tbuckley/cabot-search huggingface dataset:
Phospholipase D1 Inhibition Linked to Upregulation of ICAT Blocks Colorectal Cancer Growth Hyperactivated by Wnt/β-Catenin and PI3K/Akt Signaling
Authors: Dong Woo Kang, Bo Hui Lee, Young-Ah Suh, Yong-Seok Choi, Se Jin Jang, Yong Man Kim, Kang-Yell Choi, Do Sik Min
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer, which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of colorectal cancer. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of colorectal cancer hyperactivated by Wnt/β-catenin and PI3K/Akt signaling. Experimental Design: Expression of ICAT via targeting of PLD1 was assessed in vivo in ApcMin/+ mice, an AOM/DSS model, and in vitro using various colorectal cancer cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 colorectal cancer patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations. Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively downregulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in colorectal cancer patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of colorectal cancer activated by the Wnt/β-catenin and PI3K signaling pathways. Conclusions: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel colorectal cancer prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of colorectal cancer patients carrying APC and PI3KCA mutations. PLD1, a nodal modifier, acts as a potential therapeutic target for the treatment of colorectal cancer hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways. Clin Cancer Res; 23(23); 7340–50. ©2017 AACR.
Uptake by breast carcinoma of a lipidic nanoemulsion after intralesional injection into the patients: A new strategy for neoadjuvant chemotherapy
Authors: S. Graziani, S. Mendes, T. S. Vitório, A. F. Padoveze, R. Hegg, S. P. Bydlowski, R. C. Maranhão
Journal: Journal of Clinical Oncology (2009)

e11555 Background: Previously we showed that after intravenous injection a lipidic nanoemulsion concentrates in breast carcinoma tissue and other solid tumors may carry drugs directed against neoplastic tissues. Use of the nanoemulsion decreases toxicity of the chemotherapeutic agents without decreasing the anticancer action. Currently, the hypothesis was tested whether the nanoemulsion concentrates in breast carcinoma tissue after locoregional injection. Methods: Three different techniques of injection of the nanoemulsion were tested in patients scheduled for surgical treatment: G1 (n=4) into the mammary tissue 5 cm away from the tumor; G2 (n=4) into the peritumoral mammary tissue; G3 (n=6) into the tumoral tissue. The nanoemulsion labeled with radioactive cholesteryl oleate was injected 12 hours before surgery; plasma decay of the label was determined from blood samples collected over 24 h and the tissue fragments excised during the surgery were analyzed for radioactivity uptake. Results: Among the three nanoemulsion injection techniques, G3 showed the greatest uptake (data expressed in c.p.m/g of tissue) by the tumor (44769±54749) and by the lymph node (2356±2966), as well as the greatest concentration in tumor compared to normal tissue (844±1673). In G1 and G2, uptakes were, respectively, tumor: 60±71 and 843±1526; lymph node: 263±375 and 102±74; normal tissue: 139±102 and 217±413. Conclusions: Therefore, with intralesional injection of the nanoemulsion, a great concentration effect can be achieved. This injection technique may be thus a promising approach for drug-targeting in neoadjuvant chemotherapy in breast cancer treatment. No significant financial relationships to disclose.
Efficacy of newly developed platinum complexes against osteosarcoma, bone-targeting platinum, and proteasome inhibitory platinum.
Authors: Kentaro Igarashi, Norio Yamamoto, Toshiharu Shirai, Katsuhiro Hayashi, Hideji Nishida, Akihiko Takeuchi, Yoshikazu Tanzawa, Hiroaki Kimura, Shinji Miwa, Hiroyuki Inatani, Shingo Shimozaki, Akira Odani, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2012)

10075 Background: Cisplatin is one of the most effective anti-cancer drugs available for the treatment of human solid tumors including osteosarcoma. As we had already reported, we have utilized caffeine in our chemotherapy protocol. And we achieved excellent clinical results. But effectiveness of cisplatin has been limited by side effects, and resistance. Here we developed two novel platinum compounds. 3Pt is trinuclear platinum complex bearing geminal bisphosphonate moieties, 1Pt is mononuclear platinum complex which has proteasome inhibitory activity. We performed comparative studies of our novel platinum compounds with osteosarcoma. Methods: Two novel platinum complexes were synthesized by Prof. Odani at school of pharmaceutical sciences of our university and cisplatin and caffeine were obtained from constructor. Three cell lines (MG63, 143B, and LM8) were used. Cell survival after a 72 hrs exposure to these compounds was assessed by WST-8 assay, and IC50 value was calculated for each compound. Apoptosis was assessed by DNA fragmentation and Annexin V-FITC/propidium iodine assay. Results: Each compound strongly caused concentration-dependent cytocidal effect. IC50 value of trinuclear compound is superior to cisplatin, and both complexes showed caffeine potentiation. Apoptosis induction and acetylation of histon H2AX were observed. In vivo, 1Pt showed almost same, 3Pt showed strong antitumor effect compared to cisplatin. Conclusions: Two novel platinum compounds that we developed showed strong ant-tumor effect in osteosarcoma in vitro and in vivo. As bisphosphonate has high affinity to calcium ions, 3Pt targets bone tissue and expected to reduce side effects at extraskeletal sites and to overcome the drug resistance. Proteasome inhibitory platinum compound has never been reported before, we will investigate its anti-tumor mechanism precisely.
International Union of Pharmacology. XXXIX. Compendium of Voltage-Gated Ion Channels: Sodium Channels
Authors: William A. Catterall, Alan L. Goldin, Stephen G. Waxman
Journal: Pharmacological Reviews (2003)

This summary article presents an overview of the molecular relationships among the voltage-gated sodium channels and a standard nomenclature for them, which is derived from the <i>IUPHAR Compendium of Voltage-Gated Ion Channels</i>.1 The complete Compendium, including data tables for each member of the sodium channel family can be found at &lt;http://www.iuphar-db.org/iuphar-ic/&gt;.
Quantification of the association between malaria in pregnancy and stillbirth: a systematic review and meta-analysis
Authors: Kerryn A Moore, Julie A Simpson, Michelle J L Scoullar, Rose McGready, Freya J I Fowkes
Journal: The Lancet Global Health (2017)

Background2·6 million stillbirths occur annually worldwide. The association between malaria in pregnancy and stillbirth has yet to be comprehensively quantified. We aimed to quantify the association between malaria in pregnancy and stillbirth, and to assess the influence of malaria endemicity on the association.MethodsWe did a systematic review of the association between confirmed malaria in pregnancy and stillbirth. We included population-based cross-sectional, cohort, or case-control studies (in which cases were stillbirths or perinatal deaths), and randomised controlled trials of malaria in pregnancy interventions, identified before Feb 28, 2017. We excluded studies in which malaria in pregnancy was not confirmed by PCR, light microscopy, rapid diagnostic test, or histology. The primary outcome was stillbirth. We pooled estimates of the association between malaria in pregnancy and stillbirth using meta-analysis. We used meta-regression to assess the influence of endemicity. The study protocol is registered with PROSPERO, protocol number CRD42016038742.FindingsWe included 59 studies of 995 records identified, consisting of 141 415 women and 3387 stillbirths. Plasmodium falciparum malaria detected at delivery in peripheral samples increased the odds of stillbirth (odds ratio [OR] 1·81 [95% CI 1·42–2·30]; I2=26·1%; 34 estimates), as did P falciparum detected in placental samples (OR 1·95 [1·48–2·57]; I2=33·6%; 31 estimates). P falciparum malaria detected and treated during pregnancy was also associated with stillbirth, but to a lesser extent (OR 1·47 [95% CI 1·13–1·92]; 19 estimates). Plasmodium vivax malaria increased the odds of stillbirth when detected at delivery (2·81 [0·77–10·22]; three estimates), but not when detected and treated during pregnancy (1·09 [0·76–1·57]; four estimates). The association between P falciparum malaria in pregnancy and stillbirth was two times greater in areas of low-to-intermediate endemicity than in areas of high endemicity (ratio of ORs 1·96 [95% CI 1·34–2·89]). Assuming all women with malaria are still parasitaemic at delivery, an estimated 20% of the 1 059 700 stillbirths in malaria-endemic sub-Saharan Africa are attributed to P falciparum malaria in pregnancy; the population attributable fraction decreases to 12%, assuming all women with malaria are treated during pregnancy.InterpretationP falciparum and P vivax malaria in pregnancy both increase stillbirth risk. The risk of malaria-associated stillbirth is likely to increase as endemicity declines. There is a pressing need for context-appropriate, evidence-based interventions for malaria in pregnancy in low-endemicity settings.FundingAustralian Commonwealth Government, National Health and Medical Research Council, Australian Research Council.
Association of Prehospital Mode of Transport With Mortality in Penetrating Trauma
Authors: Michael W. Wandling, Avery B. Nathens, Michael B. Shapiro, Elliott R. Haut
Journal: JAMA Surgery (2017)

Time to definitive care following injury is important to the outcomes of trauma patients. Prehospital trauma care is provided based on policies developed by individual trauma systems and is an important component of the care of injured patients. Given a paucity of systems-level trauma research, considerable variability exists in prehospital care policies across trauma systems, potentially affecting patient outcomes.To evaluate whether private vehicle prehospital transport confers a survival advantage vs ground emergency medical services (EMS) transport following penetrating injuries in urban trauma systems.Retrospective cohort study of data included in the National Trauma Data Bank from January 1, 2010, through December 31, 2012, comprising 298 level 1 and level 2 trauma centers that contribute data to the National Trauma Data Bank that are located within the 100 most populous metropolitan areas in the United States. Of 2 329 446 patients assessed for eligibility, 103 029 were included in this study. All patients were 16 years or older, had a gunshot wound or stab wound, and were transported by ground EMS or private vehicle.In-hospital mortality.Of the 2 329 446 records assessed for eligibility, 103 029 individuals at 298 urban level 1 and level 2 trauma centers were included in the analysis. The study population was predominantly male (87.6%), with a mean age of 32.3 years. Among those included, 47.9% were black, 26.3% were white, and 18.4% were Hispanic. Following risk adjustment, individuals with penetrating injuries transported by private vehicle were less likely to die than patients transported by ground EMS (odds ratio [OR], 0.38; 95% CI, 0.31-0.47). This association remained statistically significant on stratified analysis of the gunshot wound (OR, 0.45; 95% CI, 0.36-0.56) and stab wound (OR, 0.32; 95% CI, 0.20-0.52) subgroups.Private vehicle transport is associated with a significantly lower likelihood of death when compared with ground EMS transport for individuals with gunshot wounds and stab wounds in urban US trauma systems. System-level evidence such as this can be a valuable tool for those responsible for developing and implementing policies at the trauma system level.
Aldosterone-Sensing Neurons in the NTS Exhibit State-Dependent Pacemaker Activity and Drive Sodium Appetite via Synergy with Angiotensin II Signaling
Authors: Jon M. Resch, Henning Fenselau, Joseph C. Madara, Chen Wu, John N. Campbell, Anna Lyubetskaya, Brian A. Dawes, Linus T. Tsai, Monica M. Li, Yoav Livneh, Qingen Ke, Peter M. Kang, Géza Fejes-Tóth, Anikó Náray-Fejes-Tóth, Joel C. Geerling, Bradford B. Lowell
Journal: Neuron (2017)
Racial and Ethnic Disparities in the Incidence of Pediatric Extracranial Embryonal Tumors
Authors: Paola Friedrich, Elena Itriago, Carlos Rodriguez-Galindo, Karina Ribeiro
Journal: JNCI Journal of the National Cancer Institute (2017)

Few studies have comparatively assessed differences in the incidence of childhood cancer by race and ethnicity that could inform etiologic research. We aimed to identify disparities in the incidence of pediatric extracranial embryonal tumors by race and ethnicity in the United States using a population-based cancer registry.Cases of extracranial embryonal tumors among children age 0 to 19 years diagnosed between 2000 and 2010 were retrieved from the Surveillance, Epidemiology, and End Results Program 18 (n = 8188). Age-standardized incidence rates and incidence rate ratios (IRRs) were obtained by race/ethnicity. Whites were the reference group. The percentage of families living below the poverty line by county was used to stratify by socioeconomic status (SES).All minority groups had a lower incidence of neuroblastoma (Hispanics: IRR = 0.53, 95% confidence interval [CI] = 0.47 to 0.59; blacks: IRR = 0.70, 95% CI = 0.61 to 0.81; Native-Hawaiian/Asian-Pacific-Islander (API): IRR = 0.56, 95% CI = 0.46 to 0.67; and American Indian/Alaska Native (AI/AN): IRR = 0.28, 95% CI = 0.15 to 0.48) while Hispanics had a higher incidence of retinoblastoma (IRR = 1.26, 95% CI = 1.07 to 1.48). Incidence of nephroblastoma was lower among Hispanics (IRR = 0.80, 95% CI = 0.71 to 0.91) and API (IRR = 0.43, 95% CI = 0.33 to 0.56) while equivalent for blacks. Similarly, incidence of rhabdomyosarcoma was low among Hispanics (IRR = 0.85, 95% CI = 0.74 to 0.98) and API (IRR = 0.61, 95% CI = 0.47 to 0.79) while equivalent for blacks. However, incidence of hepatoblastoma was low among blacks (IRR = 0.44, 95% CI = 0.28 to 0.68) while equivalent for Hispanics and API. Incidence of germ cell tumors was higher among Hispanics (IRR = 1.30, 95% CI = 1.19 to 1.42) and lower among blacks (IRR = 0.52, 95% CI = 0.44 to 0.61) and API (IRR = 0.79, 95% CI = 0.67 to 0.93). No effect modification by SES was observed.Unique incidence patterns of childhood extracranial embryonal tumors exist by race and ethnicity in the United States. The interplay between race/ethnicity and genetics, epigenetics, and gene-environment interactions in the causation of these cancers deserves further investigation.
Fabrication of Calcium Phosphate‐Based Nanocomposites Incorporating DNA Origami, Gold Nanorods, and Anticancer Drugs for Biomedical Applications
Authors: Hongbo Zhang, Xiangmeng Qu, Hong Chen, Haixin Kong, Ruihua Ding, Dong Chen, Xu Zhang, Hao Pei, Hélder A. Santos, Mingtan Hai, David A. Weitz
Journal: Advanced Healthcare Materials (2017)

Abstract DNA origami is designed by folding DNA strands at the nanoscale with arbitrary control. Due to its inherent biological nature, DNA origami is used in drug delivery for enhancement of synergism and multidrug resistance inhibition, cancer diagnosis, and many other biomedical applications, where it shows great potential. However, the inherent instability and low payload capacity of DNA origami restrict its biomedical applications. Here, this paper reports the fabrication of an advanced biocompatible nano‐in‐nanocomposite, which protects DNA origami from degradation and facilities drug loading. The DNA origami, gold nanorods, and molecular targeted drugs are co‐incorporated into pH responsive calcium phosphate [Ca 3 (PO 4 ) 2 ] nanoparticles. Subsequently, a thin layer of phospholipid is coated onto the Ca 3 (PO 4 ) 2 nanoparticle to offer better biocompatibility. The fabricated nanocomposite shows high drug loading capacity, good biocompatibility, and a photothermal and pH‐responsive payload release profile and it fully protects DNA origami from degradation. The codelivery of DNA origami with cancer drugs synergistically induces cancer cell apoptosis, reduces the multidrug resistance, and enhances the targeted killing efficiency toward human epidermal growth factor receptor 2 positive cells. This nanocomposite is foreseen to open new horizons for a variety of clinical and biomedical applications.
Norovirus Cell Tropism Is Determined by Combinatorial Action of a Viral Non-structural Protein and Host Cytokine
Authors: Sanghyun Lee, Craig B. Wilen, Anthony Orvedahl, Broc T. McCune, Ki-Wook Kim, Robert C. Orchard, Stefan T. Peterson, Timothy J. Nice, Megan T. Baldridge, Herbert W. Virgin
Journal: Cell Host & Microbe (2017)
Long-Term Exposure to Road Traffic Noise and Nitrogen Dioxide and Risk of Heart Failure: A Cohort Study
Authors: Mette Sørensen, Olav Wendelboe Nielsen, Ahmad Sajadieh, Matthias Ketzel, Anne Tjønneland, Kim Overvad, Ole Raaschou-Nielsen
Journal: Environmental Health Perspectives (2017)

Background: Although air pollution and road traffic noise have been associated with higher risk of cardiovascular diseases, associations with heart failure have received only little attention. Objectives: We aimed to investigate whether long-term exposure to road traffic noise and nitrogen dioxide (NO2) were associated with incident heart failure. Methods: In a cohort of 57,053 people 50–64 y of age at enrollment in the period 1993–1997, we identified 2,550 cases of first-ever hospital admission for heart failure during a mean follow-up time of 13.4 y. Present and historical residential addresses from 1987 to 2011 were found in national registers, and road traffic noise (Lden) and NO2 were modeled for all addresses. Analyses were done using Cox proportional hazard model. Results: An interquartile range higher 10-y time-weighted mean exposure for Lden and NO2 was associated with incidence rate ratios (IRR) for heart failure of 1.14 (1.08–1.21) and 1.11 (1.07–1.16), respectively, in models adjusted for gender, lifestyle, and socioeconomic status. In models with mutual exposure adjustment, IRRs were 1.08 (1.00–1.16) for Lden and 1.07 (1.01–1.14) for NO2. We found statistically significant modification of the NO2–heart failure association by gender (strongest association among men), baseline hypertension (strongest association among hypertensive), and diabetes (strongest association among diabetics). The same tendencies were seen for noise, but interactions were not statistically significant. Conclusions: Long-term exposure to NO2 and road traffic noise was associated with higher risk of heart failure, mainly among men, in both single- and two-pollutant models. High exposure to both pollutants was associated with highest risk. https://doi.org/10.1289/EHP1272
Asthma-COPD overlap syndrome: pathogenesis, clinical features, and therapeutic targets
Authors: Janice M Leung, Don D Sin
Journal: BMJ (2017)

Asthma-COPD overlap syndrome (ACOS) or asthma-COPD overlap captures the subset of patients with airways disease who have features of both asthma and chronic obstructive pulmonary disease (COPD). Although definitions of ACOS vary, it is generally thought to encompass persistent airflow limitation in a patient older than 40 years of age with either a history of asthma or large bronchodilator reversibility. ACOS affects about a quarter of patients with COPD and almost a third of patients who previously had asthma. Compared with their counterparts with asthma or COPD alone, patients with ACOS have significantly worse respiratory symptoms, poorer quality of life, and increased risk of exacerbations and hospital admissions. Whether this condition emerges after gradual shifts in airway remodelling and inflammation in a patient with COPD, as the result of noxious exposures in a patient with asthma, or even as a de novo disease with its own pathology is yet to be determined. Nevertheless, using treatments developed for asthma or COPD that target eosinophilic, neutrophilic, or paucigranulocytic airway inflammation may be a helpful approach to these patients until further clinical trials can be performed.
Erratum: PGBD5 promotes site-specific oncogenic mutations in human tumors
Authors: Anton G Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C MacArthur, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N Blackford, Christopher E Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D Socci, Elizabeth Perlman, Cristina R Antonescu, Charles W M Roberts, Hanno Steen, Elizabeth Mullen, Stephen P Jackson, David Torrents, Zhiping Weng, Scott A Armstrong, Alex Kentsis
Journal: Nature Genetics (2017)
Atrial fibrillation modifies the association between pulmonary artery wedge pressure and left ventricular end‐diastolic pressure
Authors: Michael G. Dickinson, Carolyn S. Lam, Michiel Rienstra, Ton E. Vonck, Yoran M. Hummel, Adriaan A. Voors, Elke S. Hoendermis
Journal: European Journal of Heart Failure (2017)
Hexokinases link DJ-1 to the PINK1/parkin pathway
Authors: David N. Hauser, Adamantios Mamais, Melissa M. Conti, Christopher T. Primiani, Ravindran Kumaran, Allissa A. Dillman, Rebekah G. Langston, Alexandra Beilina, Joseph H. Garcia, Alberto Diaz-Ruiz, Michel Bernier, Fabienne C. Fiesel, Xu Hou, Wolfdieter Springer, Yan Li, Rafael de Cabo, Mark R. Cookson
Journal: Molecular Neurodegeneration (2017)

Early onset Parkinson's disease is caused by variants in PINK1, parkin, and DJ-1. PINK1 and parkin operate in pathways that preserve mitochondrial integrity, but the function of DJ-1 and how it relates to PINK1 and parkin is poorly understood. A series of unbiased high-content screens were used to analyze changes at the protein, RNA, and metabolite level in rodent brains lacking DJ-1. Results were validated using targeted approaches, and cellular assays were performed to probe the mechanisms involved. We find that in both rat and mouse brains, DJ-1 knockout results in an age-dependent accumulation of hexokinase 1 in the cytosol, away from its usual location at the mitochondria, with subsequent activation of the polyol pathway of glucose metabolism in vivo. Both in the brain and in cultured cells, DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT. In cells, addition of an inhibitor of AKT (MK2206) or addition of a peptide to dissociate association of hexokinases from mitochondria both inhibit the PINK1/parkin pathway, which works to maintain mitochondrial integrity. Hexokinases are an important link between three major genetic causes of early onset Parkinson's disease. Because aging is associated with deregulated nutrient sensing, these results help explain why DJ-1 is associated with age-dependent disease.
A Potent Germline-like Human Monoclonal Antibody Targets a pH-Sensitive Epitope on H7N9 Influenza Hemagglutinin
Authors: Fei Yu, He Song, Yanling Wu, So Young Chang, Lili Wang, Wei Li, Binbin Hong, Shuai Xia, Chunyu Wang, Surender Khurana, Yang Feng, Yanping Wang, Zhiwu Sun, Biao He, Dongni Hou, Jody Manischewitz, Lisa R. King, Yuanlin Song, Ji-Young Min, Hana Golding, Xinhua Ji, Lu Lu, Shibo Jiang, Dimiter S. Dimitrov, Tianlei Ying
Journal: Cell Host & Microbe (2017)