tbuckley/cabot-search huggingface dataset:
Risk Factors for Childhood Stunting in 137 Developing Countries: A Comparative Risk Assessment Analysis at Global, Regional, and Country Levels
Authors: Goodarz Danaei, Kathryn G. Andrews, Christopher R. Sudfeld, Günther Fink, Dana Charles McCoy, Evan Peet, Ayesha Sania, Mary C. Smith Fawzi, Majid Ezzati, Wafaie W. Fawzi
Journal: PLoS Medicine (2016)

Stunting affects one-third of children under 5 y old in developing countries, and 14% of childhood deaths are attributable to it. A large number of risk factors for stunting have been identified in epidemiological studies. However, the relative contribution of these risk factors to stunting has not been examined across countries. We estimated the number of stunting cases among children aged 24-35 mo (i.e., at the end of the 1,000 days' period of vulnerability) that are attributable to 18 risk factors in 137 developing countries.We classified risk factors into five clusters: maternal nutrition and infection, teenage motherhood and short birth intervals, fetal growth restriction (FGR) and preterm birth, child nutrition and infection, and environmental factors. We combined published estimates and individual-level data from population-based surveys to derive risk factor prevalence in each country in 2010 and identified the most recent meta-analysis or conducted de novo reviews to derive effect sizes. We estimated the prevalence of stunting and the number of stunting cases that were attributable to each risk factor and cluster of risk factors by country and region. The leading risk worldwide was FGR, defined as being term and small for gestational age, and 10.8 million cases (95% CI 9.1 million-12.6 million) of stunting (out of 44.1 million) were attributable to it, followed by unimproved sanitation, with 7.2 million (95% CI 6.3 million-8.2 million), and diarrhea with 5.8 million (95% CI 2.4 million-9.2 million). FGR and preterm birth was the leading risk factor cluster in all regions. Environmental risks had the second largest estimated impact on stunting globally and in the South Asia, sub-Saharan Africa, and East Asia and Pacific regions, whereas child nutrition and infection was the second leading cluster of risk factors in other regions. Although extensive, our analysis is limited to risk factors for which effect sizes and country-level exposure data were available. The global nature of the study required approximations (e.g., using exposures estimated among women of reproductive age as a proxy for maternal exposures, or estimating the impact of risk factors on stunting through a mediator rather than directly on stunting). Finally, as is standard in global risk factor analyses, we used the effect size of risk factors on stunting from meta-analyses of epidemiological studies and assumed that proportional effects were fairly similar across countries.FGR and unimproved sanitation are the leading risk factors for stunting in developing countries. Reducing the burden of stunting requires a paradigm shift from interventions focusing solely on children and infants to those that reach mothers and families and improve their living environment and nutrition.
Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review
Authors: Gali Pariente, Tom Leibson, Alexandra Carls, Thomasin Adams-Webber, Shinya Ito, Gideon Koren
Journal: PLoS Medicine (2016)

Background Women are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy. Methods and Findings Systematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown. Conclusion This systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.
Modulation in the Expression of p70S6 Kinase Impairs the Engraftment and Self-Renewal of Hematopoietic Stem Cells
Authors: Joydeep Ghosh, Baskar Ramdas, Anindya Chatterjee, Peilin Ma, Michihiro Kobayashi, Raghuveer Mali, Yan Liu, David R. Plas, Reuben Kapur
Journal: Blood (2014)
LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner
Authors: Wen-Tao Wang, Hua Ye, Pan-Pan Wei, Bo-Wei Han, Bo He, Zhen- Hua Chen, Yue-Qin Chen
Journal: Journal of Hematology & Oncology (2016)

Long non-coding RNAs (lncRNAs) are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis, associated with chronic inflammation and damage to the biliary epithelium. The aim of the study is to identify if any lncRNA might associate with inflammation or oxidative stress in CCA and regulate the disease progression. In this study, RNA-seqs datasets were used to identify aberrantly expressed lncRNAs. Small interfering RNA and overexpressed plasmids were used to modulate the expression of lncRNAs, and luciferase target assay RNA immunoprecipitation (RIP) was performed to explore the mechanism of miRNA-lncRNA sponging. We firstly analyzed five available RNA-seqs datasets to investigate aberrantly expressed lncRNAs which might associate with inflammation or oxidative stress. We identified that two lncRNAs, H19 and HULC, were differentially expressed among all the samples under the treatment of hypoxic or inflammatory factors, and they were shown to be stimulated by short-term oxidative stress responses to H2O2 and glucose oxidase in CCA cell lines. Further studies revealed that these two lncRNAs promoted cholangiocyte migration and invasion via the inflammation pathway. H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4. Our study revealed that H19 and HULC, up-regulated by oxidative stress, regulate CCA cell migration and invasion by targeting IL-6 and CXCR4 via ceRNA patterns of sponging let-7a/let-7b and miR-372/miR-373, respectively. The results suggest that these lncRNAs might be the chief culprits of CCA pathogenesis and progression. The study provides new insight into the mechanism linking lncRNA function with CCA and may serve as novel targets for the development of new countermeasures of CCA.
BMET-06COMET: A PHASE II RANDOMIZED STUDY OF TTFIELDS VERSUS SUPPORTIVE CARE IN NON-SMALL CELL LUNG CANCER PATIENTS WITH 1-5 BRAIN METASTASES - INITIAL SAFETY RESULTS
Authors: Hana Brozova, Ana Lucas, Andrea Salmaggi, Josef Vymazal
Journal: Neuro-Oncology (2015)

BACKGROUND: Tumor Treating Fields (TTFields) are a non-invasive, anti-mitotic treatment modality, based on low intensity alternating electric fields. During mitosis, TTFields interfere with the formation of the mitotic spindle and physically translocate polarizable organelles. TTFields inhibit proliferation of non-small cell lung cancer (NSCLC) in vitro and in vivo, and have been demonstrated to prolonged survival when combined with maintenance temozolomide in GBM. METHODS: The COMET trial (NCT01755624) will enroll 60 patients with 1-5 NSCLC brain metastases who initially received definitive local treatment to all metastases. Patients are randomized (1:1) to either 150kHz TTFields applied to the entire brain or supportive care alone arms. Patients are followed-up monthly (brain MRI every 3 months). The trial is designed to study the safety, tolerability and efficacy of TTFields in this patient population. Median time to local and distant progression in the brain is the primary endpoint. Eligibility criteria include stable systemic disease and optimal systemic therapy for NSCLC. RESULTS: Seventeen patients have been enrolled in the trial to date (6 in the TTFields and 11 in the control arm of the study). The average follow-up time was 3.4 months. To date, 8 adverse events (AEs) have been reported in the TTFields arm and 18 in the control arm. Most adverse events were related to the underlying lung cancer. A single event (mild dermatitis) was related to TTFields. Two patients had a total of 4 Serious AEs (SAEs), 1 in the BSC and 1 in the TTFields arm (lower limb infection, pulmonary embolism, dyspnea and extra-cranial tumor progression). No SAE was related to TTFields. CONCLUSIONS: To date, TTFields demonstrate a high safety profile in patients suffering from brain metastases from NSCLC. The study continues to collect safety, neurocognitive and efficacy data.
PO70COMPARISON OF THE TRANSCRIPTIONAL LANDSCAPES OF POSTERIOR FOSSA EPENDYMOMA ACROSS AGE GROUPS
Authors: Anbarasu Lourdusamy, Hazel Rogers, Richard Grundy
Journal: Neuro-Oncology (2015)

INTRODUCTION: Ependymomas are rare glial tumors of the brain and spinal cord.Although common in children, posterior fossa (PF) ependymomas occur at any age and show marked clinical differences between children and adults.To better understand the biological basis for these observations, we performed a comparison of the expression profiles of PF ependymoma across age groups.METHOD: Our study included expression profiles of tumor samples from PF of 37 ependymoma patients with age ranging from 1 to 63 years.The change in gene expression among infants (0-3 years), children (4-17 years), and adults (≥18 years) was calculated using linear models based on Bayesian moderated statistics.RESULTS: We detected a total of 613 genes that show high expression levels in infants (adjusted P value, FDR , 0.05) and 444 genes in adults.In contrast, there was no significant gene expression alteration detected in Children.Similar trend of expression alterations was observed in an independent data set of 34 PF ependymomas (960 genes for infants; 434 for adults; and 1 gene for children).The infant PF ependymoma was enriched for genes associated with axon guidance, cell adhesion, ECM-receptor interaction, calcium, chemokine, MAPK, Neurotrophins, PPAR signaling pathways, whereas the adults were significantly enriched for genes associated with cilium organization and microtubule-based process.Markers of ECM signaling (LAMA2, log2 fold change (FC) ¼ 2.82, FDR , 0.009; CD44, FC ¼ 1.98, FDR , 0.007) were overexpressed in infants, while NELL2 (FC ¼ 1.99, FDR , 0.002) was overexpressed in adult PF ependymomas.CONCLUSION: Our results showed substantial differences in gene expression landscapes underlying different age groups of PF ependymoma.
Underfunded adult social care is increasing the strain on emergency departments, MPs warn
Authors: Ingrid Torjesen
Journal: BMJ (2016)

The government needs to boost funding for adult social care to reduce the pressure on emergency departments this winter, MPs on the House of Commons Health Committee have said in a report on winter planning in accident and emergency departments.1 Unless the shortfall in social care provision is tackled, people will continue to face avoidable admission and delayed discharge from hospital, they …
Predictive Value of Interim [<sup>18</sup>F]Fluorodeoxyglucose–Positron Emission Tomography in Advanced-Stage Hodgkin Lymphoma Is Not Well Established
Authors: Hugo J.A. Adams, Thomas C. Kwee
Journal: Journal of Clinical Oncology (2017)

that included 331 patients with stage III or IV Hodgkin lymphoma (HL) who underwent interim [ 18 F]fluorodeoxyglucose (FDG) -positron emission tomography (PET) after two cycles (PET2) of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).PET2-negative patients received four additional cycles of ABVD, whereas PET2-positive patients were switched to escalated BEA-COPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for six cycles.Importantly, no control arm was used to determine the additional value of this treatment strategy compared with continuation of standard ABVD treatment in terms of progression-free (PFS) and overall survival (OS).After two cycles of ABVD, 271 (82%) of 331 patients acquired FDG-PET-negative status, whereas PET2 was positive in 60 (18%) of 331 patients.The 2-year estimate of PFS for 271 PET2negative patients was 82%, with 58 patients experiencing treatment failure, and the 2-year estimate of PFS for the 60 PET2-positive patients was 64%, with 20 patients experiencing treatment failure.During follow-up, 17 deaths were reported, including six resulting from HL. Press et al concluded interim FDG-PET responseadapted therapy to be promising, considering the 2-year PFS of 64% for PET2-positive patients, which was described to be much higher than the historically observed 2-year PFS of 15% to 30%.However, we disagree with the conclusion of Press et al. 1
Phase 1 studies assessing the safety, PK, and VEGF-modulating effects of PTC299, a novel VEGF expression inhibitor
Authors: S. Hirawat, G. L. Elfring, V. J. Northcutt, N. Paquette-Lamontagne, T. Davis, M. Weetall, J. Babiak, L. L. Miller
Journal: Journal of Clinical Oncology (2007)

3562 Background: VEGF expression is regulated posttranscriptionally through the 5’- and 3’- untranslated regions (UTRs) of its mRNA. PTC299 is a novel, orally bioavailable, small molecule that acts via the VEGF 5’-UTR to selectively inhibit tumor VEGF production. In multiple preclinical human tumor xenograft models, PTC299 reduces elevated human VEGF levels in tumor and in circulation, decreases tumor microvessel density, and substantially slows tumor growth. With cytotoxic agents or with other antiangiogenics, PTC299 enhances tumor growth delay. Methods: PTC299 safety in animal toxicology studies supported Phase 1 studies in healthy volunteers. The first study was a Phase 1 single-dose (SD) trial. The second study was a Phase 1, multiple-dose (MD) study assessing BID or TID dosing for 7 days. During dose escalations, 8 subjects (4 males, 4 females; 6 PTC299, 2 placebo) per cohort were randomized in a double-blind manner. A fed-fasting crossover was performed in 12 subjects (6 males, 6 females) in the SD study. Subjects underwent clinical observations, laboratory testing, and blood sampling for PK and circulating VEGF. Results: In the SD study, 52 subjects (age range 18–55 years) were enrolled (40 at 5 dose levels and 12 to assess food effects. In the MD study, 32 subjects (age range 31–78 years) were enrolled (24 to BID dosing and 8 to TID dosing). AEs included: headache, dizziness nausea, vomiting, and stomach discomfort (all Grade 1); and diarrhea (Grade 2). No bleeding, clotting, hypertension, or proteinuria occurred. C max and AUC increased proportional to dose. There was a ∼40% increase in the C max with food, but no change in AUC. Mean PTC299 C max and AUC increased by ∼2-fold over 7 days, exceeding target trough plasma concentrations active in xenograft models. A 2-compartment model describes the PK data. Circulating VEGF levels are being assayed. Conclusions: PTC299 is the first drug designed to modulate post-transcriptional control mechanisms to treat human disease. In these initial studies, PTC299 shows safety at plasma exposures associated with preclinical activity and can be taken without regard to food. Final clinical data on dose ranging, safety, PK, and circulating VEGF levels will be presented. Studies of PTC299 in patients with cancer are being initiated. No significant financial relationships to disclose.
Global and HOX Gene DNA Methylation In Normal Karyotype Acute Myeloid Leukemia: Clinical Implications and Molecular Correlations
Authors: Stefan Deneberg, Andreas Lennartsson, Bertil Uggla, Verena Gaidzik, Andrea Corbacioglu, Hareth Nahi, Konstanze Dohner, Karl Ekwall, Ulf Tidefelt, Martin Hoglund, Sören Lehmann
Journal: Blood (2010)
Targeted Sequencing Reveals a Relationship Between Mutational Burden and Clinical Phenotype in MPNs
Authors: Bartlomiej Getta, Franck Rapaport, Sean Devlin, Chen Zhao, Kristina Marie Knapp, Minal Patel, Abhinita Mohanty, Marcel Van Den Brink, Ross L. Levine, Maria Arcila, Raajit K. Rampal
Journal: Blood (2015)
Outcome of Gastric Diffuse Large B-Cell Lymphoma and Usefulness of PET-CT in Detecting Gastric Lesion
Authors: Tomohiro Kadota, Sachiko Seo, Yoshihiro Nakagami, Hiroe Fuse, Yujiro Ueda, Genichiro Ishii, Kuniaki Itoh, Tomonori Yano, Kazuhiro Kaneko, Kunihiro Tsukasaki
Journal: Blood (2015)
Development of three-dimensional collagen scaffolds with controlled architecture for cell migration studies using breast cancer cell lines
Authors: Jonathan J. Campbell, Anke Husmann, Robert D. Hume, Christine J. Watson, Ruth E. Cameron
Journal: Biomaterials (2016)

Cancer is characterized by cell heterogeneity and the development of 3D in vitro assays that can distinguish more invasive or migratory phenotypes could enhance diagnosis or drug discovery. 3D collagen scaffolds have been used to develop analogues of complex tissues in vitro and are suited to routine biochemical and immunological assays. We sought to increase 3D model tractability and modulate the migration rate of seeded cells using an ice-templating technique to create either directional/anisotropic or non-directional/isotropic porous architectures within cross-linked collagen scaffolds. Anisotropic scaffolds supported the enhanced migration of an invasive breast cancer cell line MDA-MB-231 with an altered spatial distribution of proliferative cells in contrast to invasive MDA-MB-468 and non-invasive MCF-7 cells lines. In addition, MDA-MB-468 showed increased migration upon epithelial-to-mesenchymal transition (EMT) in anisotropic scaffolds. The provision of controlled architecture in this system may act both to increase assay robustness and as a tuneable parameter to capture detection of a migrated population within a set time, with consequences for primary tumour migration analysis. The separation of invasive clones from a cancer biomass with in vitro platforms could enhance drug development and diagnosis testing by contributing assay metrics including migration rate, as well as modelling cell-cell and cell-matrix interaction in a system compatible with routine histopathological testing.
Synergism Between Imatinib Mesylate and a BCR-ABL-Specific DNA Vaccine against Pre-Established Ph + Acute Lymphoblastic Leukemia in Syngeneic Mice.
Authors: Yvonne Rott, Stefanie Arndt, Christine Marschke, Renata Stripecke, Burghardt Wittig, Manuel Schmidt, Joachim Köchling
Journal: Blood (2009)
Use of NCCN Guidelines, Other Guidelines, and Biomarkers for Colorectal Cancer Screening
Authors: Christina D. Williams, William M. Grady, Leah L. Zullig
Journal: Journal of the National Comprehensive Cancer Network (2016)

Colorectal cancer (CRC) remains a common cancer and significant public health burden. CRC-related mortality is declining, partly due to the early detection of CRC through robust screening. NCCN has established the NCCN Guidelines for CRC Screening to help healthcare providers make appropriate screening recommendations according to the patient's risk of developing CRC. This review describes the evolution of CRC screening guidelines for average-risk individuals, discusses the role of NCCN Guidelines for CRC Screening in cancer prevention, and comments on the current and emerging use of biomarkers for CRC screening.
Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin
Authors: Da Wo, Jinhui Peng, Dan-ni Ren, Liman Qiu, Jinxiao Chen, Ye Zhu, Yingjing Yan, Hongwei Yan, Jian Wu, En Ma, Tao P. Zhong, Yihan Chen, Zhongmin Liu, Shangfeng Liu, Luoquan Ao, Zhenping Liu, Cizhong Jiang, Jun Peng, Yunzeng Zou, Qirong Qian, Weidong Zhu
Journal: Circulation (2016)

Background: Myocardial infarction is one of the leading causes of morbidity and mortality worldwide, triggering irreversible myocardial cell damage and heart failure. The role of low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) as coreceptors of the Wnt/β-catenin pathway in the adult heart remain unknown. Insulin-like growth factor binding protein 4 and dickkopf-related protein 1 (Dkk1) are 2 secreted LRP5/6 binding proteins that play a crucial role in heart development through preventing Wnt/β-catenin pathway activation. However, their roles in the adult heart remain unexplored. Methods: To understand the role of LRP5/6 and β-catenin in the adult heart, we constructed conditional cardiomyocyte-specific LRP5/6 and β-catenin knockout mice and induced surgical myocardial infarction. We also directly injected recombinant proteins of insulin-like growth factor binding protein 4 and Dkk1 into the heart immediately following myocardial infarction to further examine the mechanisms through which these proteins regulate LRP5/6 and β-catenin. Results: Deletion of LRP5/6 promoted cardiac ischemic insults. Conversely, deficiency of β-catenin, a downstream target of LRP5/6, was beneficial in ischemic injury. It is interesting to note that although both insulin-like growth factor binding protein 4 and Dkk1 are secreted Wnt/β-catenin pathway inhibitors, insulin-like growth factor binding protein 4 protected the ischemic heart by inhibiting β-catenin, whereas Dkk1 enhanced the injury response mainly through inducing LRP5/6 endocytosis and degradation. Conclusions: Our findings reveal previously unidentified dual roles of LRP5/6 involved in the cardiomyocyte response to ischemic injury. These findings suggest new therapeutic strategies in ischemic heart disease by fine-tuning LRP5/6 and β-catenin signaling within the Wnt/β-catenin pathway.