tbuckley/cabot-search huggingface dataset:
Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system
Authors: Jong Bong Lee, Atheer Zgair, Jed Malec, Tae Hwan Kim, Min Gi Kim, Joseph Ali, Chaolong Qin, Wanshan Feng, Manting Chiang, Xizhe Gao, Gregory Voronin, Aimie E. Garces, Chun Long Lau, Ting-Hoi Chan, Amy Hume, Tecashanell M. McIntosh, Fadi Soukarieh, Mohammed Al-Hayali, Elena Cipolla, Hilary M. Collins, David M. Heery, Beom Soo Shin, Sun Dong Yoo, Leonid Kagan, Michael J. Stocks, Tracey D. Bradshaw, Peter M. Fischer, Pavel Gershkovich
Journal: Journal of Controlled Release (2018)

The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.
Abstract 16511: Coronary Artery Calcium and Risk of Death, Dementia and Disability in Older 80+ Year Old Individuals
Authors: Lewis H Kuller, Oscar L Lopez, Rachel H Mackey, Caterina Rosano, James T Becker, Anne B Newman
Journal: Circulation (2012)

We previously reported that extent of coronary artery calcium (CAC) measured in 1998-2000 was an independent predictor of total and coronary heart disease (CHD) mortality and brain magnetic resonance imaging abnormalities among individuals, mean age 80 at the time of their scans. The Cardiovascular Health Study-Cognition Study (CHS-CS) has followed 532 participants to incident dementia from 1998-1999 through 2012. We linked the CHS CAC study and the CHS-CS for 434 (82%) of the 532 participants in the CHS-CS to test the long term effects of CAC on total mortality, CHD death, dementia and disability. There were 97 (23%) blacks and 264 (61%) women. Blacks and women had lower CAC scores than whites and men. Levels of CAC were strongly related to both total and CHD mortality over 12 years of follow up. For women with  100 Agatston score and for men with  100 Agatston score (p 100. Women with lower CAC scores lived longer and prevalence of dementia during lifetime and dementia among those still alive was similar to those with high CAC scores: 44% of women with CAC scores  100 developed incident dementia, 62% (31 of 51) alive with CAC score  100. Few, 33 (12%) of 270 (mean current age of 89), survived free of dementia, disability and instrumental activities of daily living
Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis
Authors: Andrew E. Jaffe, Richard E. Straub, Joo Heon Shin, Ran Tao, Yuan Gao, Leonardo Collado-Torres, Tony Kam-Thong, Hualin S. Xi, Jie Quan, Qiang Chen, Carlo Colantuoni, William S. Ulrich, Brady J. Maher, Amy Deep-Soboslay, Alan J. Cross, Nicholas J. Brandon, Jeffrey T. Leek, Thomas M. Hyde, Joel E. Kleinman, Daniel R. Weinberger
Journal: Nature Neuroscience (2018)
Multicentre trial of a transfemoral mitral valve reconstruction system
Authors: Karl-Heinz Kuck, A. Colombo, O. Alfieri, A. Vahanian, S. Baldus, F. Maisano, G. Nickenig, R. S. von Bardeleben, J. van der Heyden, J. Hausleiter, A. Kerner, C. Tamburino
Journal: European Journal of Heart Failure (2017)
Geographic Disparities in Reported US Amyloidosis Mortality From 1979 to 2015
Authors: Kevin M. Alexander, John Orav, Avinainder Singh, Sophia A. Jacob, Adil Menon, Robert F. Padera, Marie F. Kijewski, Ronglih Liao, Marcelo F. Di Carli, Jacob P. Laubach, Rodney H. Falk, Sharmila Dorbala
Journal: JAMA Cardiology (2018)

Cardiac amyloidosis is an underdiagnosed disease and is highly fatal when untreated. Early diagnosis and treatment with the emerging novel therapies significantly improve survival. A comprehensive analysis of amyloidosis-related mortality is critical to appreciate the nature and distribution of underdiagnosis and improve disease detection.To evaluate the temporal and regional trends in age-adjusted amyloidosis-related mortality among men and women of various races/ethnicities in the United States.In this observational cohort study, death certificate information from the Centers for Disease Control and Prevention's Wide-ranging ONline Data for Epidemiologic Research database and the National Vital Statistics System from 1979 to 2015 was analyzed. A total of 30 764 individuals in the United States with amyloidosis listed as the underlying cause of death and 26 591 individuals with amyloidosis listed as a contributing cause of death were analyzed.Region of residence.Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence.Of the 30 764 individuals with amyloidosis listed as the underlying cause of death, 17 421 (56.6%) were men and 27 312 (88.8%) were 55 years or older. From 1979 to 2015, the reported overall mean age-adjusted mortality rate from amyloidosis as the underlying cause of death doubled from 1.77 to 3.96 per 1 000 000 population (2.32 to 5.43 in men and 1.35 to 2.80 in women). Black men had the highest mortality rate (12.36 per 1 000 000), followed by black women (6.48 per 1 000 000). Amyloidosis contributed to age-adjusted mortality rates as high as 31.73 per 1 000 000 in certain counties. Most southern states reported the lowest US mortality rates despite having the highest proportions of black individuals.The increased reported mortality over time and in proximity to amyloidosis centers more likely reflects an overall increase in disease diagnosis rather than increased lethality. The reported amyloidosis mortality is highly variable in different US regions. The lack of higher reported mortality rates in states with a greater proportion of black residents suggests underdiagnosis of amyloidosis, including cardiac forms of the disease, in many areas of the United States. Better understanding of the determinants of geographic and racial disparity in the reporting of amyloidosis deaths are warranted.
Connecting the in vitro and in vivo experiments in electrochemotherapy - a feasibility study modeling cisplatin transport in mouse melanoma using the dual-porosity model
Authors: Janja Dermol-Černe, Janja Vidmar, Janez Ščančar, Katja Uršič, Gregor Serša, Damijan Miklavčič
Journal: Journal of Controlled Release (2018)
Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock
Authors: Jason L. Sperry, Francis X. Guyette, Joshua B. Brown, Mark H. Yazer, Darrell J. Triulzi, Barbara J. Early-Young, Peter W. Adams, Brian J. Daley, Richard S. Miller, Brian G. Harbrecht, Jeffrey A. Claridge, Herb A. Phelan, William R. Witham, A. Tyler Putnam, Therese M. Duane, Louis H. Alarcon, Clifton W. Callaway, Brian S. Zuckerbraun, Matthew D. Neal, Matthew R. Rosengart, Raquel M. Forsythe, Timothy R. Billiar, Donald M. Yealy, Andrew B. Peitzman, Mazen S. Zenati
Journal: New England Journal of Medicine (2018)

After a person has been injured, prehospital administration of plasma in addition to the initiation of standard resuscitation procedures in the prehospital environment may reduce the risk of downstream complications from hemorrhage and shock. Data from large clinical trials are lacking to show either the efficacy or the risks associated with plasma transfusion in the prehospital setting.
Case 22-2018: A 64-Year-Old Man with Progressive Leg Weakness, Recurrent Falls, and Anemia
Authors: Susan E. Bennett, William P. Schmitt, Fatima C. Stanford, Jason M. Baron
Journal: New England Journal of Medicine (2018)

A 64-year-old man was admitted to the hospital because of recurrent falls. He had proximal muscle weakness, orthostatic hypotension, and anemia. By hospital day 2, the muscle weakness had improved but orthostatic hypotension persisted. A diagnostic test was performed.
TRPM7-Mediated Ca2+ Signals Confer Fibrogenesis in Human Atrial Fibrillation
Authors: JianyangDu, JiaXie, ZhengZhang, HirotoTsujikawa, DanielFusco, DavidSilverman, BruceLiang, LixiaYue
Journal: Circulation Research (2010)

Rationale: Cardiac fibrosis contributes to pathogenesis of atrial fibrillation (AF), which is the most commonly sustained arrhythmia and a major cause of morbidity and mortality. Although it has been suggested that Ca2+ signals are involved in fibrosis promotion, the molecular basis of Ca2+ signaling mechanisms and how Ca2+ signals contribute to fibrogenesis remain unknown. Objective: To determine the molecular mechanisms of Ca2+-permeable channel(s) in human atrial fibroblasts, and to investigate how Ca2+ signals contribute to fibrogenesis in human AF. Methods and Results: We demonstrate that the transient receptor potential (TRP) melastatin related 7 (TRPM7) is the molecular basis of the major Ca2+-permeable channel in human atrial fibroblasts. Endogenous TRPM7 currents in atrial fibroblasts resemble the biophysical and pharmacological properties of heterologous expressed TRPM7. Knocking down TRPM7 by small hairpin RNA largely eliminates TRPM7 current and Ca2+ influx in atrial fibroblasts. More importan...
Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis
Authors: Stephen Hanauer, Remo Panaccione, Silvio Danese, Adam Cheifetz, Walter Reinisch, Peter D.R. Higgins, Deborah A. Woodworth, Haiying Zhang, Gary S. Friedman, Nervin Lawendy, Daniel Quirk, Chudy I. Nduaka, Chinyu Su
Journal: Clinical Gastroenterology and Hepatology (2018)

Tofacitinib is an oral, small molecule inhibitor of JAK for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post-hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2).The studies comprised patients with moderate to severe active UC who were intolerant to, or failed by previous treatment with, corticosteroids, thiopurines, and/or tumor necrosis factor (TNF) antagonists. Patients received tofacitinib (10 mg twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo stool frequency and rectal bleeding subscores were calculated using diary data from the first 15 days of therapy. We analyzed data from subgroups including failure of prior anti-TNF therapy, baseline corticosteroid use, and baseline serum levels of C-reactive protein.Mean changes were significantly greater in patients given tofacitinib vs placebo in reductions from baseline stool frequency subscore (tofacitinib: -0.27 vs placebo: -0.11; P < .01), total number of daily bowel movements (-1.06 vs -0.27; P < .0001), and rectal bleeding subscore (-0.30 vs -0.14; P < .01) by day 3. Compared with placebo, more tofacitinib-treated patients had reductions from baseline in stool frequency subscore (by ≥1 point for tofacitinib, 241/837, 28.8% vs placebo, 39/218, 17.9%) (P < .01) and rectal bleeding subscore (by ≥1 point for tofacitinib, 266/830, 32.0% vs placebo, 43/214, 20.1%) (P < .01) by day 3. A consistent effect of tofacitinib was observed in all subgroups.In a post-hoc analysis of data from phase 3 trials of induction therapy with tofacitinib in patients with UC, we found significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days. These findings indicate the rapid onset of effect of this drug in patients with UC. ClinicalTrials.gov no: NCT01465763 and NCT01458951.
No Evidence of Transdifferentiation of Human Endothelial Progenitor Cells Into Cardiomyocytes After Coculture With Neonatal Rat Cardiomyocytes
Authors: InaGruh, JaninaBeilner, UlrikeBlomer, AndreasSchmiedl, IngridSchmidt-Richter, Marie-LuiseKruse, AxelHaverich, UlrichMartin
Journal: Circulation (2006)

Background— Recent studies have suggested the differentiation of human endothelial progenitor cells (huEPCs) isolated from peripheral blood into cardiomyocytes. This study investigates whether, when cocultured, neonatal rat cardiomyocytes (NRCMs) can induce transdifferentiation of huEPCs into cardiomyocytes. Methods and Results— Coculture experiments with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine (DiI)–labeled huEPCs and NRCMs have been performed. Cocultures have been analyzed by means of flow cytometry, 3D confocal laser microscopy, species-specific reverse transcriptase–polymerase chain reaction for the expression of human cardiac marker genes, and electron microscopy. Although fluorescence-activated cell sorting (FACS) analysis and conventional wide-field fluorescence microscopy suggested the existence of DiIpos cardiomyocytes in cocultures, no convincing evidence of cardiac differentiation of huEPCs has been obtained. Apparently, DiIpos cardiomyocytes were identified as necrotic NRCMs or ...
Long‐term evaluation of a fully magnetically levitated circulatory support device for advanced heart failure—two‐year results from the HeartMate 3 CE Mark Study
Authors: Jan D. Schmitto, Yuriy Pya, Daniel Zimpfer, Thomas Krabatsch, Jens Garbade, Vivek Rao, Michiel Morshuis, Friedhelm Beyersdorf, Silvana Marasco, Poornima Sood, Laura Damme, Ivan Netuka
Journal: European Journal of Heart Failure (2018)
Stereotactic Body Radiation Therapy as an Alternative Treatment for Patients with Hepatocellular Carcinoma Compared to Sorafenib: A Propensity Score Analysis
Authors: Dominik Bettinger, David J. Pinato, Michael Schultheiss, Rohini Sharma, Lorenza Rimassa, Tiziana Pressiani, Michela E. Burlone, Mario Pirisi, Masatoshi Kudo, Joong Won Park, Nico Buettner, Christoph Neumann-Haefelin, Tobias Boettler, Nasrin Abbasi-Senger, Horst Alheit, Wolfgang Baus, Oliver Blanck, Sabine Gerum, Mathias Guckenberger, Daniel Habermehl, Christian Ostheimer, Oliver Riesterer, Jörg Tamihardja, Anca-Ligia Grosu, Robert Thimme, Thomas Baptist Brunner, Eleni Gkika
Journal: Liver Cancer (2018)

Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC.We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival.Median OS of SBRT patients was 18.1 (10.3-25.9) months compared to 8.8 (8.2-9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8-23.2) months compared to 9.6 (8.6-10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT.In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.
mTOR Inhibition via Displacement of Phosphatidic Acid Induces Enhanced Cytotoxicity Specifically in Cancer Cells
Authors: Tra-Ly Nguyen, Marie-Julie Nokin, Maxim Egorov, Mercedes Tomé, Clément Bodineau, Carmelo Di Primo, Lætitia Minder, Joanna Wdzieczak-Bakala, Maria Concepcion Garcia-Alvarez, Jérôme Bignon, Odile Thoison, Bernard Delpech, Georgiana Surpateanu, Yves-Michel Frapart, Fabienne Peyrot, Kahina Abbas, Silvia Terés, Serge Evrard, Abdel-Majid Khatib, Pierre Soubeyran, Bogdan I. Iorga, Raúl V. Durán, Pascal Collin
Journal: Cancer Research (2018)

The mTOR is a central regulator of cell growth and is highly activated in cancer cells to allow rapid tumor growth. The use of mTOR inhibitors as anticancer therapy has been approved for some types of tumors, albeit with modest results. We recently reported the synthesis of ICSN3250, a halitulin analogue with enhanced cytotoxicity. We report here that ICSN3250 is a specific mTOR inhibitor that operates through a mechanism distinct from those described for previous mTOR inhibitors. ICSN3250 competed with and displaced phosphatidic acid from the FRB domain in mTOR, thus preventing mTOR activation and leading to cytotoxicity. Docking and molecular dynamics simulations evidenced not only the high conformational plasticity of the FRB domain, but also the specific interactions of both ICSN3250 and phosphatidic acid with the FRB domain in mTOR. Furthermore, ICSN3250 toxicity was shown to act specifically in cancer cells, as noncancer cells showed up to 100-fold less sensitivity to ICSN3250, in contrast to other mTOR inhibitors that did not show selectivity. Thus, our results define ICSN3250 as a new class of mTOR inhibitors that specifically targets cancer cells.Significance: ICSN3250 defines a new class of mTORC1 inhibitors that displaces phosphatidic acid at the FRB domain of mTOR, inducing cell death specifically in cancer cells but not in noncancer cells. Cancer Res; 78(18); 5384-97. ©2018 AACR.
CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment
Authors: Clare Y. Slaney, Pin Wang, Phillip K. Darcy, Michael H. Kershaw
Journal: Cancer Discovery (2018)

The redirection of T cells against tumors holds much promise for the treatment of cancer. Two main approaches for T-cell redirection involve their genetic modification with chimeric antigen receptors (CAR), or the use of recombinant proteins designated bispecific T-cell engagers (BiTE). These approaches have demonstrated dramatic effects in patients with hematologic cancers, although limited effect against solid cancers. Here, we review and compare the successes and challenges of these two types of immunotherapies, with special focus on their mechanisms, and discuss strategies to improve their efficacy against cancer.Significance: CAR and BiTE cancer therapies have generated much excitement, but although the therapies are potentially competitive, information directly comparing the two is difficult to obtain. Here, we present the fundamentals of each approach and compare the range and level of functions they can elicit from T cells, and their efficacy against cancers. Cancer Discov; 8(8); 924-34. ©2018 AACR.
Nox4 as the Major Catalytic Component of an Endothelial NAD(P)H Oxidase
Authors: TetsuroAgo, TakanariKitazono, HiroakiOoboshi, TeruakiIyama, Youn HeeHan, JunichiTakada, MasanoriWakisaka, SetsuroIbayashi, HideoUtsumi, MitsuoIida
Journal: Circulation (2004)

Background— Recent evidence has suggested that reactive oxygen species are important signaling molecules in vascular cells and play a pivotal role in the development of vascular diseases. The activity of NAD(P)H oxidase has been identified as the major source of reactive oxygen species in vascular endothelial cells. However, the precise molecular structure and the mechanism of activation of the oxidase have remained poorly understood. Methods and Results— Here, we investigated the molecular identities and the superoxide-producing activity of endothelial NAD(P)H oxidase. We found that Nox4, a homologue of gp91phox/Nox2, was abundantly expressed in endothelial cells. The expression of Nox4 in endothelial cells markedly exceeded that of other Nox proteins, including gp91phox/Nox2, and was affected by cell growth. Using electron spin resonance and chemiluminescence, we measured the superoxide production and found that the endothelial membranes had an NAD(P)H-dependent superoxide-producing activity comparable ...
Subacromial decompression versus diagnostic arthroscopy for shoulder impingement: randomised, placebo surgery controlled clinical trial
Authors: Mika Paavola, Antti Malmivaara, Simo Taimela, Kari Kanto, Jari Inkinen, Juha Kalske, Ilkka Sinisaari, Vesa Savolainen, Jonas Ranstam, Teppo L N Järvinen
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To assess the efficacy of arthroscopic subacromial decompression (ASD) by comparing it with diagnostic arthroscopy, a placebo surgical intervention, and with a non-operative alternative, exercise therapy, in a more pragmatic setting. <h3>Design</h3> Multicentre, three group, randomised, double blind, sham controlled trial. <h3>Setting</h3> Orthopaedic departments at three public hospitals in Finland. <h3>Participants</h3> 210 patients with symptoms consistent with shoulder impingement syndrome, enrolled from 1 February 2005 with two year follow-up completed by 25 June 2015. <h3>Interventions</h3> ASD, diagnostic arthroscopy (placebo control), and exercise therapy. <h3>Main outcome measures</h3> Shoulder pain at rest and on arm activity (visual analogue scale (VAS) from 0 to 100, with 0 denoting no pain), at 24 months. The threshold for minimal clinically important difference was set at 15. <h3>Results</h3> In the primary intention to treat analysis (ASD versus diagnostic arthroscopy), no clinically relevant between group differences were seen in the two primary outcomes at 24 months (mean change for ASD 36.0 at rest and 55.4 on activity; for diagnostic arthroscopy 31.4 at rest and 47.5 on activity). The observed mean difference between groups (ASD minus diagnostic arthroscopy) in pain VAS were −4.6 (95% confidence interval −11.3 to 2.1) points (P=0.18) at rest and −9.0 (−18.1 to 0.2) points (P=0.054) on arm activity. No between group differences were seen between the ASD and diagnostic arthroscopy groups in the secondary outcomes or adverse events. In the secondary comparison (ASD versus exercise therapy), statistically significant differences were found in favour of ASD in the two primary outcomes at 24 months in both VAS at rest (−7.5, −14.0 to −1.0, points; P=0.023) and VAS on arm activity (−12.0, −20.9 to −3.2, points; P=0.008), but the mean differences between groups did not exceed the pre-specified minimal clinically important difference. Of note, this ASD versus exercise therapy comparison is not only confounded by lack of blinding but also likely to be biased in favour of ASD owing to the selective removal of patients with likely poor outcome from the ASD group, without comparable exclusions from the exercise therapy group. <h3>Conclusions</h3> In this controlled trial involving patients with a shoulder impingement syndrome, arthroscopic subacromial decompression provided no benefit over diagnostic arthroscopy at 24 months. <h3>Trial registration</h3> Clinicaltrials.gov NCT00428870.