tbuckley/cabot-search huggingface dataset:
Timing of State and Territorial COVID-19 Stay-at-Home Orders and Changes in Population Movement — United States, March 1–May 31, 2020
Authors: Amanda Moreland, Christine Herlihy, Michael A. Tynan, Gregory Sunshine, Russell F. McCord, Charity Hilton, Jason Poovey, Angela K. Werner, Christopher D. Jones, Erika B. Fulmer, Adi V. Gundlapalli, Heather Strosnider, Aaron Potvien, Macarena C. García, Sally Honeycutt, Grant Baldwin, Catherine Clodfelter, Mara Howard-Williams, Gi Jeong, Lisa Landsman, Julia Shelburne, Amanda Brown, Ryan Cramer, Siobhan Gilchrist, Rachel Hulkower, Alexa Limeres, Adebola Popoola
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

SARS-CoV-2, the virus that causes coronavirus disease 2019 , is thought to spread from person to person primarily by the respiratory route and mainly through close contact (1).Community mitigation strategies can lower the risk for disease transmission by limiting or preventing personto-person interactions (2).U.S. states and territories began implementing various community mitigation policies in March 2020.One widely implemented strategy was the issuance of orders requiring persons to stay home, resulting in decreased population movement in some jurisdictions (3).Each state or territory has authority to enact its own laws and policies to protect the public's health, and jurisdictions varied widely in the type and timing of orders issued related to stay-at-home requirements.To identify the broader impact of these stay-athome orders, using publicly accessible, anonymized location data from mobile devices, CDC and the Georgia Tech Research Institute analyzed changes in population movement relative to stay-at-home orders issued during March 1-May 31, 2020, by all 50 states, the District of Columbia, and five U.S. territories.*During this period, 42 states and territories issued mandatory stay-at-home orders.When counties subject to mandatory state-and territory-issued stay-at-home orders were stratified along rural-urban categories, movement decreased significantly relative to the preorder baseline in all strata.Mandatory stayat-home orders can help reduce activities associated with the spread of COVID-19, including population movement and close person-to-person contact outside the household.Data on state and territorial stay-at-home orders were obtained from government websites containing executive or administrative orders or press releases for each jurisdiction.Each order was analyzed and coded into one of five mutually exclusive categories: 1) mandatory for all persons; 2) mandatory only for persons in certain areas of the jurisdiction; 3) mandatory only for persons at increased risk in the jurisdiction; 4) mandatory only for persons at increased risk in certain areas of the jurisdiction; or 5) advisory or recommendation (i.e., nonmandatory).
A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer
Authors: Yuhang Hu, Fan Wang, Fengyu Xu, Kaifeng Fang, Zhi Fang, Xiaoming Shuai, Kailin Cai, Jinhuang Chen, Ping Hu, Ding Chen, Peng Xu, Chaojie Hu, Zhu Zeng, Jianxin Zhong, Wei Li, Jiang Tang, Mengqi Huang, Yong Zhao, Chunyou Wang, Gang Zhao
Journal: Theranostics (2020)

Rationale: Previous studies have reported on the role of extracellular acidity in the metastasis of numerous cancers. However, the involvement of long noncoding RNA (lncRNA) in the extracellular acidity-induced cancer metastasis of pancreatic cancer (PC) remains unclear. Methods: Different expression levels of lncRNAs in PC cells under normal and acidic conditions were compared by RNA sequencing (RNA-seq). The effects of antisense lncRNA of metastasis suppressor 1 (MTSS1-AS) on acidic PC cells were assessed by gain- and loss-of-function experiments. Fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, Western blot, luciferase reporter, and Chromatin immunoprecipitation assays were employed to determine the regulatory mechanisms of MTSS1-AS in the acidity-induced metastasis of PC cells. The expression of MTSS1-AS and associated pathways were compared in PC samples and peritumoral normal tissues. Results: RNA-seq demonstrated that MTSS1-AS was significantly downregulated in pancreatic cells cultured with the acidic medium. The overexpression of MTSS1-AS remarkably inhibited the acidity-promoted metastasis of PC cells by upregulating the expression of its sense gene metastasis suppressor 1 (MTSS1). Mechanistically, MTSS1-AS scaffolded the interaction between E3 ubiquitin-protein ligase STIP1 homology and U-box containing protein 1 (STUB1) and transcription regulator myeloid zinc finger 1 (MZF1), leading to ubiquitination-mediated degradation of MZF1. Further, MZF1 inhibited the expression of MTSS1 by binding to the MTSS1 promoter. Thus, the acidity-reduced MTSS1-AS facilitated the stability of MZF1 and its inhibitory effect on MTSS1 transcription, thereby promoting the metastasis of PC cells under acidic conditions. Moreover, MTSS1-AS was transcriptionally repressed by the binding of MYC proto-oncogene (Myc) with initiator (Inr) elements of the MTSS1-AS promoter. Meanwhile, MTSS1-AS mutually repressed the expression of Myc by impairing the MZF1-mediated transcription activation of Myc, thereby forming a negative feedback loop between MTSS1-AS and Myc in acidic PC cells. In accordance with the experimental results, MTSS1-AS and MTSS1 were downregulated in PC and correlated with poor overall survival. Conclusions: The results implicated that a reciprocal feedback loop between Myc and MTSS1-AS contributed to the extracellular acidity-promoted metastasis of PC, and indicated that MTSS1-AS was a valuable biomarker and therapeutic target for PC.
Abstract 5337: Analysis of drug combinations with the PKC inhibitor IDE196 support dual MEK and PKC inhibition as a rational combination in metastatic uveal melanoma
Authors: Christian R. Frey, Marie-Claire Wagle, Kedar Vaidya, Julie Hambleton, Mark Lackner, Zineb Mounir
Journal: Cancer Research (2020)

Abstract Uveal melanoma (UM) is the most common primary intraocular tumor. The majority (&amp;gt;90%) of uveal melanoma harbor activating mutations in the GNAQ and GNA11 Ga subunits of G protein coupled receptors. These genetic driver mutations, which are also detected in other solid tumors, lead to continuous activation of protein kinase C (PKC) and downstream signaling pathways such as the mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PKC with small molecule inhibitors is an attractive therapeutic approach in UM. IDE196 is a selective and potent protein kinase C inhibitor targeting the novel (δ, ϵ, η, θ) and classical (α, β) PKC isoforms and has shown anti-tumor activity as monotherapy in patients with metastatic uveal melanoma (MUM). Inhibiting downstream signaling pathways in addition to PKC inhibition with IDE196 may increase the anti-tumor activity in MUM patients. To address this question, we assessed pathway-focused drug combination partners for their potential to exert synergy with IDE196. In this study, we evaluated baseline-expression of different PKC isoforms in uveal melanoma or control cell lines and the response to PKC inhibition with IDE196 by western blotting (WB). We measured the sensitivity to several drug combinations utilizing a concentration matrix in a 3-day cell titer glow assay to measure cell viability and determined synergy of drug combinations. Modulation of PKC, MAPK pathway activity and other downstream markers were assessed by WB. The evaluated uveal melanoma cell lines expressed different phospho-PKC isoforms and were sensitive to increasing concentrations of IDE196 as demonstrated by decreased levels of PKC substrate p-MARCKS and reduced cell viability. Furthermore, we did not detect synergy of IDE196 with cyclin-dependent kinase (CDK) 4/6 inhibitors Palbociclib or Ribociclib in viability assay. In contrast, combination of IDE196 with MEK inhibitors Binimetinib or Trametinib showed synergy at clinically relevant doses for each compound. The observed synergy of IDE196 with MEK inhibitors is further substantiated by modulation of MARCKS and MAPK pathway activity as measured by WB. Additional work is underway in in vitro as well as in vivo models to clarify the potential benefit of combining IDE196 with MEK inhibitors in the clinic. Citation Format: Christian R. Frey, Marie-Claire Wagle, Kedar Vaidya, Julie Hambleton, Mark Lackner, Zineb Mounir. Analysis of drug combinations with the PKC inhibitor IDE196 support dual MEK and PKC inhibition as a rational combination in metastatic uveal melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5337.
Abstract 3734: Expression of serine synthetic enzymes alters the sensitivity of ER-positive breast cancer cells to tamoxifen
Authors: Stephanie Metcalf, Traci Kruer, Susan Dougherty, James L. Wittliff, Carolyn M. Klinge, Brian F. Clem
Journal: Cancer Research (2020)

Abstract Estrogen receptor positive breast cancer (ER+BC) is the most common form of breast cancer accounting for 65-75% of all diagnoses, yet, due to the availability of targeted therapies, has the best overall survival outcomes. However, it is estimated that up to 30% of all patients develop resistance to these therapies, resulting in recurrence or disease progression. Phosphoserine aminotransferase 1 (PSAT1), which is an enzyme within the serine synthetic pathway (SSP), has previously been implicated in endocrine resistance. Therefore, we sought to determine if there was a functional correlation between expression of PSAT1 or other serine synthetic enzymes and sensitivity to 4-hydroxytamoxifen (4-OHT) treatment. To investigate the correlation between PSAT1, another SSP enzyme phosphoglycerate dehydrogenase (PHGDH), and endocrine resistance, we examined clinical data from ER+ patients who received tamoxifen as their sole endocrine therapy. Using two separate cohorts, we confirmed that higher PSAT1 and PHDGH expression negatively correlates with poorer outcomes in tamoxifen treated ER+ BC patients. Next, we found that SSP enzyme expression and serine synthesis are elevated in tamoxifen resistant compared to tamoxifen-sensitive ER+ BC cells in vitro. To determine relevance to endocrine sensitivity, we modified the expression of both PSAT1 or PHGDH in each cell type. While overexpression of PSAT1 in tamoxifen-sensitive MCF-7 cells diminished 4-OHT inhibition, conversely, silencing of PSAT or PHGDH resulted in decreased proliferation in tamoxifen-resistant LCC9 treated with 4-OHT. Taken together, we postulate that overexpression of SSP enzymes appear to contribute to tamoxifen resistance in ER+BC and indicate a potential combinatorial therapeutic option. Citation Format: Stephanie Metcalf, Traci Kruer, Susan Dougherty, James L. Wittliff, Carolyn M. Klinge, Brian F. Clem. Expression of serine synthetic enzymes alters the sensitivity of ER-positive breast cancer cells to tamoxifen [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3734.
David Oliver: Is the NHS really over-managed?
Authors: David Oliver
Journal: BMJ (2020)

In a recent speech Matt Hancock attacked excessive bureaucracy and regulation for constraining clinical leadership, agile service, and the digital innovation we’ve seen in the NHS during the pandemic.1

Ten years ago another Conservative health secretary, Andrew Lansley, made it a key plank of his white paper on NHS reform to purge it of bureaucracy, reduce NHS managers and quangos, and give clinicians more control over resources and decisions.2 The Health and Social Care Act 2012 was described by David Nicholson, then NHS chief, as a reorganisation “big enough to be seen from outer space.” It was subsequently estimated by the King’s Fund to have cost at least £4bn …
COMPLICATIONS FOLLOWING LUNG SURGERY IN THE NELSON LUNG CANCER SCREENING TRIAL: A COMPARISON WITH THE LITERATURE
Authors: S.V. Westeinde, H.J. de Koning, P. de Leyn, N. Horeweg, F.B. Thunnissen, M. Oudkerk, H.J.M. Groen, J.W.J. Lammers, C. Weenink, R. Vernhout, K. Nackaerts, W. Mali, R.J. van Klaveren
Journal: Journal of Thoracic Oncology (2011)
Overexpression of ODF1 in Gastrointestinal Tract Neuroendocrine Neoplasms: a Novel Potential Immunohistochemical Biomarker for Well-differentiated Neuroendocrine Tumors
Authors: Baicheng Li, Xinjun Li, Ruiqi Mao, Min Liu, Limei Fu, Lifang Shi, Songlin Zhao, Mingxia Fu
Journal: Endocrine Pathology (2020)
Publisher Correction: SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function
Authors: Emma S. Winkler, Adam L. Bailey, Natasha M. Kafai, Sharmila Nair, Broc T. McCune, Jinsheng Yu, Julie M. Fox, Rita E. Chen, James T. Earnest, Shamus P. Keeler, Jon H. Ritter, Liang-I Kang, Sarah Dort, Annette Robichaud, Richard Head, Michael J. Holtzman, Michael S. Diamond
Journal: Nature Immunology (2020)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
OF BEAUTY CONTESTS
Journal: JAMA (1965)

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Beclin 2 negatively regulates innate immune signaling and tumor development
Authors: Motao Zhu, Guangtong Deng, Peng Tan, Changsheng Xing, Cuiping Guan, Chongming Jiang, Yinlong Zhang, Bo Ning, Chaoran Li, Bingnan Yin, Kaifu Chen, Yuliang Zhao, Helen Y. Wang, Beth Levine, Guangjun Nie, Rong-Fu Wang
Journal: Journal of Clinical Investigation (2020)

Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3–independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3–independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer.
Abstract 5300: A survey of EphA2 expression by immunohistochemistry (IHC) in tumor tissue microarrays (TMAs) to support BT5528 indication selection
Authors: Carly T. Campbell, Robert Smale, James Lee, Josette William Ragheb, Michael Rigby, Tara Gelb, Lisa Mahnke, Gavin Bennett, Stephen J. Blakemore
Journal: Cancer Research (2020)

Abstract Introduction: BT5528 is a Bicycle® Toxin Conjugate (BTC) which contains an EphA2 binding peptide (Bicycle) conjugated through a molecular spacer and cleavable linker to the antimitotic toxin MMAE. EphA2 is an attractive tumor target; overexpression has been reported in multiple tumor types. Preclinical activity of BT5528 has been described previously, demonstrating increased efficacy is associated with high EphA2 tumor cell expression levels in xenograft models. Enrollment to a Phase I dose escalation study with BT5528 (BT5528-100) has started in patients with advanced solid tumors associated with EphA2 expression. Here we describe the analysis of TMAs stained using an EphA2 IHC assay developed for retrospective analysis of archive tumor from the BT5528-100 clinical trial. Methods: A clinical grade EphA2 IHC assay was developed on the Dako platform using R&amp;D Systems EphA2 primary antibody (AF3035) at 10 µg/mL and the Dako FLEX detection kit. TMAs of indications reported to have high EphA2 including pancreatic, bladder, head &amp; neck, stomach, NSCLC, TNBC, and ovarian cancer were stained and scored for EphA2 expression. H-scores (the product of stain intensity on a scale of 0-3 and % positive tumor cells) were generated by a pathologist independently for tumor cell membrane (TM) and tumor cytoplasm (TC). H-scores ≥20 were considered positive for EphA2. Results: The pattern of EphA2 expression was different across indications tested with pancreas having the greatest frequency of EphA2 expression. In contrast to the other indications assessed, pancreas and bladder had a greater percentage of cores positive for TM over TC. These differences may be relevant for BT5528 indication selection given that the mechanism of BTCs may be enhanced in cases which are TM positive. Conclusion: Use of an IHC assay assessing expression of EphA2 across multiple TMAs and scoring TM and TC individually may help guide indication selection for the BT5528 clinical program. EphA2 expression by IHC in multiple indicationsIndicationTotal cores (N)TM Positive N (%)TC Positive N(%)TM or TC Positive N (%)Pancreatic9248 (52)14 (15)48 (52)Bladder14242 (30)37 (26)51 (36)Head &amp; Neck6914 (20)17 (25)22 (32)Stomach5310 (19)15 (28)15 (28)NSCLC22145 (20)52 (24)60 (27)Ovarian838 (10)13 (16)17 (20)TNBC1243 (2)25 (20)25 (20) Citation Format: Carly T. Campbell, Robert Smale, James Lee, Josette William Ragheb, Michael Rigby, Tara Gelb, Lisa Mahnke, Gavin Bennett, Stephen J. Blakemore. A survey of EphA2 expression by immunohistochemistry (IHC) in tumor tissue microarrays (TMAs) to support BT5528 indication selection [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5300.
Inhibition of the Histone Chaperone, FACT (Facilitates Chromatin Transcription) By the Novel Small Molecule CBL0137 (Curaxin) Shows Promising Efficacy in Pre-Clinical Models of Acute Myeloid Leukemia
Authors: Scott Portwood, Eunice S. Wang, Alfiya Safina, Katerina Gurova
Journal: Blood (2017)
Abstract 4597: 5-Hydroxymethylcytosine signatures in cell-free DNA as a potential biomarker for colorectal cancer andprecancerous adenoma
Authors: Zewen Xiao, Jiayan Wu, Chunlong Wu, Man Li, Fuming Sun, Lu Zheng, Gaojing Liu, Xiaoling Li, Zhiyuan Yun, Jiebing Tang, Yang Yu, Shengnan Luo, Wenji Sun, Xiaohong Feng, Qian Cheng, Xue Tao, Jian Bai, Lin Wu, Shuangxiu Wu, Ji Tao
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) is a serious malignancy with the third incidence and second mortality throughout the world. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) is an important epigenetic mark linked with human cancer pathogenesis. Here we explored the genome-wide 5-hydroxymethylcytosine profiling in the plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 from plasma and 38 from tissues), collected from 21 CRC patients, 21 precancerous adenoma (AD) patients and 21 healthy control individuals (HC). 5hmC modifications exhibited distinct features in promoter and gene body regions in all 5 groups (3 groups from plasma and 2 groups from tissues), which offered a global overview of epigenetic changes of colon pathogenic statuses between early stage CRC and AD. Adenoma showed an independent property in the 5hmC profiles compared to cancer and healthy control. The 5hmC signatures in tumor were more comprehensive and could be divided into two clusters, one was similar to the healthy individuals and the other was similar to the AD patients. The results indicated that the candidate biomarkers to distinguish colorectal cancer from the blood-test population should be generated in two ways, one focused on the differential 5hmC features between CRC patients and healthy individuals; the other should detect the adenoma and tumor patients more extensive according to their precise pathological diagnosis and clinical information. Candidate cfDNA 5hmC biomarkers were further identified in the differential 5hmC modification regions between CRC and HC with a higher sensitivity than the classical CEA marker in non-invasive blood-based diagnosis. We suggested that the differentially enriched 5hmC regions in cfDNA were potential biomarkers to track colorectal cancer, even precancerous adenoma, with further large-scale follow-up studies. Citation Format: Zewen Xiao, Jiayan Wu, Chunlong Wu, Man Li, Fuming Sun, Lu Zheng, Gaojing Liu, Xiaoling Li, Zhiyuan Yun, Jiebing Tang, Yang Yu, Shengnan Luo, Wenji Sun, Xiaohong Feng, Qian Cheng, Xue Tao, Jian Bai, Lin Wu, Shuangxiu Wu, Ji Tao. 5-Hydroxymethylcytosine signatures in cell-free DNA as a potential biomarker for colorectal cancer andprecancerous adenoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4597.
SEVERE ACUTE RESPIRATORY SYNDROME-- TAIWAN, 2003
Authors: M. L. Lee, C. J. Chen, I. J. Su, K. T. Chen, C. C. Yeh, C. C. King, H. L. Chang, Y. C. Wu, M. S. Ho, D. D. Jiang, D. Wong
Journal: MMWR Morbidity and Mortality Weekly Report (2003)
Epigenetic Awakening of Viral Mimicry in Cancer
Authors: Maxime Janin, Manel Esteller
Journal: Cancer Discovery (2020)

In this issue, Deblois and colleagues show how taxane-resistant triple-negative breast cancer cells evade viral mimicry response as a result of metabolic alteration, DNA hypomethylation, and relocation of histone H3K27 trimethylation (H3K27me3). This adaptation confers a therapeutic vulnerability to the inhibition of the H3K27me3 methyltransferase EZH2 in resistant cells, leading to tumor growth inhibition by viral mimicry reactivation.See related article by Deblois et al., p. 1312.