tbuckley/cabot-search huggingface dataset:
Selective Internal Radiation Therapy for Liver Metastasis of Papillary Thyroid Carcinoma
Authors: Selin Kesim, Tunc Ones, Salih Ozguven, Ender Dulundu, Feyyaz Baltacioglu
Journal: Clinical Nuclear Medicine (2019)

Abstract Papillary carcinoma of thyroid (PTC) is the most common neoplasm of the thyroid gland that usually invades lymphatics rather than blood vessels. Hematogenous metastasis of PTC is rare, and distant metastasis to the liver is even rarer. Selective internal radiation therapy with 90 Y microspheres is a well-recognized technique in the treatment of liver metastases. Herein, we present a case of PTC with radioactive iodine-negative hepatic metastasis detected by 18 F-FDG PET/CT and treated with selective internal radiation therapy.
COPD exacerbations: 2 much NEWS?
Authors: Eui-Sik Suh, Beth Sage
Journal: Thorax (2019)

Exacerbations of chronic obstructive pulmonary disease (ECOPD) remain a common cause of hospital admission in the UK, despite the huge amount of effort and resources that have been invested in COPD services in recent years, and in-hospital mortality has been unchanged at around 4%.1 Clinical teams looking after patients with ECOPD need well-validated tools to assess mortality risk at admission and detect clinical deterioration in a timely manner. Several such tools have been developed to predict in-hospital mortality, of which the Dyspnoea, Eosinopenia, Consolidation, Acidaemia and atrial Fibrillation (DECAF) score has received the greatest attention2 3 indeed, the 2014 UK National COPD Audit report recommended the DECAF score for all patients hospitalised for ECOPD, in part to enable adjustment for mortality risk in a mixed cohort. Yet despite being robustly derived and validated, the DECAF score has not been widely adopted into clinical practice; in the 2019 National COPD Audit report, DECAF was recorded in only 17.5% of admissions1 and it is therefore worthwhile to consider alternatives.

Introduced in 2012, the National Early Warning Score (NEWS) was designed to standardise the clinical response to the deteriorating patient. Derived from routinely measured physiological parameters, it was validated as an indicator of clinical deterioration and mortality in several acute medical conditions. Despite its widespread use, questions were raised over its safety in the management of patients at risk of hypercapnic respiratory failure, for whom the addition of supplemental oxygen might lower their NEWS, but inadvertently place them at risk of worsening hyperoxic hypercapnia.4 Furthermore, patients with chronic hypoxaemia and on long-term oxygen therapy may have inappropriately elevated scores by virtue of their being on supplementary oxygen even when their acute illness has stabilised, resulting in inappropriate escalation for medical review. In response, the Royal College of Physicians introduced …
Association Between Plasma Diacetylspermine and Tumor Spermine Synthase With Outcome in Triple-Negative Breast Cancer
Authors: Johannes F Fahrmann, Jody Vykoukal, Alia Fleury, Satyendra Tripathi, Jennifer B Dennison, Eunice Murage, Peng Wang, Chuan-Yih Yu, Michela Capello, Chad J Creighton, Kim-Anh Do, James P Long, Ehsan Irajizad, Christine Peterson, Hiroyuki Katayama, Mary L Disis, Banu Arun, Samir Hanash
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression. Methods Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n = 87) and cancer-free controls (n = 115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 estrogen receptor negative (ER−) and progesterone receptor negative (PR−) and HER2 positive (HER2+), and 73 ER+ case patients, and 30 cancer-free control subjects. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas repository and the Oncomine database, respectively. Relationships between plasma diacetylspermine (DAS) and tumor spermine synthase (SMS) mRNA expression with metastasis-free survival and overall survival were determined using Cox proportional hazard models; Fisher exact tests were used to assess risk of distant metastasis in relation to tumor SMS mRNA expression. Results An increase in plasma DAS, a catabolic product of spermine mediated through SMS, was observed in the TNBC subtype of breast cancer. Plasma levels of DAS in TNBC associated with increased risk of metastasis (plasma DAS value ≥ 1.16, hazard ratio = 3.06, 95% confidence interval [CI] = 1.15 to 8.13, two-sided P = .03). SMS mRNA expression in TNBC tumor tissue was also found to be predictive of poor overall survival (top 25th percentile hazard ratio = 2.06, 95% CI = 1.04 to 4.08, one-sided P = .04) and increased risk of distant metastasis in TNBC (comparison of lowest SMS quartile [reference] to highest SMS quartile relative risk = 1.90, 95% CI = 0.97 to 4.06, one-sided Fisher exact test P=.03). Conclusions Metabolomic profiling identified plasma DAS as a predictive marker for TNBC progression and metastasis.
Local Area Variation in Morbidity Among Low-Income, Older Adults in the United States
Authors: Maria Polyakova, Lynn M. Hua
Journal: Annals of Internal Medicine (2019)

Recent studies have reported that low-income adults living in more affluent areas of the United States have longer life expectancies. Less is known about the relationship between the affluence of a geographic area and morbidity of the low-income population.To evaluate the association between the prevalence of chronic conditions among low-income, older adults and the economic affluence of a local area.Cross-sectional association study.Medicare in 2015.6 363 097 Medicare beneficiaries aged 66 to 100 years with a history of low-income support under Medicare Part D.Adjusted prevalence of 48 chronic conditions was computed for 736 commuting zones (CZs). Factor analysis was used to assess spatial covariation of condition prevalence and to construct a composite condition prevalence index for each CZ. The association between morbidity and area affluence was measured by comparing the average of condition prevalence index across deciles of median CZ house values.The mean age of study participants was 77.7 years (SD, 8.2); 67% were women, and 61% were white. The crude prevalence of 48 chronic conditions ranged from 72.5 per 100 for hypertension to 0.6 per 100 for posttraumatic stress disorder. The prevalence of these 48 chronic conditions was highly spatially correlated. Composite condition prevalence was on average substantially lower in more affluent CZs.Low-income status measured on the basis of receipt of Medicare Part D low-income subsidies and not capturing persons not enrolled in Medicare Part D.Low-income, older adults living in more affluent areas of the country are healthier, and areas with poor health in the low-income, older adult population tend to have a high prevalence of most chronic conditions.National Institute on Aging.
Increasing the low lipid phosphate phosphatase 1 activity in breast cancer cells decreases transcription by AP-1 and expressions of matrix metalloproteinases and cyclin D1/D3
Authors: Xiaoyun Tang, Todd P.W. McMullen, David N. Brindley
Journal: Theranostics (2019)

Metastasis is the leading cause of mortality in breast cancer patients and lysophosphatidate (LPA) signaling promotes this process.LPA signaling is attenuated by lipid phosphate phosphatase-1 (LPP1) whose activity is decreased in cancers.Consequently, increasing LPP1 levels suppresses breast tumor growth and metastasis.This study shows that increasing LPP1 in breast cancer cells decreases transcription through cFos and cJun.This decreases production of cyclin D1/D3 and matrix metalloproteinases (MMPs), which provides new insights into the role of LPP1 in controlling tumor growth and metastasis.Methods: Invasiveness was determined by a Matrigel invasion assay.MMP expression was measured by qPCR, multiplex LASER bead technology and gelatin zymography.Levels of cJUN, cFOS, FRA1, cyclin D1, and cyclin D3 were determined by qPCR and western blotting.Collagen was determined by Picro-Sirius Red staining.Results: Increasing LPP1 expression inhibited invasion of MDA-MB-231 breast cancer cells through Matrigel.This was accompanied by decreases in expression of MMP-1, -3, -7, -9, -10, -12 and -13, which are transcriptionally regulated by the AP-1 complex.Increasing LPP1 attenuated the induction of mRNA of MMP-1, -3, cFOS, and cJUN by EGF or TNFα, but increased FRA1.LPP1 expression also decreased the induction of protein levels for cFOS and cJUN in nuclei and cytoplasmic fractions by EGF and TNFα.Protein levels of cyclin D1 and D3 were also decreased by LPP1.Although FRA1 in total cell lysates or cytoplasm was increased by LPP1, nuclear FRA1 was not affected.LPP1-induced decreases in MMPs in mouse tumors created with MDA-MB-231 cells were accompanied by increased collagen in the tumors and fewer lung metastases.Knockdown of LPP1 in MDA-MB-231 cells increased the protein levels of MMP-1 and -3.Human breast tumors also have lower levels of LPP1 and higher levels of cJUN, cFOS, MMP-1, -7, -8, -9, -12, -13, cyclin D1, and cyclin D3 relative to normal breast tissue. Conclusion:This study demonstrated that the low LPP1 expression in breast cancer cells is associated with high levels of cyclin D1/D3 and MMPs as a result of increased transcription by cFOS and cJUN.Increasing LPP1 expression provides a novel approach for decreasing transcription through AP-1, which could provide a strategy for decreasing tumor growth and metastasis.
Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation
Authors: Victoria E. Wang, Jenny Y. Xue, Dennie T. Frederick, Yi Cao, Eva Lin, Catherine Wilson, Anatoly Urisman, David P. Carbone, Keith T. Flaherty, Rene Bernards, Piro Lito, Jeff Settleman, Frank McCormick
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Combined MAPK pathway inhibition using dual BRAF and MEK inhibitors has prolonged the duration of clinical response in patients with BRAFV600E-driven tumors compared with either agent alone. However, resistance frequently arises. Experimental Design: We generated cell lines resistant to dual BRAF/MEK inhibition and utilized a pharmacologic synthetic lethal approach to identify a novel, adaptive resistance mechanism mediated through the fibroblast growth factor receptor (FGFR) pathway. Results: In response to drug treatment, transcriptional upregulation of FGF1 results in autocrine activation of FGFR, which potentiates extracellular signal-regulated kinases (ERK) activation. FGFR inhibition overcomes resistance to dual BRAF/MEK inhibitors in both cell lines and patient-derived xenograft (PDX) models. Abrogation of this bypass mechanism in the first-line setting enhances tumor killing and prevents the emergence of drug-resistant cells. Moreover, clinical data implicate serum FGF1 levels in disease prognosis. Conclusions: Taken together, these results describe a new, adaptive resistance mechanism that is more commonly observed in the context of dual BRAF/MEK blockade as opposed to single-agent treatment and reveal the potential clinical utility of FGFR-targeting agents in combination with BRAF and MEK inhibitors as a promising strategy to forestall resistance in a subset of BRAF-driven cancers.
Taking a Ride on the Stewardship Side of Long-term Care
Authors: Barbara W. Trautner, Aanand D. Naik
Journal: JAMA Network Open (2019)

James H. Ford II, PhD; Lillian Vranas, MS; DaRae Coughlin, RN, MSN, FNP-BC; Kathi M. Selle, RN-BC, MA; Susan Nordman-Oliveira, MS; Brenda Ryther, RN, MSN; Tola Ewers, PhD; Victoria L. Griffin, RN; Anna Eslinger, RN; Joe Boero, MD, CMD; Paula Hardgrove, MD, CMD; Christopher J. Crnich, MD, PhD
Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox
Authors: Jane A. Mitchell, Fisnik Shala, Youssef Elghazouli, Timothy D. Warner, Carles Gaston-Massuet, Marilena Crescente, Paul C. Armstrong, Harvey R. Herschman, Nicholas S. Kirkby
Journal: Circulation Research (2019)

Endothelial cells (ECs) and platelets, which respectively produce antithrombotic prostacyclin and prothrombotic thromboxane A2, both express COX1 (cyclooxygenase1). Consequently, there has been no way to delineate any antithrombotic role for COX1-derived prostacyclin from the prothrombotic effects of platelet COX1. By contrast, an antithrombotic role for COX2, which is absent in platelets, is straightforward to demonstrate. This has resulted in an incomplete understanding of the relative importance of COX1 versus COX2 in prostacyclin production and antithrombotic protection in vivo.We sought to identify the role, if any, of COX1-derived prostacyclin in antithrombotic protection in vivo and compare this to the established protective role of COX2.We developed vascular-specific COX1 knockout mice and studied them alongside endothelial-specific COX2 knockout mice. COX1 immunoreactivity and prostacyclin production were primarily associated with the endothelial layer of aortae; freshly isolated aortic ECs released >10-fold more prostacyclin than smooth muscle cells. Moreover, aortic prostacyclin production, the ability of aortic rings to inhibit platelet aggregation and plasma prostacyclin levels were reduced when COX1 was knocked out in ECs but not in smooth muscle cells. When thrombosis was measured in vivo after FeCl3 carotid artery injury, endothelial COX1 deletion accelerated thrombosis to a similar extent as prostacyclin receptor blockade. However, this effect was lost when COX1 was deleted from both ECs and platelets. Deletion of COX2 from ECs also resulted in a prothrombotic phenotype that was independent of local vascular prostacyclin production.These data demonstrate for the first time that, in healthy animals, endothelial COX1 provides an essential antithrombotic tone, which is masked when COX1 activity is lost in both ECs and platelets. These results help us define a new 2-component paradigm wherein thrombotic tone is regulated by both COX1 and COX2 through complementary but mechanistically distinct pathways.
CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia
Authors: Lei Xu, Jun Wang, Yulin Liu, Liangfu Xie, Bin Su, Danlei Mou, Longteng Wang, Tingting Liu, Xiaobao Wang, Bin Zhang, Long Zhao, Liangding Hu, Hongmei Ning, Yufeng Zhang, Kai Deng, Lifeng Liu, Xiaofan Lu, Tong Zhang, Jun Xu, Cheng Li, Hao Wu, Hongkui Deng, Hu Chen
Journal: New England Journal of Medicine (2019)

The safety of CRISPR (clustered regularly interspaced short palindromic repeats)-based genome editing in the context of human gene therapy is largely unknown. CCR5 is a reasonable but not absolutely protective target for a cure of human immunodeficiency virus type 1 (HIV-1) infection, because CCR5-null blood cells are largely resistant to HIV-1 entry. We transplanted CRISPR-edited CCR5-ablated hematopoietic stem and progenitor cells (HSPCs) into a patient with HIV-1 infection and acute lymphoblastic leukemia. The acute lymphoblastic leukemia was in complete remission with full donor chimerism, and donor cells carrying the ablated CCR5 persisted for more than 19 months without gene editing-related adverse events. The percentage of CD4+ cells with CCR5 ablation increased by a small degree during a period of antiretroviral-therapy interruption. Although we achieved successful transplantation and long-term engraftment of CRISPR-edited HSPCs, the percentage of CCR5 disruption in lymphocytes was only approximately 5%, which indicates the need for further research into this approach. (Funded by the Beijing Municipal Science and Technology Commission and others; ClinicalTrials.gov number, NCT03164135.).
Bleeding and New Cancer Diagnosis in Patients With Atherosclerosis
Authors: John W. Eikelboom, Stuart J. Connolly, Jacqueline Bosch, Olga Shestakovska, Victor Aboyans, Marco Alings, Sonia S. Anand, Alvaro Avezum, Scott D. Berkowitz, Deepak L. Bhatt, Nancy Cook-Bruns, Camilo Felix, Keith A.A. Fox, Robert G. Hart, Aldo P. Maggioni, Paul Moayyedi, Martin O’Donnell, Lars Rydén, Peter Verhamme, Petr Widimsky, Jun Zhu, Salim Yusuf
Journal: Circulation (2019)

Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer.We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites.Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2-27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20-2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7-42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0-142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32-3.91]).In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.
Acid sphingomyelinase regulates T<sub>H</sub>2 cytokine release and bronchial asthma
Authors: Svenja Böll, Sebastian Ziemann, Kim Ohl, Patricia Klemm, Annette D. Rieg, Erich Gulbins, Katrin Anne Becker, Markus Kamler, Norbert Wagner, Stefan Uhlig, Christian Martin, Klaus Tenbrock, Eva Verjans
Journal: Allergy (2019)

Abstract Background Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of T H 1‐directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in T H 2‐regulated allergic bronchial asthma. Methods To determine the role of Asm under baseline conditions, wild‐type (WT) and Asm −/− mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro T H 2 differentiations with cells from WT and Asm −/− mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin‐induced model of asthma in WT‐ and Asm −/− mice. Results At baseline, Asm −/− mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm −/− T cells in bronchoalveolar lavage fluid released lower levels of IL‐4 and IL‐5, and these results were paralleled by decreased production of typical T H 2 cytokines in Asm −/− T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbumin asthma model, Asm −/− animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and T H 2 cytokines. Conclusion Asm deficiency could induce higher numbers of T H 2 cells in the lung, but those cells release decreased T H 2 cytokine levels. Hereby, Asm −/− animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade.
First-in-Human Intravenous Seprehvir in Young Cancer Patients: A Phase 1 Clinical Trial
Authors: Keri A. Streby, Mark A. Currier, Melinda Triplet, Kristy Ott, Devon J. Dishman, Michele R. Vaughan, Mark A. Ranalli, Bhuvana Setty, Micah A. Skeens, Stacy Whiteside, Nicholas D. Yeager, Kellie B. Haworth, Kathleen Simpson, Joe Conner, Timothy P. Cripe
Journal: Molecular Therapy (2019)

Seprehvir (HSV1716) is an oncolytic herpes simplex virus-1 (HSV-1) previously demonstrated to be well tolerated in pediatric patients when administered intratumorally. To determine the safety of administering Seprehvir systemically, we conducted the first-in-human phase I trial of intravenous injection in young patients with relapsed or refractory extra-cranial solid cancers. We delivered a single dose of 5 × 104 infectious units (iu)/kg (maximum dose of 2 × 106) or 2.5 × 105 iu/kg (maximum dose of 1 × 107 iu) of Seprehvir via the peripheral vein, monitored adverse events, and measured tumor responses by imaging. We monitored HSV-1 serology as well as viremia and shedding by PCR and culture. We administered a single dose of Seprehvir to seven patients and multiple doses to two patients. We did not observe any dose-limiting toxicities. All five HSV-1 seronegative patients seroconverted by day 28. Four of nine patients had detectable HSV-1 genomes in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had stable disease in response to Seprehvir. Intravenous Seprehvir is well tolerated without viral shedding in children and young adults with late-stage cancer. Viremia consistent with virus replication holds promise for future Seprehvir studies at higher doses and/or in combination with other anti-neoplastic therapies. Seprehvir (HSV1716) is an oncolytic herpes simplex virus-1 (HSV-1) previously demonstrated to be well tolerated in pediatric patients when administered intratumorally. To determine the safety of administering Seprehvir systemically, we conducted the first-in-human phase I trial of intravenous injection in young patients with relapsed or refractory extra-cranial solid cancers. We delivered a single dose of 5 × 104 infectious units (iu)/kg (maximum dose of 2 × 106) or 2.5 × 105 iu/kg (maximum dose of 1 × 107 iu) of Seprehvir via the peripheral vein, monitored adverse events, and measured tumor responses by imaging. We monitored HSV-1 serology as well as viremia and shedding by PCR and culture. We administered a single dose of Seprehvir to seven patients and multiple doses to two patients. We did not observe any dose-limiting toxicities. All five HSV-1 seronegative patients seroconverted by day 28. Four of nine patients had detectable HSV-1 genomes in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had stable disease in response to Seprehvir. Intravenous Seprehvir is well tolerated without viral shedding in children and young adults with late-stage cancer. Viremia consistent with virus replication holds promise for future Seprehvir studies at higher doses and/or in combination with other anti-neoplastic therapies.