tbuckley/cabot-search huggingface dataset:
Single-cell RNA sequencing identifies macrophage transcriptional heterogeneities in granulomatous diseases
Authors: Shu-Yi Liao, Shaikh M. Atif, Kara Mould, Iain R. Konigsberg, Rui Fu, Elizabeth Davidson, Li Li, Andrew P. Fontenot, Lisa A. Maier, Ivana V. Yang
Journal: European Respiratory Journal (2021)

<b>scRNA-seq characterised macrophage transcriptional and chromatin accessibility profiles in BAL cells in granulomatous lung diseases, chronic beryllium disease and sarcoidosis, and identified signatures of disease progression in sarcoidosis.</b>https://bit.ly/3piFIBy
Proper vascular development and heart morphogenesis require tumor suppressor VHL in zebrafish development.
Authors: Ellen Van Rooijen, Carina Van Rooijen, Emile E. Voest, Rachel H. Giles, Freek Van Eeden
Journal: Cancer Research (2006)

5125  We have generated two different zebrafish lines carrying germline inactivating mutations of an ortholog of the von Hippel-Lindau tumor suppressor (VHL). Homozygotes and trans-heterozygotes survive approximately 11-14 days post fertilization. Mutant embryos lack a swim bladder, gasp for air, and manifest increased blood volumes, including elevated erythrocyte counts (polycythemia). In situ hybridizations reveal marked increased expression of hematopoietic stem/progenitor cell markers. Microarray gene expression experiments demonstrate the upregulation of a suite of HIF target genes, supporting the notion that these fish experience an artificial hypoxic response under normoxic conditions. Furthermore, by crossing vhl1 mutant alleles into a fli-gfp transgenic background, we observe aberrant vascular development in vivo, which can be attenuated by administration of VEGF receptor inhibitors. Lastly, vhl1 mutant embryos display a severely enlarged heart with altered cell morphology. We are currently examining the exact nature of these defects and are screening the oldest heterozygotes (1.5 years old) for tumor formation. Transplantation experiments (lineage labeled vh1l-/- cells into vhl1 zebrafish) are being performed to assess the question whether mutant cells are able to induce tumors. Vhl1 fish are also being crossed with PTEN, p53, APC, and LKB1 mutant fish to determine how HIF signaling affects different tumor suppressor pathways.
Abstract 16002: Insulin and Neuropilin-1 Interaction Promote Insulin Resistance
Authors: Imoh Okon, Ming-Hui Zou, Sean Carr, Ramprasath Tharmarajan
Journal: Circulation (2019)

Introduction: Obesity remains a major risk factor associated with several pathological conditions, including cardiovascular diseases (CVDs), type 2 diabetes and insulin resistance. However, the sig...
Baricitinib in patients with moderate-to-severe atopic dermatitis: Results from a randomized monotherapy phase 3 trial in the United States and Canada (BREEZE-AD5)
Authors: Eric L. Simpson, Seth Forman, Jonathan I. Silverberg, Matthew Zirwas, Emanual Maverakis, George Han, Emma Guttman-Yassky, Daniel Marnell, Robert Bissonnette, Jill Waibel, Fabio P. Nunes, Amy M. DeLozier, Robinette Angle, Margaret Gamalo, Katrin Holzwarth, Orin Goldblum, Jinglin Zhong, Jonathan Janes, Kim Papp
Journal: Journal of the American Academy of Dermatology (2021)
Abstract OT-09-11: AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer
Authors: Mario Campone, Christina Herold, Qiuyan Wang, Vasiliki Pelekanou, Sylvaine Cartot-Cotton, Bethany Ling
Journal: Cancer Research (2021)

Abstract Background Endocrine therapy targeting estrogen receptor (ER) signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER- breast cancer. AMEERA-4 (NCT04191382; ACT16106) is a 14-day preoperative, non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods This international, open-label, Phase 2 randomized study evaluates SAR439859 at two dose levels vs the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing AMEERA-1 Phase 1/2 study (NCT03284957; TED14856) in metastatic breast cancer. Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0-1, and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological complete response will also be assessed. The study is currently recruiting. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Citation Format: Mario Campone, Christina Herold, Qiuyan Wang, Vasiliki Pelekanou, Sylvaine Cartot-Cotton, Bethany Ling. AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer [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 OT-09-11.
Abstract PS7-27: Trends in breast cancer mortality in Brazil - a 14-year registry-based study
Authors: Guilherme Nader Marta, Laura Testa, Rodrigo Santa Cruz Guindalini, Gustavo Nader Marta, Maria Del Pilar Estevez Diz, Paulo M. Hoff
Journal: Cancer Research (2021)

Abstract Background: Breast cancer (BC) is the leading cause of cancer-related deaths among women worldwide. BC mortality rates have been decreasing over the past decades in the developed countries. In the United States, BC mortality declined on average 1.5% each year over 2008-2017. Given the paucity of BC mortality data in Brazil, we sought to characterize BC mortality trends in southeastern Brazil and its relationship with demographic variables. Methods: A cross-sectional registry-based analysis was conducted to describe BC mortality trends in the State of Sao Paulo (Brazil) from 2004 to 2017. Sao Paulo is the most populous state in Brazil, with 45.5 million inhabitants, corresponding to 21.8% of the country's total population. BC-related death records, including gender and age were collected from SEADE Foundation’s database, an official entity charged with generating statistical data for the State of Sao Paulo. Mortality rates are expressed in units of deaths per 100,000 individuals per year. The annual percentage change (APC) was calculated to identify mortality trends over the period. Trend analysis was carried out by linear regression and an increase or decrease in trend was considered statistically significant when p-value &amp;lt; 0.05. Results: From 2004 to 2017, 52,005 deaths from BC were recorded in the State of São Paulo, Brazil. Average annual mortality was 8.96/100,000 (17.38/100,000 for females and 0.11/100,000 for males). Average mortality rates were higher in the age group over 65 years-old (46.47/100,000). BC mortality rates remained stable during the period analyzed (APC 0, 95%CI -0.2% to +0.3%, P = 0.9) for both females (APC 0, 95%CI -0.3% to +0.2%, P = 0.7) and males (APC +2.4%, 95%CI -1.7% to +6.6%, P = 0.2). Among females, an increasing BC mortality trend was detected for patients under 40 years-old (APC +2.4%, 95%CI +1.6% to +3.2%, P &amp;lt; 0.0001) and remained stable for the age groups between 40 - 65 years-old (APC -0.3%, 95%CI -0.7% to +0.1%, P = 0.1) and over 65 years-old (APC -0.1%, 95%CI -0.4% to +0.2%, P 0.5). Conclusion: In contrast with data from other developing countries, a stable BC mortality has been demonstrated in southeastern Brazil over a 14-year period for the general population. However, a significant increase in BC mortality rates has been demonstrated among patients under 40 years-old. Citation Format: Guilherme Nader Marta, Laura Testa, Rodrigo Santa Cruz Guindalini, Gustavo Nader Marta, Maria Del Pilar Estevez Diz, Paulo M. Hoff. Trends in breast cancer mortality in Brazil - a 14-year registry-based study [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 PS7-27.
Small changes in the length of diselenide bond-containing linkages exert great influences on the antitumor activity of docetaxel homodimeric prodrug nanoassemblies
Authors: Lingxiao Li, Shiyi Zuo, Fudan Dong, Tian Liu, Yanlin Gao, Yinxian Yang, Xin Wang, Jin Sun, Bingjun Sun, Zhonggui He
Journal: Asian Journal of Pharmaceutical Sciences (2021)

Homodimeric prodrug-based self-assembled nanoparticles, with carrier-free structure and ultrahigh drug loading, is drawing more and more attentions. Homodimeric prodrugs are composed of two drug molecules and a pivotal linkage. The influence of the linkages on the self-assembly, in vivo fate and antitumor activity of homodimeric prodrugs is the focus of research. Herein, three docetaxel (DTX) homodimeric prodrugs are developed using different lengths of diselenide bond-containing linkages. Interestingly, compared with the other two linkages, the longest diselenide bond-containing linkage could facilitate the self-delivery of DTX prodrugs, thus improving the stability, circulation time and tumor targeting of prodrug nanoassemblies. Besides, the extension of linkages reduces the redox-triggered drug release and cytotoxicity of prodrug nanoassemblies in tumor cells. Although the longest diselenide bond-containing prodrug nanoassemblies possessed the lowest cytotoxicity to 4T1 cells, their stable nanostructure maintained intact during circulation and achieve the maximum accumulation of DTX in tumor cells, which finally "turned the table". Our study illustrates the crucial role of linkages in homodimeric prodrugs, and gives valuable proposal for the development of advanced nano-DDS for cancer treatment.
Multiomics analysis reveals the presence of a microbiome in the gut of fetal lambs
Authors: Yanliang Bi, Yan Tu, Naifeng Zhang, Shiqing Wang, Fan Zhang, Garret Suen, Dafu Shao, Shengli Li, Qiyu Diao
Journal: Gut (2021)

Microbial exposure is critical to neonatal and infant development, growth and immunity. However, whether a microbiome is present in the fetal gut prior to birth remains debated. In this study, lambs delivered by aseptic hysterectomy at full term were used as an animal model to investigate the presence of a microbiome in the prenatal gut using a multiomics approach.Lambs were euthanised immediately after aseptic caesarean section and their cecal content and umbilical cord blood samples were aseptically acquired. Cecal content samples were assessed using metagenomic and metatranscriptomic sequencing to characterise any existing microbiome. Both sample types were analysed using metabolomics in order to detect microbial metabolites.We detected a low-diversity and low-biomass microbiome in the prenatal fetal gut, which was mainly composed of bacteria belonging to the phyla Proteobacteria, Actinobacteria and Firmicutes. Escherichia coli was the most abundant species in the prenatal fetal gut. We also detected multiple microbial metabolites including short chain fatty acids, deoxynojirimycin, mitomycin and tobramycin, further indicating the presence of metabolically active microbiota. Additionally, bacteriophage phiX174 and Orf virus, as well as antibiotic resistance genes, were detected in the fetal gut, suggesting that bacteriophage, viruses and bacteria carrying antibiotic resistance genes can be transmitted from the mother to the fetus during the gestation period.This study provides strong evidence that the prenatal gut harbours a microbiome and that microbial colonisation of the fetal gut commences in utero.
Patients’ access to drugs with rebates in Switzerland – Empirical analysis and policy implications for drug pricing in Europe
Authors: David L Carl, Kerstin N Vokinger
Journal: The Lancet Regional Health - Europe (2021)

Many European countries introduced (confidential) rebates in the past years. Authorities and manufacturers argue that this strategy allows reduction of spending on high-cost drugs, and quick access of innovative drugs. We evaluated these arguments using Switzerland as an example, one of the last countries with transparent rebates. We identified all drugs granted rebates in Switzerland and all new drugs without rebates between January 2012 and October 2020. We assessed the amount of introduced drugs with and without rebates over time, clinical benefit of drugs with rebates, and duration between approval and price determination. Our study cohort included 51 drugs with rebates, the majority were cancer drugs (32; 63%). 15/51 (29%) had high clinical benefit, 25/51 (49%) low benefit and for 11/51 (22%) benefit could not be assessed. The number of drugs with rebates increased in recent years. Time duration between approval and price determination was 302 days in median for drugs with and 106 days for drugs without rebates. Drugs with rebates may hamper access to drugs and lead to overpayment. Improving transparency on actual drug prices and stronger cooperation between countries could help national authorities to make better informed pricing decisions, and improve access of innovative drugs to patients. This study was partially funded by the Swiss Cancer Research Foundation (Krebsforschung Schweiz) and the Swiss National Foundation (SNF).
RETRACTED ARTICLE: Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4
Authors: Shaowei Wang, Boyang Li, Victoria Solomon, Alfred Fonteh, Stanley I. Rapoport, David A. Bennett, Zoe Arvanitakis, Helena C. Chui, Carol Miller, Patrick M. Sullivan, Hoau-Yan Wang, Hussein N. Yassine
Journal: Molecular Neurodegeneration (2021)

Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress.Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of patients with AD carrying APOE3/E4 compared to APOE3/E3. Greater cPLA2 phosphorylation was also observed in human postmortem frontal cortical synaptosomes and primary astrocytes after treatment with recombinant ApoE4 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition.Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.
Tumor metabolism and neurocognition in CNS lymphoma
Authors: Huimin Geng, Mazie Tsang, Lakshmipriya Subbaraj, Joseph Cleveland, Lingjing Chen, Ming Lu, Jigyasa Sharma, Daniel B Vigneron, John Kurhanewicz, Marisa LaFontaine, Tracy Luks, Bruce A Barshop, Jon Gangoiti, Javier E Villanueva-Meyer, James L Rubenstein
Journal: Neuro-Oncology (2021)

The mechanistic basis for neurocognitive deficits in central nervous system (CNS) lymphoma and other brain tumors is incompletely understood. We tested the hypothesis that tumor metabolism impairs neurotransmitter pathways and neurocognitive function.We performed serial cerebrospinal fluid (CSF) metabolomic analyses using liquid chromatography-electrospray tandem mass spectrometry to evaluate changes in the tumor microenvironment in 14 patients with recurrent CNS lymphoma, focusing on 18 metabolites involved in neurotransmission and bioenergetics. These were paired with serial mini-mental state examination (MMSE) and MRI studies for tumor volumetric analyses. Patients were analyzed in the setting of the phase I trial of lenalidomide/rituximab. Associations were assessed by Pearson and Spearman correlation coefficient. Generalized estimating equation (GEE) models were also established, adjusting for within-subject repeated measures.Of 18 metabolites, elevated CSF lactate correlated most strongly with lower MMSE score (P < 8E-8, ρ = -0.67). High lactate was associated with lower gamma-aminobutyric acid (GABA), higher glutamate/GABA ratio, and dopamine. Conversely, high succinate correlated with higher MMSE scores. Serial analysis demonstrated a reproducible, time-dependent, reciprocal correlation between changes in lactate and GABA concentrations. While high lactate and low GABA correlated with tumor contrast-enhancing volume, they correlated more significantly with lower MMSE scores than tumor volumes.We provide evidence that lactate production and Warburg metabolism may impact neurotransmitter dysregulation and neurocognition in CNS lymphomas. We identify novel metabolomic biomarkers that may be applied in future studies of neurocognition in CNS lymphomas. Elucidation of mechanistic interactions between lymphoma metabolism, neurotransmitter imbalance, and neurocognition may promote interventions that preserve cognitive function.
Colin Bennett Keith
Authors: Paul Keith
Journal: BMJ (2021)

Compassionate, modest and dedicated, Colin Bennett Keith was the epitome of the quiet man who served the community as a general practitioner. He was born into two families with longstanding connections to medicine—the Grogonos and the Prestons—who had trained at the London Hospital in Whitechapel for generations. Both families also shared a love of sailing. The pursuit of both shaped Colin’s life and gave rise to many of his happiest moments.

Colin Bennett Grogono was born in April 1940 and divided his first four years between the family home in Stratford, London, and escaping the blitz to Abingdon and the Preston family home in St Mawes, Cornwall.

Antipathy towards the Axis powers extended to those with Italian sounding names, so his father adopted “Keith” as the family surname and, in 1944, moved to Littlehampton to go into practice with his father-in-law, Arthur Preston.

Colin attended Millfield School, where his housemaster, Robert Bolt—later a celebrated playwright and two-time …
Abstract PS11-40: A novel and highly selective CDK9 inhibitor (D11) suppresses proliferation of triple negative breast cancer cells
Authors: Ebtihal Mustafa
Journal: Cancer Research (2021)

Abstract Targeted treatment for triple-negative breast cancer (TNBC) remains an elusive clinical challenge. Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator shown to promote growth of multiple cancers, including TNBC, and represents a potential new therapeutic target. CDK9 increases RNA Polymerase II (RNAPII) activity, which facilitates sustained expression of normally short-lived oncogenic and anti-apoptotic proteins. However, preclinical evaluation of CDK9 as a therapeutic target has been hampered by the poor selectivity of existing CDK9 inhibitors (CDK9i). Herein, we evaluated the preclinical efficacy of a newly developed, highly selective CDK9i (D-11) across a panel of TNBC cell lines: MDA-MB-453, MDA-MB-468, MDA-MB-231 and MFM-223. Cells were treated with increasing concentrations of D-11 and effects on proliferation, apoptosis, cell cycle and expression of known CDK9 substrates were examined. Treatment with D-11 significantly reduced cell proliferation, induced G2/M cell cycle arrest and increased apoptosis in MDA-MB-453 and MDA-MB-468 cell lines (IC50s of 160 and 258 nM, respectively). Cell proliferation was also inhibited by D-11 in MDA-MB-231 and MFM-223 cells, but with IC50s of 400 and 468 nM, respectively, but without inducing apoptosis. Protein expression of known CDK9 targets, including phosphorylated-RNAPII, the proto-oncogene C-MYC, and the anti-apoptotic marker MCL-1, were examined by Western blot using the optimal D-11 dose determined for each cell line. As expected, D-11 suppressed phosphorylation of RNAPII (Ser2) without affecting total RNAPII expression in all cell lines, indicative of targeted CDK9 inhibition. C-MYC and MCL-1, which highly expressed in the TNBC models, were significantly decreased by treatment with D-11. To determine whether D-11 influenced normal breast epithelial cells, breast tissues were collected from women undergoing reduction mammoplasty and cultured ex vivo as explants treated with or without different doses of D-11 for 48h. A high dose of D-11 (2.7µM) elicited a 20% decrease in the proliferative index (Ki67 positivity) of epithelial cells within normal tissue explants but had no effect on their histology. Collectively, these data demonstrate that D-11 effectively inhibits CDK9 in TNBC cell lines, resulting in growth inhibition with non-toxic effects on histologically normal breast tissues. Citation Format: Ebtihal Mustafa. A novel and highly selective CDK9 inhibitor (D11) suppresses proliferation of triple negative breast cancer cells [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 PS11-40.
SARS-CoV-2 Positivity on or After 9 Days Among Quarantined Student Contacts of Confirmed Cases
Authors: Eric J. Nelson, Sarah L. McKune, Kathleen A. Ryan, John A. Lednicky, Susanne R. Crowe, Paul D. Myers, J. Glenn Morris
Journal: JAMA (2021)

This study describes coronavirus test positivity rates among elementary, middle, and high school student contacts of confirmed COVID-19 cases in a Florida county where schools required a negative test on day 9 before return to school on day 10.
A RUNX–CBFβ-driven enhancer directs the Irf8 dose-dependent lineage choice between DCs and monocytes
Authors: Koichi Murakami, Haruka Sasaki, Akira Nishiyama, Daisuke Kurotaki, Wataru Kawase, Tatsuma Ban, Jun Nakabayashi, Satoko Kanzaki, Yoichi Sekita, Hideaki Nakajima, Keiko Ozato, Tohru Kimura, Tomohiko Tamura
Journal: Nature Immunology (2021)
Abstract 20765: Cardiac Rehabilitation is Associated With Lower Rates of Cardiac Events Amongst Veterans
Authors: Alaaeeddin Alrohaibani, Arash Harzand, A. Maziar Zafari, Amit J Shah
Journal: Circulation (2017)

Introduction: Cardiac Rehabilitation (CR) is a class I indication after coronary intervention but referral and completion rates are low. This is particularly true amongst Veterans, who may face fin...