tbuckley/cabot-search huggingface dataset:
Should exercise be considered as an alternative to drug treatment in patients with low-risk mild hypertension?
Authors: James P Sheppard
Journal: British Journal of Sports Medicine (2019)

High blood pressure affects one in five adults globally1 and is a major risk factor for cardiovascular disease. Clinical guidelines have traditionally recommended that patients with a sustained clinic blood pressure of ≥140/90 mm Hg be considered for lifestyle or pharmacological intervention, depending on their underlying risk of cardiovascular disease.2 However, recent guidelines from the American College of Cardiology/American Heart Association (ACC/AHA)3 recommended that doctors begin antihypertensive treatment at lower thresholds, based on the results from the Systolic Blood Pressure Intervention Trial (SPRINT).4 This study showed that aggressive treatment to systolic levels below 120 mm Hg can reduce the risk of cardiovascular disease compared with standard targets.4 These recommendations are controversial because they apply the results from a trial which enrolled high-risk individuals, to much larger populations of low-risk patients where there is, as yet, no evidence to support prescription of antihypertensive treatment. Indeed, for patients with low cardiovascular disease risk and ‘mild’ hypertension (ie, sustained blood pressure between 140/90 and 159/99 mm Hg), …
Abstract 13381: Changes in Quality of Life and Utility in Patients with Cardiovascular Disease: A Comparison of Trajectories
Authors: Paul Kolm, Zugui Zhang, John A Spertus, Claudine T Jurkovitz, William S Weintraub
Journal: Circulation (2010)

Background: Patients' perceptions of health-related quality of life (HRQOL) and utility have become important data to collect in clinical trials and patient registries. We examined the longitudinal...
A nasobiliary drain connected to a waterjet system to facilitate endoscopic ultrasound-guided gastrojejunostomy
Authors: Marion Schaefer, Abdelkader Taibi, Hugo Lepetit, Romain Legros, Sylvaine Durand-Fontanier, Mathieu Pioche, Jérémie Jacques
Journal: Endoscopy (2019)

Gastric outlet obstruction (GOO) reduces quality of life and compromises nutrition. Duodenal stenting is the first-line treatment but does not completely relieve symptoms. Surgical gastrojejunostomy improves the quality of life in patients who are expected to survive for a long time. In patients with benign conditions such as chronic pancreatitis, duodenal stents are ineffective (being associated with high migration rates), and surgical gastrojejunostomy is both difficult and risky because of the significant malnutrition and frequent portal hypertension attributable to portosplenic thromboses. Recently, endoscopic ultrasound (EUS)-guided gastrojejunostomy using electrocautery to place a lumen-apposing metal stent has emerged as a new minimally invasive procedure.
Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer
Authors: Dong Mei, Binlong Chen, Bing He, Haibin Liu, Zhiqiang Lin, Jialiang Lin, Xiaoyan Zhang, Ning Sun, Libo Zhao, Xiaoling Wang, Qiang Zhang
Journal: Acta Pharmaceutica Sinica B (2019)

Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target (mTOR), inhibition of which could result in autophagic cell death (ACD). Though novel combination chemotherapy of autophagy inducers with chemotherapeutic agents is extensively investigated, nanomedicine-based combination therapy for ACD remains in infancy. In attempt to actively trigger ACD for synergistic chemotherapy, here we incorporated autophagy inducer rapamycin (RAP) into 7pep-modified PEG-DSPE polymer micelles (7pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor (TfR). Cytotoxic paclitaxel (PTX)-loaded micelle (7pep-M-PTX) was regarded as chemotherapeutic drug model. We discovered that with superior intracellular uptake in vitro and more tumor accumulation of micelles in vivo, 7pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7pep-M-PTX. Mechanism study further revealed that 7pep-M-RAP and 7pep-M-PTX used in combination provided enhanced efficacy through induction of both apoptosis- and mitochondria-associated autophagic cell death. Together, our findings suggested that the targeted excess autophagy may provide a rational strategy to improve therapeutic outcome of breast cancer, and simultaneous induction of ACD and apoptosis may be a promising anticancer modality.
Effect of green tea polyphenol EGCG on COX-2 expression in human colon cancer cells
Authors: Guang Peng, Dan A. Dixon, Theresa J. Smith, Michael J. Wargovich
Journal: Cancer Research (2005)

5211  Tea, one of the most widely consumed beverages worldwide, has been shown to have anti-cancer activity in various cancers including colon cancer. It has been demonstrated that overexpression of cyclooxygenase (COX-2) occurs during colon tumorigenesis and inhibition of COX-2 by NSAIDs is chemopreventive. To determine whether the anti-cancer effect of green tea is associated with the alteration of COX-2 expression, human colon cancer cell lines HT-29 and HCA-7, which constitutively express COX-2, were treated with various concentrations of (-)-epigallocatechin-3-gallate (EGCG), the most abundant and effective polyphenol of green tea. We found that EGCG inhibited cell growth in both cell lines. Furthermore, EGCG treatment significantly attenuated PGE2 synthesis that correlated with decreased COX-2 mRNA and protein expression. We further investigated the mechanism responsible for EGCG dependent regulation of COX-2 gene expression. Luciferase reporter constructs indicated that EGCG inhibited COX-2 promoter activity and decreased mRNA stability through the COX-2 3’UTR, suggesting that EGCG regulates COX-2 expression at both transcriptional and posttranscriptional levels. The signaling pathways related to the inhibitory effect of EGCG on COX-2 expression were determined. We observed that EGCG inhibited the constitutive activation of ERK1/2 and Akt in colon cancer cells. In contrast, EGCG slightly activated p38. Different effects of EGCG on signaling transduction pathways led us to examine their downstream transcription factors. Electrophoretic mobility shift assay (EMSA) demonstrated that EGCG decreased activator protein 1 (AP-1) and nuclear factor κB (NF-κB) DNA binding activity. In conclusion, these data demonstrate that EGCG inhibits constitutive COX-2 gene expression at both transcriptional and post-transcriptional levels in colon cancer cells. This data provides a mechanism for the anti-proliferative effect of green tea and implies that dietary factors have the potential to be anti-cancer agents.
Functional networks are impaired by elevated tau-protein but reversible in a regulatable Alzheimer’s disease mouse model
Authors: Claudia Green, Astrid Sydow, Stefanie Vogel, Marta Anglada-Huguet, Dirk Wiedermann, Eckhard Mandelkow, Eva-Maria Mandelkow, Mathias Hoehn
Journal: Molecular Neurodegeneration (2019)

Aggregation of tau proteins is a distinct hallmark of tauopathies and has been a focus of research and clinical trials for Alzheimer's Disease. Recent reports have pointed towards a toxic effect of soluble or oligomeric tau in the spreading of tau pathology in Alzheimer's disease. Here we investigated the effects of expressing human tau repeat domain (tauRD) with pro- or anti-aggregant mutations in regulatable transgenic mouse models of Alzheimer's Disease on the functional neuronal networks and the structural connectivity strength.Pro-aggregant and anti-aggregant mice were studied when their mutant tauRD was switched on for 12 months to reach the stage where pro-aggregant mice show cognitive impairment, whereas anti-aggregant mice remained cognitively normal. Then, mutant tauRD was switched off by doxycycline treatment for 8 weeks so that soluble transgenic tau disappeared and cognition recovered in the pro-aggregant mice, although some aggregates remained. At these two time points, at baseline after 12 months of mutant tau expression and after 8 weeks of doxycycline treatment, resting state fMRI and diffusion MRI were used to determine functional neuronal networks and fiber connectivities. Results of the transgenic mice were compared with wildtype littermates.Functional connectivity was strongly reduced in transgenic animals during mutant tauRD expression, in relation to WT mice. Interestingly, transgenic mice with the non-aggregant tau mutant showed identical functional deficits as the pro-aggregant mice, even though in this case there was no cognitive decline by behavioral testing. Upon 8 weeks doxycycline treatment and transgene switch-off, functional connectivity in both transgenic groups presented complete normalization of functional connectivity strength, equivalent to the situation in WT littermates. Structural connectivity was found only marginally sensitive to mutant tau expression (both pro- and anti-aggregant tauRD) and by doxycycline treatment.Our in vivo investigations unravel for the first time a strong reduction of functional neuronal networks by the presence of increased soluble rather than fibrillary tau, independent of its intrinsic propensity of aggregation, which is reversible by switching tau off. Our functional MRI study thus is an unexpected in vivo validation of a novel property of tau, while previous results pointed to a role of aggregation propensity for a pathological state by histopathology and cognitive decline. Our results present further evidence for early tauopathy biomarkers or a potential early stage drug target by functional networks analysis.
Confidence intervals in dermatology
Authors: Z.H. Hopkins, C. Moreno, A.M. Secrest
Journal: British Journal of Dermatology (2019)

This study from the U.S.A. aimed to find out how often confidence intervals are used when reporting dermatology research. Confidence intervals relate to two values (‘intervals’) that the researchers, using data analysis, believe that the actual, true value will fall within. A 95% confidence interval indicates that if an experiment were repeated 100 times, and a 95% confidence interval was calculated each time, 95 of the intervals would contain the true value while five of the intervals would not contain the true value. A confidence interval might be used when you want to estimate something about a very large number of people, and can therefore only use a sample of those people. For example, if you want to know how many people in the UK have dry skin, you cannot ask every person, so you use a sample and then calculate a range for the mean number of people in your sample who have dry skin. As the sample is never going to be an exact representation of the whole population, you might say that you are 95% confident that the mean number of people in the UK with dry skin is, for example, between 20% and 30%. Confidence intervals help readers understand both the statistical significance and the clinical significance more easily. Most modern statistical software packages conveniently calculate confidence intervals and provide an intuitive way to understand study results. The authors collected dermatology articles from a variety of major dermatology journals as well as dermatology articles from the New England Journal of Medicine over the past decade. The authors found that reporting of this important metric is disappointingly low in dermatology journals, with only 1 in 5 articles containing confidence intervals, which was significantly lower than reporting in the New England Journal of Medicine. Articles published more recently were more likely to report confidence intervals. After controlling for factors like type of study and year of publication, the New England Journal of Medicine still reported confidence intervals more frequently. This is likely due to their extremely rigorous statistical peer review process. While such strict requirements cannot be adopted by all journals, increased awareness of this simple metric could significantly improve the statistical reporting of the dermatology literature. We urge dermatology researchers to include this important metric in their findings. Likewise, we recommend improved statistical training as part of dermatology residency training.
Thermoresponsive Stiffness Softening of Hierarchically Porous Nanohybrid Membranes Promotes Niches for Mesenchymal Stem Cell Differentiation
Authors: Linxiao Wu, Adrián Magaz, Arnold Darbyshire, Ashley Howkins, Alan Reynolds, Ian W. Boyd, Hang Song, Jin‐Hua Song, Marilena Loizidou, Mark Emberton, Martin Birchall, Wenhui Song
Journal: Advanced Healthcare Materials (2019)

Abstract Despite the attention given to the development of novel responsive implants for regenerative medicine applications, the lack of integration with the surrounding tissues and the mismatch with the dynamic mechanobiological nature of native soft tissues remain in the current products. Hierarchical porous membranes based on a poly (urea–urethane) (PUU) nanohybrid have been fabricated by thermally induced phase separation (TIPS) of the polymer solution at different temperatures. Thermoresponsive stiffness softening of the membranes through phase transition from the semicrystalline phase to rubber phase and reverse self‐assembly of the quasi‐random nanophase structure is characterized at body temperature near the melting point of the crystalline domains of soft segments. The effects of the porous structure and stiffness softening on proliferation and differentiation of human bone‐marrow mesenchymal stem cells (hBM‐MSCs) are investigated. The results of immunohistochemistry, histological, ELISA, and qPCR demonstrate that hBM‐MSCs maintain their lineage commitment during stiffness relaxation; chondrogenic differentiation is favored on the soft and porous scaffold, while osteogenic differentiation is more prominent on the initial stiff one. Stiffness relaxation stimulates more osteogenic activity than chondrogenesis, the latter being more influenced by the synergetic coupling effect of softness and porosity.
IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival
Authors: Saikat Majumder, Nilesh Amatya, Shankar Revu, Chetan V. Jawale, Dongwen Wu, Natalie Rittenhouse, Ashley Menk, Saran Kupul, Fang Du, Itay Raphael, Amrita Bhattacharjee, Ulrich Siebenlist, Timothy W. Hand, Greg M. Delgoffe, Amanda C. Poholek, Sarah L. Gaffen, Partha S. Biswas, Mandy J. McGeachy
Journal: Nature Immunology (2019)
Is it time to move away from short-acting beta-agonists in asthma management?
Authors: Matthew J. Martin, Tim W. Harrison
Journal: European Respiratory Journal (2019)

<b>Frequent SABA use is associated with adverse asthma outcomes and evidence suggests replacing SABA with fast-acting LABA/ICS as reliever therapy reduces asthma exacerbation risk. We believe the time has come to move away from SABAs in asthma management.</b>http://ow.ly/87UJ30nVGNc
Coupling of the Na+/K+-ATPase to Ankyrin B controls Na+/Ca2+ exchanger activity in cardiomyocytes
Authors: Jonas Skogestad, Jan Magnus Aronsen, Nils Tovsrud, Pimthanya Wanichawan, Karina Hougen, Mathis Korseberg Stokke, Cathrine Rein Carlson, Ivar Sjaastad, Ole Mathias Sejersted, Fredrik Swift
Journal: Cardiovascular Research (2019)

Abstract Aims Ankyrin B (AnkB) is an adaptor protein that assembles Na+/K+-ATPase (NKA) and Na+/Ca2+ exchanger (NCX) in the AnkB macromolecular complex. Loss-of-function mutations in AnkB cause the AnkB syndrome in humans, characterized by ventricular arrhythmias and sudden cardiac death. It is unclear to what extent NKA binding to AnkB allows regulation of local Na+ and Ca2+ domains and hence NCX activity. Methods and results To investigate the role of NKA binding to AnkB in cardiomyocytes, we synthesized a disruptor peptide (MAB peptide) and its AnkB binding ability was verified by pulldown experiments. As opposed to control, the correlation between NKA and NCX currents was abolished in adult rat ventricular myocytes dialyzed with MAB peptide, as well as in cardiomyocytes from AnkB+/− mice. Disruption of NKA from AnkB (with MAB peptide) increased NCX-sensed cytosolic Na+ concentration, reduced Ca2+ extrusion through NCX, and increased frequency of Ca2+ sparks and Ca2+ waves without concomitant increase in Ca2+ transient amplitude or SR Ca2+ load, suggesting an effect in local Ca2+ domains. Selective inhibition of the NKAα2 isoform abolished both the correlation between NKA and NCX currents and the increased rate of Ca2+ sparks and waves following NKA/AnkB disruption, suggesting that an AnkB/NKAα2/NCX domain controls Ca2+ fluxes in cardiomyocytes. Conclusion NKA binding to AnkB allows ion regulation in a local domain, and acute disruption of the NKA/AnkB interaction using disruptor peptides lead to increased rate of Ca2+ sparks and waves. The functional effects were mediated through the NKAα2 isoform. Disruption of the AnkB/NKA/NCX domain could be an important pathophysiological mechanism in the AnkB syndrome.
Ultra-sensitive <i>EGFR</i>T790M Detection as an Independent Prognostic Marker for Lung Cancer Patients Harboring <i>EGFR</i>del19 Mutations and Treated with First-generation TKIs
Authors: Julie A. Vendrell, Julien Mazieres, Romain Senal, Isabelle Rouquette, Xavier Quantin, Jean-Louis Pujol, Benoit Roch, Abdelali Bouidioua, Sylvain Godreuil, Etienne Coyaud, Pierre Brousset, Jérôme Solassol
Journal: Clinical Cancer Research (2019)

The detection of preexisting EGFRT790M subclones and the assessment of their clinical significance in the pretreatment of patients with EGFRT790M non-small cell lung cancer (NSCLC) remain unclear.A total of 179 tumor samples from patients treated or not with a first-generation tyrosine kinase inhibitor (TKI) was analyzed. The presence of ultra-low levels of preexisting EGFRT790M mutation was evaluated using ultra-sensitive droplet digital PCR (ddPCR) and the clinical implication of these mutations on first-generation TKI efficiency assessed.With a ddPCR linear performance of 0.999 and an analytical sensitivity of approximately 0.001%, we observed a 66% (99/150) overall incidence of ultra-low EGFRT790M mutation. Among 82 patients harboring EGFRactivating mutations, the presence of a preexisting EGFRT790M mutation prior to any treatment was significantly associated with a longer progression-free survival (PFS; P = 0.009; log-rank test). Interestingly, longer PFS was linked to concomitant EGFRdel19 and ultra-low EGFRT790M mutations. Moreover, the presence of both EGFRdel19 and ultra-low EGFRT790M mutations was identified as the best fit for predicting the clinical outcome of patients treated with TKI compared with an ultra-low EGFRT790M mutation status or an activating mutation alone (P = 0.042 and P = 0.0071, respectively).We demonstrate that the detection of the ultra-low EGFRT790M mutation in TKI-naïve patients is not a rare event. We suggest that ddPCR should be used in clinical practice to distinguish patients who may respond to first- or third-generation TKIs.
Evaluating the role of Id-1 in lung cancer.
Authors: Raka Bhattacharya, Rhoda Alani
Journal: Cancer Research (2008)

4400  Id-1 (inhibitor of differentiation/ DNA binding) is a helix-loop-helix transcription factor that is normally expressed during development and embryogenesis while lacking in most adult tissues. Recent studies have associated the over-expression of Id1 with highly aggressive, less-differentiated tumor types and a propensity for tumor metastasis. A striking correlation between elevated levels of Id-1 and tumor progression is observed in several cancers, however, not much is known about Id-1 in lung cancer. The aim of this study is to investigate the role of Id-1 in lung cancer, specifically in non small cell lung cancer (NSCLC).  Our preliminary data demonstrate that many of the patients treated at Johns Hopkins for lung cancer have elevated levels of Id1 in cancerous tissue relative to surrounding normal tissue as shown by Quantitative Real-Time Polymerase Chain Reaction (q-RT-PCR). Most of these patients have either adenocarcinoma or squamous cell carcinoma and are either smokers or exposed to second hand smoke. We have used q-RT-PCR to evaluate the expression level of Id1 in primary lung cancer samples at various stages of malignant progression in order to determine whether Id1 expression is an early, intermediate, or late event. Our data shows that Id1 expression is found at an early stage of the disease in patients that later present with metastasis to the lymph nodes. At present, we are also establishing a correlation between Id1 expression and aggressive forms of the disease by looking at various histopathologic subtypes and grades of lung cancer using immunohistochemistry and in situ hybridization. We have also shown that most NSCLC express elevated levels of Id1 when grown in media containing fetal bovine serum (FBS). This serum responsiveness suggests growth-factor dependent Id1 expression. We are currently evaluating the specific effects of Id1 on tumor cell growth, invasiveness and metastasis by upregulating its expression using a bicistronic lentiviral Id1 construct with GFP marker in lung cells that have low or no Id1 expression. Thus, our studies to date suggests that Id-1 may be involved in the development and progression of lung cancer associated with tobacco smoke exposure. Additional studies aimed at identifying Id1 target genes in pre-malignant lung cells will allow us to better define the molecular pathways altered by Id1 expression in lung cancer. Ultimately, we expect to determine whether Id-1 will be a useful biomarker for lung cancer and whether inactivating Id1 or its downstream effectors will be a useful therapeutic strategy in certain subtypes of lung cancer.
Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness
Authors: Jingxia Wu, Sicong Ma, Roger Sandhoff, Yanan Ming, Agnes Hotz-Wagenblatt, Vincent Timmerman, Nathalie Bonello-Palot, Beate Schlotter-Weigel, Michaela Auer-Grumbach, Pavel Seeman, Wolfgang N. Löscher, Markus Reindl, Florian Weiss, Eric Mah, Nina Weisshaar, Alaa Madi, Kerstin Mohr, Tilo Schlimbach, Rubí M.-H. Velasco Cárdenas, Jonas Koeppel, Florian Grünschläger, Lisann Müller, Maren Baumeister, Britta Brügger, Michael Schmitt, Guido Wabnitz, Yvonne Samstag, Guoliang Cui
Journal: Immunity (2019)
Efficacy of a New Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) in Preclinical Models of B-Cell Lymphoma and Acute Myeloid Leukemia
Authors: Montserrat Perez-Salvia, Aldaba Eneko, Vara Yosu, Fabre Myriam, Ferrer Cristina, Masdeu Carme, Zubia Aizpea, San Sebastian Eider, Otaegui Dorleta, Llinàs-Arias Pere, Rosselló-Tortella Margalida, Berdasco Maria, Setien Fernando, Moutinho Catia, Villanueva Alberto, Eva González-Barca, Josep Muncunill, Jose Tomas Navarro, Miguel Angel Piris, Cossio Fernando, Manel Esteller
Journal: Blood (2018)
Neutrophil Extracellular Traps Confine Pseudomonas aeruginosa Ocular Biofilms and Restrict Brain Invasion
Authors: Ajitha Thanabalasuriar, Brittney Noelle Vivian Scott, Moritz Peiseler, Michelle Elizabeth Willson, Zhutian Zeng, Paul Warrener, Ashley Elaine Keller, Bas Gerardus Johannes Surewaard, Elizabeth Ashley Dozier, Juha Tapio Korhonen, Lily I-ting Cheng, Mihaela Gadjeva, C. Kendall Stover, Antonio DiGiandomenico, Paul Kubes
Journal: Cell Host & Microbe (2019)