tbuckley/cabot-search huggingface dataset:
Therapeutic advantage of genetically engineered Salmonella typhimurium carrying short hairpin RNA against inhibin alpha subunit in cancer treatment
Authors: W. Yoon, Y. Yoo, Y.S. Chae, S.-H. Kee, B.M. Kim
Journal: Annals of Oncology (2018)

<h2>Abstract</h2><h3>Background</h3> In contrast to its well-known endocrine function, the role of inhibin in cancer development and therapeutic response is unclear. <i>Salmonella</i>, particularly less toxic attenuated <i>Salmonella</i> strains, are used to treat cancer in two ways. First, <i>Salmonella</i> accumulate around tumors, penetrate the cell barrier, and replicate inside the tumors. Second, <i>Salmonella</i> can act as a vehicle for delivering anticancer agents or proapoptotic genes to attack tumors. In this study, we aimed to develop a suitable cancer therapeutic strategy by genetically modifying attenuated <i>Salmonella typhimurium</i> to harbor short hairpin RNA (shRNA) expression plasmids targeting alpha subunit of inhibin (sh-INHA). <h3>Methods</h3> We analyzed the expression of human INHA in normal and cancer cells and tissues. We developed genetically engineered attenuated <i>S. typhimurium</i> harboring sh-INHA (<i>S. typhimurium</i>/sh-INHA) and assessed its cancer therapeutic effects by using cell culture models and syngeneic mouse tumor models. <h3>Results</h3> INHA expression levels were markedly higher in colon cancer and melanoma cells and tissues than in their normal counterparts. Suppression of INHA expression mildly reduced cancer cell survival and induced caspase activation and downregulation of anti-apoptotic Bcl-2 and Bcl-xL expressions. Although the genetically engineered <i>S. typhimurium</i> mildly interfered with the invasion of <i>S. typhimurium</i> into host colon cancer and melanoma cells, <i>S. typhimurium</i>/sh-INHA caused remarkable cytotoxicity in cancer compared with unmodified <i>S. typhimurium</i> or <i>S. typhimurium</i> expressing a control scrambled shRNA (<i>S. typhimurium</i>/sh-Cont). <i>Salmonella typhimurium</i>/sh-INHA-treated mice also showed a significantly inhibited growth of colon cancers and melanomas, with a survival advantage. <h3>Conclusion</h3> Our results suggest that tumor-targeted therapy using <i>S. typhimurium</i>/sh-INHA may provide a novel cancer treatment option.
Live-Born Major Congenital Heart Disease in Denmark
Authors: Rebekka Lytzen, Niels Vejlstrup, Jesper Bjerre, Olav Bjørn Petersen, Stine Leenskjold, James Keith Dodd, Finn Stener Jørgensen, Lars Søndergaard
Journal: JAMA Cardiology (2018)

The occurrence of major congenital heart disease (CHD) is affected by several variables. Determining the development of the true incidence is critical to the establishment of proper treatment of these patients.To evaluate time trends in incidence, detection rate, and termination of pregnancy (TOP) rate of major CHD in fetuses in Denmark and assess the influence of the introduction of general prenatal screening in 2004.Nationwide, population-based, retrospective observational study in Denmark from 1996 to 2013 that included a consecutive sample of 14 688 live-born children and terminated fetuses diagnosed as having CHD. Patient records on TOP and children with major CHD were reviewed to validate the diagnoses. Major CHD included univentricular heart, transposition of the great arteries, congenitally corrected transposition of the great arteries, truncus arteriosus, interrupted aortic arch, atrioventricular septal defects, double outlet right ventricle, coarctatio of the aorta, Ebstein anomaly, pulmonary atresia with ventricular septal defect, pulmonary atresia with intact ventricular septum, and tetralogy of Fallot. Data were analyzed between January 2017 and March 2018.Temporal changes in incidence, detection rate, and TOP of major CHD.Of 14 688 children and fetuses diagnosed with CHD, 2695 (18.4%; 95% CI, 17.8-19.1) had major CHD. A total of 7131 boys (1304 with major CHD) and 6926 girls (920 with major CHD) were included, with a median age of 11 years (interquartile range, 6-15 years). During the study period, the live-birth incidence of CHD was constant at 1.22% (95% CI, 1.18-1.26), whereas it decreased for major CHD. When including TOP, the incidence of major CHD did not change over time. The detection rate of major CHD increased from 4.5% (95% CI, 1.2-7.8) to 71.0% (95% CI, 63.3-78.7) (P < .001). At the end of the study, all cases of double outlet right ventricle, Ebstein anomaly, congenitally corrected transposition of the great arteries, and pulmonary atresia with ventricular septal defect were detected prenatally, whereas coarctation of the aorta had the lowest detection rate (21.7%; 95% CI, 3.5-40.0). The TOP rate increased from 0.6% (95% CI, -0.6 to 1.9) to 39.1% (95% CI, 30.9-47.4) (P < .001) among all major CHD. For prenatally diagnosed major CHD, 57.8% of cases were terminated and the proportion did not change significantly throughout the study. Diagnoses leading to TOP included all major CHD diagnoses.Detection rates of major CHD improved during the study. This has led to increased TOP rates, with a subsequent 39% decrease in the live-birth incidence of major CHD.
Design and clinical validation of a point-of-care device for the diagnosis of lymphoma via contrast-enhanced microholography and machine learning
Authors: Hyungsoon Im, Divya Pathania, Philip J. McFarland, Aliyah R. Sohani, Ismail Degani, Matthew Allen, Benjamin Coble, Aoife Kilcoyne, Seonki Hong, Lucas Rohrer, Jeremy S. Abramson, Scott Dryden-Peterson, Lioubov Fexon, Misha Pivovarov, Bruce Chabner, Hakho Lee, Cesar M. Castro, Ralph Weissleder
Journal: Nature Biomedical Engineering (2018)
Abstract 18419: Remote Ischemic Preconditioning Does Not Improve Coronary Hemodynamics
Authors: Tadashi Ashida, Hiroshi Takahashi, Shigemasa Tani, Kimio Kikushima, Shingo Furuya, Takehiko Washio, Shinichirou Niizuma, Kenji Kawauchi, Masashi Kobori, Masakazu Matsuzaki, Naoya Matsumoto
Journal: Circulation (2016)

Introduction:  Remote ischemic preconditioning (RIPC) reportedly reduces the risk of myocardial injury after coronary artery bypass grafting and percutaneous coronary intervention. Limb ischemia produces nitric oxide (NO), which leads to increased blood flow.   Hypothesis:  We assessed the hypothesis that RIPC might improve coronary hemodynamics.   Methods:  In 27 patients with angiographically normal coronary arteries (% diameter stenosis    Results:  The mean parameter values during RIPC changed as follows (baseline, first, second, and third measurements; compared using a one-way ANOVA): for APV, 25.0, 22.9, 22.4, and 23.0 cm/s,  P  = 0.96; for CBF, 53.6, 44.3, 43.0, and 42.6 mL/min,  P  = 0.92; and for HMR, 3.23, 3.47, 3.99, and 3.69,  P  = 0.87.   Conclusions:  Although a recent study showed that RIPC generates NO and transfers it to the heart, we were unable to demonstrate an increase in coronary blood flow during RIPC. These findings suggest that the cardioprotective effect of RIPC would not be provided by the improvement of coronary hemodynamics, suggesting that NO generated by RIPC would not activate the adenosine triphosphate-sensitive potassium channels.
Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications
Authors: Eknath Ahire, Shreya Thakkar, Mahesh Darshanwad, Manju Misra
Journal: Acta Pharmaceutica Sinica B (2018)

Advancements in in silico techniques of lead molecule selection have resulted in the failure of around 70% of new chemical entities (NCEs). Some of these molecules are getting rejected at final developmental stage resulting in wastage of money and resources. Unfavourable physicochemical properties affect ADME profile of any efficacious and potent molecule, which may ultimately lead to killing of NCE at final stage. Numerous techniques are being explored including nanocrystals for solubility enhancement purposes. Nanocrystals are the most successful and the ones which had a shorter gap between invention and subsequent commercialization of the first marketed product. Several nanocrystal-based products are commercially available and there is a paradigm shift in using approach from simply being solubility enhancement technique to more novel and specific applications. Some other aspects in relation to parenteral nanosuspensions are concentrations of surfactant to be used, scalability and in vivo fate. At present, there exists a wide gap due to poor understanding of these critical factors, which we have tried to address in this review. This review will focus on parenteral nanosuspensions, covering varied aspects especially stabilizers used, GRAS (Generally Recognized as Safe) status of stabilizers, scalability challenges, issues of physical and chemical stability, solidification techniques to combat stability problems and in vivo fate.
TFF1 is expressed early in pancreatic cancer and increases cancer cell invasion and growth and migration of stellate cells within the tumor microenvironment.
Authors: Thiruvengadam Arumugam, Rosa Hwang, Todd Moore, Huamin Wang, William Brandt, Bruce Westley, Craig Logsdon
Journal: Cancer Research (2008)

3714  Background: Trefoil factor 1 (TFF1) is a member of the trefoil family of small peptides,that are co-secreted with mucins in mucin-secretingepithelial cells. Our gene profiling (Cancer Res. 2003 May 15;63(10):2649-57) indicated that TFF1 is specifically over expressed in human pancreatic cancer tissues. In this study, we examined the effects of TFF1 on pancreatic cancer cells and on the stromal cells found within the tumor microenvironment. Methods: TFF1 expression in pancreatic cancer tissues and cell lines was analyzed using microarray, QRT-PCR, and immunohistochemistry (IHC). The effects of recombinant TFF1 on cell growth and invasion of pancreatic cancer cell lines BxPC3 and Mpanc96 were analyzed using MTS and Matrigel coated invasion chambers. Immortalized human pancreatic stellate cells (HPSCs), stromal cells, were also analyzed for TFF1 expression and TFF1 effects on growth and migration in vitro. In vivo studies were also conducted in which Mpanc96 cells stably transfected to express TFF1 were implanted orthotopically into nude mice. Results: Microarray analysis indicated a 178-fold increase in TFF1 expression in human pancreatic cancer tissues when compared to normal pancreas tissues and this difference was confirmed by QRT-PCR. IHC showed early expression of TFF1 in pre-neoplastic lesions (5/6 PanIN1; 6/6 PanIN2 and 5/6 PanIN3) as well as in cancer cells within highly invasive tumors (50/70). In contrast, 11 pancreatic cancer cell lines and a line of immortalized stromal cells expressed very low or no TFF1 in vitro. But, interestingly, TFF1 expression was induced when the BxPC3 cells were implanted orthotopically into nude mice, suggesting an effect of interaction with the microenvironment. However, this response was not duplicated in vitro in two-dimensional co-cultures with immortalized stromal cells. In vitro assays indicated that exogenous TFF1 increased cancer cell invasion (MPanc96) in a dose-dependent manner (0nM 0.17±0.02, 1nM 0.20±0.01, 10nM 1.12±0.05*, 100nM 1.55±0.06* O.D units *p
Abstract 14932: Long-term Incidence of Stroke and Transient Ischemic Attack after Coronary Artery Bypass Grafting
Authors: HengZhang, XinYuan, YanZhao, ChenfeiRao, WeiWang, ShengshouHu, ZheZheng
Journal: Circulation (2014)

Introduction: Stroke and transient ischemic attack (TIA) after cardiac surgery are important concerns for both short term and long term disability, which is associated with increased medical costs and decreased cognitive function and quality of life. Hypothesis: This study aims to examine the epidemiology, risk factors and healthcare burden of new-onset stroke and TIA during the long term following coronary artery bypass grafting (CABG). Methods: All 9,172 consecutive patients who underwent isolated CABG and discharged alive between January 1999 and December 2008 were included and analyzed for long-term new-onset stroke and TIA after the procedure. Patients were defined with stroke or TIA, according to the definitions of the 2013 American Heart Association criteria. Predictors of stroke and TIA were determined by developing a multivariate regression model. Results: After an average of 3.7 years of follow-up, the prevalence of new-onset ischemic stroke, hemorrhagic stroke, undetermined stroke and TIA was 5...
Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma
Authors: Chiaki T. Ishida, Yiru Zhang, Elena Bianchetti, Chang Shu, Trang T.T. Nguyen, Giulio Kleiner, Maria J. Sanchez-Quintero, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Varun V. Prabhu, Joshua E. Allen, Markus D. Siegelin
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM). Experimental Design: Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency. Results: Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo. ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3β at serine 9. GSK3β promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells in vitro and in vivo. Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction in vitro and in vivo. Conclusions: These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies. Clin Cancer Res; 24(21); 5392–406. ©2018 AACR.
Association of Digital Media Use With Subsequent Symptoms of Attention-Deficit/Hyperactivity Disorder Among Adolescents
Authors: Chaelin K. Ra, Junhan Cho, Matthew D. Stone, Julianne De La Cerda, Nicholas I. Goldenson, Elizabeth Moroney, Irene Tung, Steve S. Lee, Adam M. Leventhal
Journal: JAMA (2018)

Modern digital platforms are easily accessible and intensely stimulating; it is unknown whether frequent use of digital media may be associated with symptoms of attention-deficit/hyperactivity disorder (ADHD).To determine whether the frequency of using digital media among 15- and 16-year-olds without significant ADHD symptoms is associated with subsequent occurrence of ADHD symptoms during a 24-month follow-up.Longitudinal cohort of students in 10 Los Angeles County, California, high schools recruited through convenience sampling. Baseline and 6-, 12-, 18-, and 24-month follow-up surveys were administered from September 2014 (10th grade) to December 2016 (12th grade). Of 4100 eligible students, 3051 10th-graders (74%) were surveyed at the baseline assessment.Self-reported use of 14 different modern digital media activities at a high-frequency rate over the preceding week was defined as many times a day (yes/no) and was summed in a cumulative index (range, 0-14).Self-rated frequency of 18 ADHD symptoms (never/rare, sometimes, often, very often) in the 6 months preceding the survey. The total numbers of 9 inattentive symptoms (range, 0-9) and 9 hyperactive-impulsive symptoms (range, 0-9) that students rated as experiencing often or very often were calculated. Students who had reported experiencing often or very often 6 or more symptoms in either category were classified as being ADHD symptom-positive.Among the 2587 adolescents (63% eligible students; 54.4% girls; mean [SD] age 15.5 years [0.5 years]) who did not have significant symptoms of ADHD at baseline, the median follow-up was 22.6 months (interquartile range [IQR], 21.8-23.0, months). The mean (SD) number of baseline digital media activities used at a high-frequency rate was 3.62 (3.30); 1398 students (54.1%) indicated high frequency of checking social media (95% CI, 52.1%-56.0%), which was the most common media activity. High-frequency engagement in each additional digital media activity at baseline was associated with a significantly higher odds of having symptoms of ADHD across follow-ups (OR, 1.11; 95% CI, 1.06-1.16). This association persisted after covariate adjustment (OR, 1.10; 95% CI, 1.05-1.15). The 495 students who reported no high-frequency media use at baseline had a 4.6% mean rate of having ADHD symptoms across follow-ups vs 9.5% among the 114 who reported 7 high-frequency activities (difference; 4.9%; 95% CI, 2.5%-7.3%) and vs 10.5% among the 51 students who reported 14 high-frequency activities (difference, 5.9%; 95% CI, 2.6%-9.2%).Among adolescents followed up over 2 years, there was a statistically significant but modest association between higher frequency of digital media use and subsequent symptoms of ADHD. Further research is needed to determine whether this association is causal.
Outrageous prices of orphan drugs: a call for collaboration
Authors: Lucio Luzzatto, Hanna I Hyry, Arrigo Schieppati, Enrico Costa, Steven Simoens, Franz Schaefer, Jonathan C P Roos, Giampaolo Merlini, Helena Kääriäinen, Silvio Garattini, Carla E Hollak, Giuseppe Remuzzi, Tiziano Barbui, Ariela Benigni, Enrico Costa, Erica Daina, Silvio Garattini, Donatella Gramaglia, Carla E M Hollak, Hanna Hyry, Helena Kaarinen, Christoph Licht, Lucio Luzzatto, Giampaolo Merlini, Rosario Notaro, Giuseppe Remuzzi, Franz Schaefer, Arrigo Schieppati, Steven Simoens
Journal: The Lancet (2018)
Association of Transforming Growth Factor β Polymorphism C−509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer
Authors: Aaron J. Grossberg, Xiudong Lei, Ting Xu, Simona F. Shaitelman, Karen E. Hoffman, Elizabeth S. Bloom, Michael C. Stauder, Welela Tereffe, Pamela J. Schlembach, Wendy A. Woodward, Thomas A. Buchholz, Benjamin D. Smith
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed. <h3>Objective</h3> To assess the association between the C−509T variant allele in the promoter region of<i>TGFB1</i>and breast fibrosis 3 years after radiotherapy. <h3>Design, Setting, and Participants</h3> This is an a priori–specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. <h3>Exposures</h3> A C-to-T single-nucleotide polymorphism at position −509 relative to the first major transcription start site (C−509T) of the<i>TGFB1</i>gene. <h3>Main Outcomes and Measures</h3> The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. <h3>Results</h3> Among 287 women enrolled in the trial,<i>TGFB1</i>genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C−509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C−509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%;<i>P</i> = .02). The results of multivariable analyses indicated that only C−509T (odds ratio, 4.47; 95% CI, 1.25-15.99;<i>P</i> = .02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90;<i>P</i> &lt; .001) were significantly associated with breast fibrosis risk. <h3>Conclusions and Relevance</h3> To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C−509T allele in<i>TGFB1</i>is a key determinant of breast fibrosis risk. Assessing<i>TGFB1</i>genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT01266642
Deciphering mechanisms of brain metastasis in melanoma - the gist of the matter
Authors: Torben Redmer
Journal: Molecular Cancer (2018)

Metastasis to distant organs and particularly the brain still represents the most serious obstacle in melanoma therapies. Melanoma cells acquire a phenotype to metastasize to the brain and successfully grow there through complex mechanisms determined by microenvironmental than rather genetic cues. There do appear to be some prerequisites, including the presence of oncogenic BRAF or NRAS mutations and a loss of PTEN. Further mediators of the brain metastatic phenotype appear to be the high activation of the PI3K/AKT or STAT3 pathway or high levels of PLEKHA5 and MMP2 in metastatic cells. A yet undefined subset of brain metastases exhibit a high level of expression of CD271 that is associated with stemness, migration and survival. Hence, CD271 expression may determine specific properties of brain metastatic melanoma cells. Environmental cues – in particular those provided by brain parenchymal cells such as astrocytes - seem to help specifically guide melanoma cells that express CCR4 or CD271, potential "homing receptors". Upon entering the brain, these cells interact with brain parenchyma cells and are thereby reprogrammed to adopt a neurological phenotype. Several lines of evidence suggest that current therapies may have a negative effect by activating a program that drives tumor cells toward stemness and metastasis. Yet significant improvements have expanded the therapeutic options for treating brain metastases from melanoma, by combining potent BRAF inhibitors such as dabrafenib with checkpoint inhibitors or stereotactic surgery. Further progress toward developing new therapeutic strategies will require a more profound understanding of the mechanisms that underlie brain metastasis in melanoma.
Potential impact of implementing and scaling up harm reduction and antiretroviral therapy on HIV prevalence and mortality and overdose deaths among people who inject drugs in two Russian cities: a modelling study
Authors: Javier A Cepeda, Ksenia Eritsyan, Peter Vickerman, Alexandra Lyubimova, Marina Shegay, Veronika Odinokova, Leo Beletsky, Annick Borquez, Matthew Hickman, Chris Beyrer, Natasha K Martin
Journal: The Lancet HIV (2018)
Abstract 15893: The Impact of Different Antiplatelet Agents on Platelet Reactivity and Endothelial Function in Patients After Percutaneous Coronary Intervention
Authors: Evangelos Oikonomou, Gerasimos Siasos, Eleni Kokkou, Marina Zaromitidou, Sotirios Tsalamandris, Miriam Anastasiou, Manolis Vavuranakis, Harilila Ververeli, Kostas Maniatis, Theodoros Zografos, Alexis Antonopoulos, Kostas Mourouzis, Anastasia Giannaki, Dimitris Tousoulis
Journal: Circulation (2016)

Introduction: The use of prasugrel or ticagrelor as part of dual antiplatelet therapy with acetylsalicylic acid after percutaneous coronary intervention (PCI) improves clinical outcomes relative to...