tbuckley/cabot-search huggingface dataset:
Placental Expression of Imprinted Genes, Overall and in Sex-Specific Patterns, Associated with Placental Cadmium Concentrations and Birth Size
Authors: Todd M. Everson, Carmen Marable, Maya A. Deyssenroth, Tracy Punshon, Brian P. Jackson, Luca Lambertini, Margaret R. Karagas, Jia Chen, Carmen J. Marsit
Journal: Environmental Health Perspectives (2019)

Background: Prenatal cadmium (Cd) exposure has been recognized to restrict growth, and male and female fetuses may have differential susceptibility to the developmental toxicity of Cd. Imprinted genes, which exhibit monoallelic expression based on parent of origin, are highly expressed in placental tissues. The function of these genes is particularly critical to fetal growth and development, and some are expressed in sex-specific patterns. Objectives: We aimed to examine whether prenatal Cd associates with the expression of imprinted placental genes, overall or in fetal sex-specific patterns, across two independent epidemiologic studies. Methods: We tested for Cd–sex interactions in association with gene expression, then regressed the placental expression levels of 74 putative imprinted genes on placental log-Cd concentrations while adjusting for maternal age, sex, smoking history, and educational attainment. These models were performed within study- and sex-specific strata in the New Hampshire Birth Cohort Study (NHBCS; n=326) and the Rhode Island Child Health Study (RICHS; n=211). We then used fixed-effects models to estimate the sex-specific and overall associations across strata and then examine heterogeneity in the associations by fetal sex. Results: We observed that higher Cd concentrations were associated with higher expression of distal-less homeobox 5 (DLX5) (p=0.000025), and lower expression of h19 imprinted maternally expressed transcript (H19) (p=0.00027) and necdin, MAGE family member (NDN) (p=0.00064) across study and sex-specific strata, while three other genes [carboxypeptidase A4 (CPA4), growth factor receptor bound protein 10 (GRB10), and integrin-linked kinase (ILK)] were significantly associated with Cd concentrations, but only among female placenta (pinteraction<0.05). Additionally, the expression of DLX5, H19, and NDN, the most statistically significant Cd-associated genes, were also associated with standardized birth weight z-scores. Discussion: The differential regulation of a set of imprinted genes, particularly DLX5, H19 and NDN, in association with prenatal Cd exposure may be involved in overall developmental toxicity, and some imprinted genes may respond to Cd exposure in a manner that is specific to infant gender. https://doi.org/10.1289/EHP4264
Volumetric Optoacoustic Imaging Unveils High-Resolution Patterns of Acute and Cyclic Hypoxia in a Murine Model of Breast Cancer
Authors: Avihai Ron, Xosé Luís Deán-Ben, Sven Gottschalk, Daniel Razansky
Journal: Cancer Research (2019)

Abstract Mapping tumor heterogeneity and hypoxia within a living intact organism is essential for understanding the processes involved in cancer progression and assessing long-term responses to therapies. Efficient investigations into tumor hypoxia mechanisms have been hindered by the lack of intravital imaging tools capable of multiparametric probing of entire solid tumors with high spatial and temporal resolution. Here, we exploit volumetric multispectral optoacoustic tomography (vMSOT) for accurate, label-free delineation of tumor heterogeneity and dynamic oxygenation behavior. Mice bearing orthotopic MDA-MB-231 breast cancer xenografts were imaged noninvasively during rest and oxygen stress challenge, attaining time-lapse three-dimensional oxygenation maps across entire tumors with 100 μm spatial resolution. Volumetric quantification of the hypoxic fraction rendered values of 3.9% to 21.2%, whereas the oxygen saturation (sO2) rate declined at 1.7% to 2.3% per mm in all tumors when approaching their core. Three distinct functional areas (the rim, hypoxic, and normoxic cores) were clearly discernible based on spatial sO2 profiles and responses to oxygen challenge. Notably, although sO2 readings were responsive to the challenge, deoxyhemoglobin (HbR) trends exhibited little to no variations in all mice. Dynamic analysis further revealed the presence of cyclic hypoxia patterns with a 21% average discrepancy between cyclic fractions assessed via sO2 (42.2% ± 17.3%) and HbR fluctuations (63% ± 14.1%) within the hypoxic core. These findings corroborate the strong potential of vMSOT for advancing preclinical imaging of cancer and informing clinical decisions on therapeutic interventions. Significance: vMSOT provides quantitative measures of volumetric hypoxic fraction and cyclic hypoxia in a label-free and noninvasive manner, providing new readouts to aid tumor staging and treatment decision making.
Abstract 19031: Utilization and Outcomes of Anti-Tachycardia Pacing Therapy in Children and Young Adults With Implantable-Cardioverter Defibrillators
Authors: Chris Janson, Maully Shah
Journal: Circulation (2013)

Background: Inappropriate and unnecessary ICD shocks are a concern in the growing pediatric device population. Historically, ICDs have been programmed as “shock boxes,” with a single therapy zone for ventricular fibrillation (VF). Adult trials have demonstrated safe shock reduction by programming a second zone for ventricular tachycardia (VT), with anti-tachycardia pacing (ATP) as initial therapy. The utilization and outcomes of ATP therapy have not been described in the pediatric population. Methods: Subjects ≤ 30 years of age with ICDs implanted at a single tertiary pediatric center between 9/30/2009 and 9/30/2012 were included. Patient characteristics, ICD programming, and outcomes were retrospectively reviewed. Results: 45 patients underwent ICD implantation at a mean age of 13.9 ± 4 years (55% primary electrical disorder, 36% cardiomyopathy, 9% congenital heart disease). A primary prevention indication was present in 64% (n=29). A single VF zone with shock therapy only was programmed in 32 patients (71%). Thirteen patients (29%) had a second VT zone with ATP as initial therapy. Of 11 patients with a history of monomorphic VT, 45% (n=5) had two zone programming. ATP during charging was programmed in the VF zone in 91% of devices. At a median follow-up of 19.2 months (IQR 8.4-26.1 months), 37 events (2 VF, 28 monomorphic VT, 7 polymorphic VT) met criteria for therapy in 4 patients; 16 (43%) events were treated with shocks, including 9 that required multiple shocks; 21 (57%) events, all monomorphic VT, were pace-terminated in 2 patients. ATP was successful in 21 of 22 (95%) attempts. In 3 events, VT terminated with ATP while charging, so shocks were aborted. There were no syncopal events due to delay in shocks by ATP failure. There was no difference in the number of inappropriate shocks between single (n=6) and two zone (n=4) programming groups, although 2 patients with two zone programming were shocked for sinus tachycardia in the VT zone. Conclusions: The pediatric ICD population is heterogeneous, making it difficult to adopt a uniform programming strategy. ATP can prevent unnecessary shocks in children with monomorphic VT. Two zone programming should be considered for patients at risk for monomorphic VT.
The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy
Authors: Yuan Wei, Qiyi Zhao, Zhiliang Gao, Xiang-Ming Lao, Wei-Ming Lin, Dong-Ping Chen, Ming Mu, Chun-Xiang Huang, Zheng-Yu Liu, Bo Li, Limin Zheng, Dong-Ming Kuang
Journal: Journal of Clinical Investigation (2019)

Programmed death-1 receptor ligand 1 (PD-L1) is a promising therapeutic target in aggressive cancers. However, immune landscapes and cancer hallmarks of human PD-L1+ tumors as well as their roles in determining therapeutic efficacies are unknown. Here, we showed, in detailed studies of gene data regarding 9769 patients of 32 types of human cancers, that PD-L1 could not exclusively represent the IFN-γ signature and potentially signified proinflammatory myeloid responses in a tumor. PD-L1 heterogeneity endowed by local immune landscapes controlled cancer hallmarks and clinical outcomes of patients. Mechanically, NF-κB signal elicited by macrophage inflammatory responses generated PD-L1+ cancer cells exhibiting capabilities to aggressively survive, support angiogenesis, and metastasize, whereas STAT1 signal triggered by activated T cells induced PD-L1+ cancer cells susceptive to apoptosis. Importantly, PD-L1+ cancer cells generated by macrophages established great resistance to conventional chemotherapy, cytotoxicity of tumor-specific effector T cells, and therapy of immune-checkpoint blockade. Therapeutic strategy combining immune-checkpoint blockade with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Our results provide insight into the functional features of PD-L1+ tumors and suggest that strategies to influence functional activities of inflammatory cells may benefit immune-checkpoint blockade therapy.
THE ROLE OF INFLAMMATORY MARKERS IN EARLY RE-BLEEDING RATES IN PATIENTS PRESENTING WITH ACUTE PEPTIC ULCER BLEEDING REQUIRING ENDOSCOPIC HAEMOSTASIS
Authors: N Viazis, H Keimali, I Papanikolaou, C Pontas, L Varytimiadis, A Sioulas, K Triantafyllou, V Smirniotis, N Arkadopoulos, G Mantzaris
Journal: Endoscopy (2019)

To identify the role of white blood cells, C-reactive protein and procalcitonin in the early re-bleeding rate of patients presenting with acute peptic ulcer bleeding that need endoscopic haemostasis.
ENDOSCOPIC TRANSPAPILLARY GALLBLADDER DRAINAGE FOR MANAGEMENT OF THE PATIENT WITH ACUTE CALCULUS CHOLECYSTITIS WHO WAS UNSUITABLE FOR URGENT CHOLECYSTECTOMY
Authors: TH Kim, HK Chon
Journal: Endoscopy (2019)

Endoscopic transpapillary gallbladder drainage (ETGBD) is useful modality for patients who are no candidate for urgent cholecystectomy. We aim to evaluate the safety and efficacy of ETGBD by using either endoscopic traspapillary gallbladder stenting (ETGBS) or endoscopic nasogallbladder drainage (ENGBD) for managing acute cholecystitis (AC).
Supporting doctors who make mistakes
Authors: Rebecca Lawton, Judith Johnson, Gillian Janes, Robbie Foy, Ruth Simms-Ellis
Journal: BMJ (2019)

The term “second victim” is provocative, and to those who have lost loved ones to medical error, it may seem abhorrent.1 We agree that current systems often fail patients who are harmed and their families, not least by excluding them from investigations into what went wrong.

Our research shows that the current adversarial approach does nothing to support learning and improvement. Rather, it perpetuates …
In search of stool donors: a multicenter study of prior knowledge, perceptions, motivators, and deterrents among potential donors for fecal microbiota transplantation
Authors: Breanna McSweeney, Jessica R. Allegretti, Monika Fischer, Huiping Xu, Karen J. Goodman, Tanya Monaghan, Carmen McLeod, Benjamin H. Mullish, Elaine O. Petrof, Emmalee L. Phelps, Roxana Chis, Abby Edmison, Angela Juby, Ralph Ennis-Davis, Brandi Roach, Karen Wong, Dina Kao
Journal: Gut Microbes (2019)

Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridioides difficile infection. Stool donors are essential, but difficult to recruit and retain. We aimed to identify factors influencing willingness to donate stool. This multi-center study with a 32-item questionnaire targeted young adults and health care workers via social media and university email lists in Edmonton and Kingston, Canada; London and Nottingham, England; and Indianapolis and Boston, USA. Items included baseline demographics and FMT knowledge and perception. Investigated motivators and deterrents included economic compensation, screening process, time commitment, and stool donation logistics. Logistic regression and linear regression models estimated associations of study variables with self-assessed willingness to donate stool. 802 respondents completed our questionnaire: 387 (48.3%) age 21-30 years, 573 (71.4%) female, 323 (40%) health care workers. Country of residence, age and occupation were not associated with willingness to donate stool. Factors increasing willingness to donate were: already a blood donor (OR 1.64), male, altruism, economic benefit, knowledge of how FMT can help patients (OR 1.32), and positive attitudes towards FMT (OR 1.39). Factors decreasing willingness to donate were: stool collection unpleasant (OR 0.92), screening process invasive (OR 0.92), higher stool donation frequency, negative social perception of stool, and logistics of collection/transporting feces. We conclude that 1) blood donors and males are more willing to consider stool donation; 2) altruism, economic compensation, and positive feedback are motivators; and 3) screening process, high donation frequency, logistics of collection/transporting feces, lack of public awareness, and negative social perception are deterrents. Considering these variables could maximize donor recruitment and retention.
Photothermal therapy mediated by phase-transformation nanoparticles facilitates delivery of anti-PD1 antibody and synergizes with antitumor immunotherapy for melanoma
Authors: Ni Zhang, Jiao Song, Yi Liu, Mingzhu Liu, Liang Zhang, Danli Sheng, Liming Deng, Hengjing Yi, Meng Wu, Yuanyi Zheng, Zhigang Wang, Zhu Yang
Journal: Journal of Controlled Release (2019)
PROPHYLACTIC CLIPPING FOR THE PREVENTION OF DELAYED COMPLICATION AFTER ENDOSCOPIC RESECTION FOR SUPERFICIAL NON-AMPULLARY DUODENAL TUMOR
Authors: JY An, BW Kim, JM Park, TH Kim, J Lee
Journal: Endoscopy (2019)

Although endoscopic resection (ER) has been accepted as a standard treatment modality for superficial non-ampullary duodenal tumor (SNADT) recently, it can cause adverse events such as perforation and bleeding. The effect of prophylactic mucosal closure after ER is controversial. The aim of this study was to investigate the efficacy of prophylactic clipping for the prevention of delayed complications.
Chronic myeloid leukemia stem cells
Authors: Mohammad Houshmand, Giorgia Simonetti, Paola Circosta, Valentina Gaidano, Alessandro Cignetti, Giovanni Martinelli, Giuseppe Saglio, Robert Peter Gale
Journal: Leukemia (2019)

Chronic myeloid leukemia (CML) is caused by BCRABL1 in a cell with the biological potential, intrinsic or acquired, to cause leukemia. This cell is commonly termed the CML leukemia stem cell (LSC). In humans a CML LSC is operationally-defined by ≥1 in vitro or in vivo assays of human leukemia cells transferred to immune-deficient mice. Results of these assays are sometimes discordant. There is also the unproved assumption that biological features of a CML LSC are stable. These considerations make accurate and precise identification of a CML LSC difficult or impossible. In this review, we consider biological features of CML LSCs defined by these assays. We also consider whether CML LSCs are susceptible to targeting by tyrosine kinase inhibitors (TKIs) and other drugs, and whether elimination of CML LSCs is needed to achieve therapy-free remission or cure CML.
Pension tax charges: don’t quit just yet, says NHS chief
Authors: Tom Moberly
Journal: BMJ (2019)

Doctors should hold off making any rash career decisions over concerns about pension tax charges, says NHS England’s chief executive, as proposed changes to the NHS pension scheme will be announced “very soon.”

At the Health Foundation’s annual event on 23 May, Simon Stevens spoke of the need to stop “some of the counterproductive arrangements” that were affecting retention in the NHS. He highlighted the impact of current pension arrangements on senior doctors and said that he expected details of proposed changes to be announced “really very soon.” …
Diagnostic and interventional digital pancreatoscopy as an “all-in-one” approach in chronic pancreatitis: a case report
Authors: Mark Ellrichmann, Johannes Bethge, Heiko Aselmann, Thomas Becker, Stefan Schreiber, Alexander Arlt
Journal: Endoscopy (2019)

A 77-year-old man was admitted with severe abdominal pain. His laboratory tests and abdominal ultrasound revealed an acute-on-chronic pancreatitis, with a dilated main pancreatic duct (MPD) up to 10 mm and multiple stones causing the symptoms ([Video 1]).
Neddylation: a novel modulator of the tumor microenvironment
Authors: Lisha Zhou, Yanyu Jiang, Qin Luo, Lihui Li, Lijun Jia
Journal: Molecular Cancer (2019)

Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition.
ENDOROTOR ABLATION OF BARRETT'S ESOPHAGUS; A SAFETY AND FEASIBILITY STUDY
Authors: AW Gotink, Y Peters, MJ Bruno, PD Siersema, AD Koch
Journal: Endoscopy (2019)

The aim of this study was to assess the safety and efficacy of a novel, non-thermal resection device (EndoRotor) for the ablation of Barrett's esophagus (BE).
Measures to control protracted large Lassa fever outbreak in Nigeria, 1 January to 28 April 2019
Authors: Chioma C. Dan-Nwafor, Yuki Furuse, Elsie A Ilori, Oladipupo Ipadeola, Kachikwulu O Akabike, Anthony Ahumibe, Winifred Ukponu, Lawal Bakare, Tochi J Okwor, Gbenga Joseph, Nwando G Mba, Adejoke Akano, Adebola T Olayinka, Ihekerenma Okoli, Rita A Okea, Favour Makava, Nkem Ugbogulu, Saliu Oladele, Geoffrey Namara, Esther N Muwanguzi, Dhamari Naidoo, Samuel K Mutbam, Ifeanyi Okudo, Solomon F Woldetsadik, Clement LP Lasuba, Chikwe Ihekweazu
Journal: Eurosurveillance (2019)

Lassa fever cases have increased in Nigeria since 2016 with the highest number, 633 cases, reported in 2018. From 1 January to 28 April 2019, 554 laboratory-confirmed cases including 124 deaths were reported in 21 states in Nigeria. A public health emergency was declared on 22 January by the Nigeria Centre for Disease Control. We describe the various outbreak responses that have been implemented, including establishment of emergency thresholds and guidelines for case management.
The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist
Authors: Joke G. van Bemmel, Rafael Galupa, Chris Gard, Nicolas Servant, Christel Picard, James Davies, Anthony James Szempruch, Yinxiu Zhan, Jan J. Żylicz, Elphège P. Nora, Sonia Lameiras, Elzo de Wit, David Gentien, Sylvain Baulande, Luca Giorgetti, Mitchell Guttman, Jim R. Hughes, Douglas R. Higgs, Joost Gribnau, Edith Heard
Journal: Nature Genetics (2019)
Phase 1 first-in-human trial of the anti-CD37 antibody BI 836826 in relapsed/refractory chronic lymphocytic leukemia
Authors: Stephan Stilgenbauer, Thérèse Aurran Schleinitz, Barbara Eichhorst, Fabian Lang, Fritz Offner, Jean-François Rossi, Wilfried Schroyens, Eric Van Den Neste, Loïc Ysebaert, Ute von Wangenheim, Uta Ursula Kress, Petra Blum, Thorsten Zenz
Journal: Leukemia (2019)
Inotilone interferes with chromosome replication as an attractive anti-cancer drug target for breast cancer
Authors: L.-C. Chen, S.-H. Tu, Y.-S. Ho
Journal: Annals of Oncology (2019)

Background: The function of DNA primase is to synthesize the small RNA primers for Okazaki fragments generated during discontinuous DNA replication. This primase is required because DNA polymerases cannot initiate RNA polymer synthesis and they can elongate polymers only using RNA polymers that have already been synthesized. Eukaryotic cells contain PRIM1 and PRIM2 subunits of nuclear DNA primase. PRIM1 is the smallest subunit of the heterotetrameric eukaryotic Pol alpha/primase complex. It alone carries the catalytic function of the enzyme and can elongate primers, whereas PRIM2 does not exert such enzymatic activity. Methods: The methods in this study include: real-time quantitative PCR, cell proliferation and viability assays, DNA synthesis analysis, western blotting, wound-healing cell migration and invasion assay, animal experiments, immunohistochemistry, and chromatin immunoprecipitation assay. Results: Our results show that PRIM1 mRNA is highly expressed in human breast tumor tissues, particular in poorly differentiated tumor tissues. In the cell model, higher PRIM1 protein expression was detected in ER+ breast cancer cell lines (BT483, BT474, and MCF-7) than in normal breast cell lines (MCF-10A). Stable expression of PRIM1-siRNA in the ER+ BT-474 cells-xenograft tumors significantly reduced tumor volume in SCID mice (*p = 0.005). The anti-tumoral effects of inotilone isolated from Phellinus linteus was tested and had significant effects on the inhibition of PRIM1 protein expression in ER+ breast cancer cells. In vivo study was performed by administering inotilone (10 mg/kg, twice a week for 6 weeks), which resulted in significantly reduced BT-474-xenografted tumor growth volume compared with control (n = 5 per group, *p < 0.05). Conclusions: This study provides evidences for the prognostic effects of PRIM1 with poor overall survival rate in the ER+ patients and will be valuable to test for therapeutic purpose. Legal entity responsible for the study: Li-Ching Chen. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
COLORECTAL CANCER INCIDENCE AND THE PREVALENCE OF PRECURSOR LESIONS IN YOUNGER ADULTS
Authors: D Penz, A Ferlitsch, E Waldmann, D Pammer, B Majcher, I Gessl, A Hinterberger, A Szymanska, A Asaturi, M Trauner, M Ferlitsch
Journal: Endoscopy (2019)

In the USA, Colorectal cancer (CRC) incidence and mortality decreases among the screening population. However more often younger (< 50y) get diagnosed with CRC. Therefore, the American-Cancer-Society recommend to start screening colonoscopy (SC) at the age of 45. Aim of our study is to assess the CRC incidence in Austria within different age groups and compare it with the occurrence of precursor lesions.
COMPUTER-AIDED DIAGNOSIS OF GASTRIC LESIONS USING MAGNIFYING NARROW BAND IMAGING ENDOSCOPY
Authors: S Kashin, R Kuvaev, E Kraynova, H Edelsbrunner, O Dunaeva, A Rusakov, E Nikonov
Journal: Endoscopy (2019)

The aims of this study were to develop and evaluate a computer-aided diagnosis system for histology prediction of gastric lesions using magnifying narrow band imaging (M-NBI) endoscopy.