the number of tests to only the necessary amount to reduce consumables.DiscussionThe calculations contribute to map CO2-related emissions in clinical microbiology laboratory activities, and the proposed initiatives to reduce the CO2 may serve as starting point for further discussions.
Annals Graphic Medicine - Am I Going to Die?
Authors: Arun Thekkekarott Kuruvila, Nikita Hegde
Journal: Annals of Internal Medicine (2022)

Web ExclusivesMarch 2022Annals Graphic Medicine - Am I Going to Die?FREEArun Thekkekarott Kuruvila, MBBS, MD and Nikita Hegde, MBBS, MDArun Thekkekarott Kuruvila, MBBS, MDAsante Rogue Regional Medical Center, Medford, Oregon (A.T.K.)Search for more papers by this author and Nikita Hegde, MBBS, MDA.J. Institute of Medical Sciences, Mangalore, India (N.H.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G21-0082 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Asante Rogue Regional Medical Center, Medford, Oregon (A.T.K.)A.J. Institute of Medical Sciences, Mangalore, India (N.H.)Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0082.Author/Illustrator Information: Arun Thekkekarott Kuruvila, MBBS, MD, is a hospitalist in Oregon and an acclaimed artist whose artwork was displayed at high-quality exhibitions in India and the United States (e-mail, [email protected]com). Nikita Hegde, MBBS, MD, is an anesthesiologist and art enthusiast (e-mail, [email protected]com).This article was published at Annals.org on 25 January 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics March 2022Volume 175, Issue 3Page: W33-W34 ePublished: 25 January 2022 Issue Published: March 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Inter-species geographic signatures for tracing horizontal gene transfer and long-term persistence of carbapenem resistance
Authors: Rauf Salamzade, Abigail L. Manson, Bruce J. Walker, Thea Brennan-Krohn, Colin J. Worby, Peijun Ma, Lorrie L. He, Terrance P. Shea, James Qu, Sinéad B. Chapman, Whitney Howe, Sarah K. Young, Jenna I. Wurster, Mary L. Delaney, Sanjat Kanjilal, Andrew B. Onderdonk, Cassiana E. Bittencourt, Gabrielle M. Gussin, Diane Kim, Ellena M. Peterson, Mary Jane Ferraro, David C. Hooper, Erica S. Shenoy, Christina A. Cuomo, Lisa A. Cosimi, Susan S. Huang, James E. Kirby, Virginia M. Pierce, Roby P. Bhattacharyya, Ashlee M. Earl
Journal: Genome Medicine (2022)

Carbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms.To overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years.Our CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment.Collectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.
ANGPTL4-Mediated Promotion of Glycolysis Facilitates the Colonization of<i>Fusobacterium nucleatum</i>in Colorectal Cancer
Authors: Xin Zheng, Rui Liu, Chenchen Zhou, Haopeng Yu, Wanyi Luo, Jianhui Zhu, Jiaxin Liu, Zhe Zhang, Na Xie, Xian Peng, Xin Xu, Lei Cheng, Quan Yuan, Canhua Huang, Xuedong Zhou
Journal: Cancer Research (2021)

Colorectal cancer is a severe health problem worldwide, and accumulating evidence supports the contribution of Fusobacterium nucleatum (F. nucleatum) to colorectal cancer development, metastasis, and chemoresistance. However, the mechanisms underlying the colonization of F. nucleatum in colorectal cancer tissue are not yet clarified. Here we demonstrate that F. nucleatum infection mediated elevation of angiopoietin-like 4 (ANGPTL4) expression. Upregulated ANGPTL4 promoted glucose uptake and glycolysis activity in colorectal cancer cells in vitro and in vivo, which are necessary for the colonization of F. nucleatum. Furthermore, overall increased acetylation of histone H3 lysine 27 was observed in F. nucleatum-infected colorectal cancer cells and patient tumors, which was responsible for the corresponding transcriptional upregulation of ANGPTL4. These data indicate that the metabolic reprogramming of cancer cells induced by F. nucleatum is essential for its enrichment and persistence in colorectal cancer, providing a novel potential target for the clinical intervention of F. nucleatum-related colorectal cancer. SIGNIFICANCE: F. nucleatum colonization in colorectal cancer is regulated by ANGPTL4-mediated glycolysis, suggesting that this axis could be targeted for combined repression of F. nucleatum and cancer progression.
Single-cell RNA sequencing identifies G-protein coupled receptor 87 as a basal cell marker expressed in distal honeycomb cysts in idiopathic pulmonary fibrosis
Authors: Katharina Heinzelmann, Qianjiang Hu, Yan Hu, Evgenia Dobrinskikh, Meshal Ansari, M. Camila Melo-Narváez, Henrik M. Ulke, Colton Leavitt, Carol Mirita, Tammy Trudeau, Maxwell L. Saal, Pamela Rice, Bifeng Gao, William J. Janssen, Ivana V. Yang, Herbert B. Schiller, Eszter K. Vladar, Mareike Lehmann, Melanie Königshoff
Journal: European Respiratory Journal (2022)

<b>Bronchiolisation and honeycombing are features of IPF. ScRNA sequencing identified GPR87 as a novel marker of basal cells in IPF, enriched in honeycomb cysts. GPR87 overexpression resulted in aberrant airway cell differentiation.</b>https://bit.ly/3i4dXeT