tbuckley/cabot-search huggingface dataset:
CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow
Authors: Ayako Nakamura-Ishizu, Keiyo Takubo, Hiroshi Kobayashi, Katsue Suzuki-Inoue, Toshio Suda
Journal: The Journal of Experimental Medicine (2015)

Hematopoietic stem cells (HSCs) depend on the bone marrow (BM) niche for their maintenance, proliferation, and differentiation. The BM niche is composed of nonhematopoietic and mature hematopoietic cells, including megakaryocytes (Mks). Thrombopoietin (Thpo) is a crucial cytokine produced by BM niche cells. However, the cellular source of Thpo, upon which HSCs primarily depend, is unclear. Moreover, no specific molecular pathway for the regulation of Thpo production in the BM has been identified. Here, we demonstrate that the membrane protein C-type lectin-like receptor-2 (CLEC-2) mediates the production of Thpo and other factors in Mks. Mice conditionally deleted for CLEC-2 in Mks (Clec2MkΔ/Δ) produced lower levels of Thpo in Mks. CLEC-2–deficient Mks showed down-regulation of CLEC-2–related signaling molecules Syk, Lcp2, and Plcg2. Knockdown of these molecules in cultured Mks decreased expression of Thpo. Clec2MkΔ/Δ mice exhibited reduced BM HSC quiescence and repopulation potential, along with extramedullary hematopoiesis. The low level of Thpo production may account for the decline in HSC potential in Clec2MkΔ/Δ mice, as administration of recombinant Thpo to Clec2MkΔ/Δ mice restored stem cell potential. Our study identifies CLEC-2 signaling as a novel molecular mechanism mediating the production of Thpo and other factors for the maintenance of HSCs.
Mediastinitis due to perforation by a metal stent after endoscopic ultrasound-guided hepaticogastrostomy: a rare complication
Authors: Junichi Kaneko, Hirotoshi Ishiwatari, Kohei Takizawa, Tatsunori Satoh, Junya Sato, Hiroyuki Matsubayashi, Hiroyuki Ono
Journal: Endoscopy (2019)

Stents must be of a sufficient length to prevent their migration into the abdominal cavity after endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) [1] [2]. Although a self-expandable metal stent (SEMS) with a long intragastric portion can occasionally migrate to the esophagus, this hardly ever leads to severe complications. However, we present here a case of mediastinitis due to perforation caused by a SEMS.
A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease
Authors: G. A. Horne, J. Stobo, C. Kelly, A. Mukhopadhyay, A. L. Latif, J. Dixon-Hughes, L. McMahon, P. Cony-Makhoul, J. Byrne, G. Smith, S. Koschmieder, T. H. BrÜmmendorf, P. Schafhausen, P. Gallipoli, F. Thomson, W. Cong, R. E. Clark, D. Milojkovic, G. V. Helgason, L. Foroni, F. E. Nicolini, T. L. Holyoake, M. Copland
Journal: Leukemia (2020)
Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8 <sup>+</sup> T cells
Authors: Son Nguyen, Claire Deleage, Samuel Darko, Amy Ransier, Duc P. Truong, Divyansh Agarwal, Alberto Sada Japp, Vincent H. Wu, Leticia Kuri-Cervantes, Mohamed Abdel-Mohsen, Perla M. Del Rio Estrada, Yuria Ablanedo-Terrazas, Emma Gostick, James A. Hoxie, Nancy R. Zhang, Ali Naji, Gustavo Reyes-Terán, Jacob D. Estes, David A. Price, Daniel C. Douek, Steven G. Deeks, Marcus Buggert, Michael R. Betts
Journal: Science Translational Medicine (2019)

Elite control of HIV replication is linked to polyfunctional lymphoid CD8 + T cells that lack overt cytolytic activity and home to B cell follicles.
A Phase III randomized parallel-group study of gefitinib (IRESSA) versus methotrexate (IMEX) in patients with recurrent squamous cell carcinoma of the head and neck
Authors: J. Simon Stewart, Ezra Cohen, Lisa Licitra, Carla Van Herpen, Chonlakiet Khorprasert, Denis Soulieres, Pavel Vodvarka, Danny Rischin, Avgust Garin, Serban Ghiorghiu, Laura Hargreaves, Alison Armour, Everett Vokes
Journal: Cancer Research (2007)

3522  Background: In Phase I and II studies, gefitinib (IRESSA) has demonstrated evidence of anti-tumor activity in patients with head and neck cancer. This multi-center, randomized, partially-blinded, parallel-group, comparative Phase III trial (IMEX: IRESSA vs MEthotreXate) investigated gefitinib versus methotrexate in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN).  Methods: Patients with histologically-confirmed recurrent SCCHN were randomized (1:1:1) to gefitinib 250 mg/day, gefitinib 500 mg/day or methotrexate 40 mg/m2 weekly (with the option to escalate to a maximum of 60 mg/m2 in the absence of unacceptable toxicity). Gefitinib doses were blinded. The primary endpoint was overall survival. Secondary endpoints were objective response rate (ORR, assessed by the treating physician by RECIST), safety and tolerability, symptom improvement and quality-of-life (assessed using the Functional Assessment of Cancer Therapy-Head & Neck [FACT-HN P=0.12] and HR 1.12 [95% CI 0.87 - 1.43; P=0.39], respectively). Median overall survival times in the 3 groups were 5.6 (gefitinib 250 mg/day), 6.0 (gefitinib 500 mg/day) and 6.7 (methotrexate) months. ORRs were 2.7%, 7.6% and 3.9% in the gefitinib 250 mg/day, 500 mg/day and methotrexate groups, respectively, with no statistically significant difference between each of the gefitinib arms and methotrexate. Adverse events were consistent with those previously observed for gefitinib and methotrexate with the exception of tumor hemorrhage, which was observed in: 8.9% (14/158), 11.4% (19/166), and 1.9% (3/159) in the gefitinib 250 mg/day, 500 mg/day and methotrexate groups, respectively.  Conclusions: Neither gefitinib (IRESSA) 250 mg/day nor 500 mg/day demonstrated improvement in overall survival compared to methotrexate. With the exception of tumor hemorrhage with gefitinib, the adverse event profiles were generally consistent with those previously observed for each agent.   IRESSA is a trademark of the AstraZeneca group of companies
Polysaccharide‐Peptide Cryogels for Multidrug‐Resistant‐Bacteria Infected Wound Healing and Hemostasis
Authors: Sen Hou, Yuanyuan Liu, Fang Feng, Jin Zhou, Xinxing Feng, Yubo Fan
Journal: Advanced Healthcare Materials (2019)

Abstract Wound dressings that can simultaneously treat bacterial infections and various bleeding complications are highly desirable in clinics. Moreover, multidrug‐resistant (MDR) bacterial infection has posed another great challenge for clinical wound care, as there are fewer effective antimicrobial agents available for killing these bacteria. To meet the clinical need, serials of polysaccharide‐peptide cryogels have been developed with excellent antibacterial efficacy and hemostatic property. With glycol chitosan (GC) and ε‐poly lysine (EPL) as the major components, the cryogels yield significantly lower amounts of blood loss compared with commercially available hemostatic dressings. The incorporation of EPL significantly enhances the antibacterial activity including killing MDR bacteria capacity and prevents the bacterial infection of skin wounds. The cryogel treated wounds demonstrate significantly higher healing efficiency compared to the controlled MDR bacteria infected wounds. The GC‐EPL polysaccharide‐peptide cryogels may become competitive multifunctional wound dressings for bleeding control and bacteria‐infected wound healing.
Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension
Authors: Guadalupe Garcia-Tsao, Jaime Bosch, Zeid Kayali, Stephen A. Harrison, Manal F. Abdelmalek, Eric Lawitz, Sanjaya K. Satapathy, Marwan Ghabril, Mitchell L. Shiffman, Ziad H. Younes, Paul J. Thuluvath, Annalisa Berzigotti, Agustin Albillos, James M. Robinson, David T. Hagerty, Jean L. Chan, Arun J. Sanyal, M. Abdelmalek, K. Bhamidimarri, B. Borg, S. Caldwell, J. Fenkel, B. Freilich, M. Fuchs, M. Ghabril, R. Ghalib, S. Gonzalez, S. Gordon, B. Hameed, S. Harrison, Z. Kayali, N. Kemmer, K. Korenblat, M. Lai, C. Landis, E. Lawitz, W. Lee, S. Lidofsky, E. Mena, M. Noureddin, A. Paredes, N. Pyrsopoulos, R. Reddy, M. Rinella, D. Rockey, M. Rodriguez, M. Ryan, S. Sarkar, S. Satapathy, A. Scanga, M. Shiffman, M. Siddiqui, D. Simonetto, W. Syn, P. Thuluvath, R. Vemulapalli, J. Vierling, Z. Younes, A. Albillos, J. Arenas Ruiz-Tapiador, S. Augustin, J. Calleja, J. Crespo Garcia, L. Garcia Buey, J.C. Garcia-Pagan, C. Villanueva, C. Bureau, N. Carbonell, V. Leroy, P.-E. Rautou, H. Heinzow, I. Schiefke, A. Zipprich, A. Berzigotti, B. Muellhaupt
Journal: Journal of Hepatology (2019)
Indication of Measures of Uncertainty for Statistical Significance in Abstracts of Published Oncology Trials
Authors: Samuel M. Rubinstein, Elizabeth A. Sigworth, Shervin Etemad, Richard L. Martin, Qingxia Chen, Jeremy L. Warner
Journal: JAMA Network Open (2019)

There is growing consensus that reliance on P values, particularly a cutoff level of .05 for statistical significance, is a factor in the challenges in scientific reproducibility. Despite this consensus, publications describing clinical trial results with P values near .05 anecdotally use declarative statements that do not express uncertainty.To quantify uncertainty expression in abstracts describing the results of cancer randomized clinical trials (RCTs) with P values between .01 and .10 and examine whether trial features are associated with uncertainty expression.A total of 5777 prospective trials indexed on HemOnc.org, as of September 15, 2019.Two-arm RCTs with a superiority end point with P values between .01 and .10.Abstracts were evaluated based on an uncertainty expression algorithm. Ordinal logistic regression modeling with multiple imputation was performed to identify whether characteristics of study design, results, trial authors, and context P values were normalized by dividing by prespecified α value.Uncertainty expression in abstracts as determined by the algorithm and its association with trial and publication characteristics.Of 5777 trials screened, 556 met analysis criteria. Of these, 222 trials (39.9%) did not express uncertainty, 161 trials (29.0%) expressed some uncertainty, and 173 trials (31.1%) expressed full uncertainty. In ordinal logistic regression with multiple imputation, trial features with statistically significant associations with uncertainty expression included later year of publication (odds ratio [OR], 1.70; 95% CI, 1.24-2.32; P < .001), normalized P value (OR, 1.36; 95% CI, 1.11-1.67; P = .003), noncooperative group studies (OR, 1.72; 95% CI, 1.12-2.63; P = .01), and reporting an end point other than overall survival (OR, 1.41; 95% CI, 1.01-1.96; P = .047). Funding source, number of authors, journal impact tier, author nationality, study of unapproved drugs, abstract word count, whether the marginal end point was a primary or coprimary end point, and effect size (in subgroup analysis) did not have statistically significant associations with uncertainty expression.Published oncology articles with marginally significant results may often incompletely convey uncertainty. Although it appears that more uncertainty is expressed in recent abstracts, full uncertainty expression remains uncommon, and seemingly is less common when reporting overall survival, results with P values lower than α levels, and cooperative group studies.
Abstract 16673: Exposure to Ambient Polycyclic Aromatic Hydrocarbons Results in Lipoxygenase Activation and Decreased Paraoxonase-1 Activity
Authors: Yan Lin, Fen Yin, Xinghua Qiu, Gajalakshmi Ramanathan, Nolan D Rea, Kym F Faull, Yifang Zhu, Jesus A Araujo
Journal: Circulation (2018)

Introduction: There is cumulative evidence in support of causal associations between exposure to air pollution, atherosclerosis and cardiovascular mortality. However, the mechanisms for responsible for those associations are not known. Animal studies have found that exposure to ambient particulate matter (PM) promotes lipoprotein oxidation, together with decreased paraoxonase 1 (PON-1) activity, and activation of 5- and 12/15-lipoxygenase pathways but evidence on human subjects is lacking. Hypothesis: Exposure to polycyclic aromatic hydrocarbon (PAHs), a group of airborne chemicals originated from combustion sources highly prevalent in ambient PM, inhibit PON-1 activity and induce oxidative stress. Methods: We recruited 26 healthy non-smoking young adults traveling from Los Angeles to Beijing in summer. Paired urine and plasma samples were collected before (LA 1 ), during (BJ) and after (LA 2 ) the travel. Urinary monohydroxylated metabolites of five PAHs (i.e. naphthalene, dibenzofuran, fluorene, phenanthrene and pyrene) were measured as indicators of PAHs exposure. We also assessed plasma levels of PON-1 enzymatic activities, 5-, 12- and 15- hydroxyeicosatetraenoic (HETE) acids as well as 9- and 13-hydroxyoctadecadienoic acid (HODE) acids, which are oxidative products of polyunsaturated arachidonic and linoleic acid. Data was analyzed by a mixed-effect model with random intercepts. Results: Four out of five PAHs metabolites (all except for naphthalene) were elevated by 1.6-9.0 folds ( p &lt;0.001) in BJ as compared with levels in LA 1 or LA 2 indicating increased exposure to PAHs in BJ. On the contrary, there was a significant decrease in plasma paraoxonase and arylesterase activities ( p&lt; 0.05) without changes in plasma PON-1 concentration, indicating functional alteration of PON-1. There was also a significant increase in plasma levels of all HETEs and HODEs ( p&lt; 0.05) indicating elevated oxidative stress. The increase in 5-, 12- and 15-HETEs observed in BJ remained statistically significant after normalization by arachidonic acid ( p&lt; 0.05), indicating activation of 5 and 12/15 lipoxygenases. In addition, there were strong associations ( p &lt;0.05) between changes in all PAHs (except naphthalene), with HETEs, HODEs and changes in PON-1-associated paraoxonase and arylesterase enzymatic activities, after adjusting city’s effects. Conclusion: PM promotes atherosclerosis likely by its high content in PAHs, and their concomitant pro-oxidative effects resulting in activation of lipoxygenases and inhibition of PON-1 activity.
Role of RhoA in survival of dormant breast cancer cells.
Authors: Michael E. Lindy, Reju Korah, Monika Boots, Robert Wieder
Journal: Cancer Research (2004)

2435  Breast cancer cells metastasize to the bone marrow early in the course of the disease where they can remain dormant for years. These dormant cells are resistant to chemotherapy. To determine the survival mechanisms of dormant cells, we developed an invitro dormancy model where well-differentiated breast cancer cells exposed to FGF-2 in the stroma stop proliferating at the 2-10 cell stage and adopt a flattened appearance with large cytoplasm to nucleus ratios. These cells increase the expression of integrin α5β1 through which they receive survival signaling through PI3K /Akt by ligation of fibronectin in the stroma. Inhibition of PI3K with LY294002 20 μM and Akt inhibitor 25 μM (Calbiochem), a concentration that reduced the Ser473 phosphorylation of Akt in cells treated with FGF-2 10 ng/ml, caused a 50-70% decrease in 2-10 cell dormant clone survival in T-47D breast cancer cells on fibronectin-coated tissue culture plates. Because of the morphologic changes that accompanied this dormant state, we investigated the role of the small GTPase RhoA in their survival. Bacterial C3 transferase 5 μg/ml, a concentration that inhibited RhoA GTP loading in a pulldown assay, or Rho kinase inhibitor Y27632 3 μM inhibited dormant clone survival by approximately 70%. Addition of Akt inhibitor to either C3 transferase or Y27632 did not increase the inhibitory effect of either C3 transferase or Y27632. However combining LY294002 with either C3 transferase or Y27632 resulted in almost complete eradication in the survival of dormant clones. The morphology of the surviving clones following treatment with the various inhibitors was impressive. Dormant cells that survived LY294002, C3 transferase or Y27632 were small, dendritic and appeared distressed and dying, with LY294002 having the most dramatic effect. In contrast, dormant cells that survived Akt inhibitor retained their large, flat and spread out appearance. These data suggest that survival in these clones is mediated by PI3 kinase primarily through RhoA and partially, through another branch of the pathway, by Akt. These data provide support for these pathways as potential therapeutic targets for eradication of dormant breast cancer cells.
Identification of a novel PAK1 inhibitor to treat pancreatic cancer
Authors: Jiaqi Wang, Yonghua Zhu, Jiao Chen, Yuhan Yang, Lingxia Zhu, Jiayu Zhao, Yang Yang, Xueting Cai, Chunping Hu, Rafael Rosell, Xiaoyan Sun, Peng Cao
Journal: Acta Pharmaceutica Sinica B (2019)

Pancreatic cancer is one of the most aggressive cancers with poor prognosis and a low 5-year survival rate. The family of P21-activated kinases (PAKs) appears to modulate many signaling pathways that contribute to pancreatic carcinogenesis. In this work, we demonstrated that PAK1 is a critical regulator in pancreatic cancer cell growth. PAK1-targeted inhibition is therefore a new potential therapeutic strategy for pancreatic cancer. Our small molecule screening identified a relatively specific PAK1-targeted inhibitor, CP734. Pharmacological and biochemical studies indicated that CP734 targets residue V342 of PAK1 to inhibit its ATPase activity. Further in vitro and in vivo studies elucidated that CP734 suppresses pancreatic tumor growth through depleting PAK1 kinase activity and its downstream signaling pathways. Little toxicity of CP734 was observed in murine models. Combined with gemcitabine or 5-fluorouracil, CP734 also showed synergistic effects on the anti-proliferation of pancreatic cancer cells. All these favorable results indicated that CP734 is a new potential therapeutic candidate for pancreatic cancer.
Baseline features of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial
Authors: Burkert Pieske, Mahesh J. Patel, Cynthia M. Westerhout, Kevin J. Anstrom, Javed Butler, Justin Ezekowitz, Adrian F. Hernandez, Joerg Koglin, Carolyn S.P. Lam, Piotr Ponikowski, Lothar Roessig, Adriaan A. Voors, Christopher M. O'Connor, Paul W. Armstrong
Journal: European Journal of Heart Failure (2019)

Aim Describe the distinguishing features of heart failure (HF) patients with reduced ejection fraction (HFrEF) in the VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) trial. Methods and results Key background characteristics were evaluated in 5050 patients randomized in VICTORIA and categorized into three cohorts reflecting their index worsening HF event. Differences within the VICTORIA population were assessed and compared with PARADIGM‐HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure). VICTORIA patients had increased risk of mortality and rehospitalization: New York Heart Association class (40% class III), atrial fibrillation (45%), diabetes (47%), hypertension (79%) and mean estimated glomerular filtration rate of 61.5 mL/min/1.73 m 2 . Baseline standard of HF care was very good: 60% received triple therapy. Their N‐terminal pro‐B‐type natriuretic peptide was 3377 pg/mL [interquartile range (IQR) 1992–6380]. Natriuretic peptides were 30% higher level in the 67% patients with HF hospitalization &lt;3 months, compared to those within 3–6 months of HF hospitalization and those randomized after recent outpatient intravenous diuretic therapy. Overall the median MAGGIC (Meta‐Analysis Global Group in Chronic Heart Failure) risk score in VICTORIA was 23 (IQR 18–27) as compared to the MAGGIC risk score in PARADIGM‐HF of 20 (IQR 16–24). Conclusions VICTORIA comprises a broadly generalizable high‐risk population of three unique clinical strata of worsening chronic HFrEF despite very good HF therapy. VICTORIA will establish the role of vericiguat, a soluble guanylate cyclase stimulator, in HFrEF.
Recent advances in porphyrin-based nanocomposites for effective targeted imaging and therapy
Authors: Navid Rabiee, Mohammad Tavakkoli Yaraki, Soha Mokhtari Garakani, Shima Mokhtari Garakani, Sepideh Ahmadi, Aseman Lajevardi, Mojtaba Bagherzadeh, Mohammad Rabiee, Lobat Tayebi, Mohammadreza Tahriri, Michael R. Hamblin
Journal: Biomaterials (2019)
Non-invasive estimation of relative pressure in turbulent flow using virtual work-energy
Authors: David Marlevi, Hojin Ha, Desmond Dillon-Murphy, Joao F. Fernandes, Daniel Fovargue, Massimiliano Colarieti-Tosti, Matilda Larsson, Pablo Lamata, C. Alberto Figueroa, Tino Ebbers, David A. Nordsletten
Journal: Medical Image Analysis (2019)

Vascular pressure differences are established risk markers for a number of cardiovascular diseases. Relative pressures are, however, often driven by turbulence-induced flow fluctuations, where conventional non-invasive methods may yield inaccurate results. Recently, we proposed a novel method for non-turbulent flows, νWERP, utilizing the concept of virtual work-energy to accurately probe relative pressure through complex branching vasculature. Here, we present an extension of this approach for turbulent flows: νWERP-t. We present a theoretical method derivation based on flow covariance, quantifying the impact of flow fluctuations on relative pressure. νWERP-t is tested on a set of in-vitro stenotic flow phantoms with data acquired by 4D flow MRI with six-directional flow encoding, as well as on a patient-specific in-silico model of an acute aortic dissection. Over all tests νWERP-t shows improved accuracy over alternative energy-based approaches, with excellent recovery of estimated relative pressures. In particular, the use of a guaranteed divergence-free virtual field improves accuracy in cases where turbulent flows skew the apparent divergence of the acquired field. With the original νWERP allowing for assessment of relative pressure into previously inaccessible vasculatures, the extended νWERP-t further enlarges the method's clinical scope, underlining its potential as a novel tool for assessing relative pressure in-vivo.
Letter to the Editor on the article “Long non-coding RNA MALAT1 as a valuable biomarker for prognosis in osteosarcoma: A systematic review and meta-analysis” (Int J Surg 2019; Nov 15;72:206–213. doi: 10.1016/j.ijsu.2019.11.004. [Epub ahead of print])
Authors: Lanhua Tang, Zhe Ruan, Shushan Zhao
Journal: International Journal of Surgery (2019)
Myocardial Extracellular and Cardiomyocyte Volume Expand After Doxorubicin Treatment Similar to Adjuvant Breast Cancer Therapy
Authors: Giselle C. Meléndez, Sujethra Vasu, Edward J. Lesnefsky, Jay R. Kaplan, Susan Appt, Ralph B. D’Agostino, W. Gregory Hundley, Jennifer H. Jordan
Journal: JACC. Cardiovascular imaging (2019)