tbuckley/cabot-search huggingface dataset:
Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory
Authors: Lalit K. Beura, Jason S. Mitchell, Emily A. Thompson, Jason M. Schenkel, Javed Mohammed, Sathi Wijeyesinghe, Raissa Fonseca, Brandon J. Burbach, Heather D. Hickman, Vaiva Vezys, Brian T. Fife, David Masopust
Journal: Nature Immunology (2018)
Abstract 14194: Sphingosine 1-Phosphate Possesses the Carrier-dependent Effects on the Plasminogen Activator Inhibitor 1 Expression in Adipocytes
Authors: Chiharu Takahashi, Makoto Kurano, Masako Nishikawa, Kuniyuki Kano, Tomotaka Dohi, Katsumi Miyauchi, Hiroyuki Daida, Tomo Shimizu, Junken Aoki, Yutaka Yatomi
Journal: Circulation (2016)

Introduction:  Thrombosis-related diseases are still causing mortality and morbidity worldwide. Plasminogen activator inhibitor-1 (PAI-1) is one of the pro-coagulant factors and reported to be associated with cardiovascular diseases. Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid mediator, has been demonstrated to increase the PAI-1 expression in adipocytes, however, many basic and clinical researches has suggested that S1P is an anti-atherosclerotic mediator.   Hypothesis:  S1P might possess different properties on the PAI-1 expression in adipocytes, depending on its carrier, since S1P is bound to apolipoprotein M (apoM) on HDL or albumin in plasma.   Methods:  First, we measured concentrations of S1P, apoM, and PAI-1 in the plasma of normal coronary artery, stable angina pectoris, and acute coronary syndrome subjects (n = 32, 71, and 38, respectively), and investigated the correlation among these molecules. Secondly, we treated 3T3L1 adipocytes with S1P, utilizing various vehicles, and compared the effects of S1P on the PAI-1 expression levels, as well as on the signal pathways involved in the induction of PAI-1 by S1P. Thirdly, we investigated the modulation of the PAI-1 level in mice infected with adenovirus coding apoM.   Results:  Among subjects with acute coronary syndrome, the plasma PAI-1 level was positively correlated with the S1P level, while not with the apoM level. In 3T3L1 adipocytes, S1P bound to apoM-rich vehicle induced PAI-1 expression to a lesser extent than S1P bound to the control vehicle, while S1P bound to apoM-depleted vehicle induced PAI-1 expression to a greater extent than S1P bound to the control vehicle. Moreover, adenoviral apoM overexpression in mice failed to modulate the plasma PAI-1 level and the expression of PAI-1 in adipose tissue.   Conclusions:  S1P bound to albumin, but not S1P bound to apoM, induces PAI-1 expression in adipocytes, indicating that S1P can exert different properties on the pathogenesis of vascular diseases, depending on its carrier.
Proteomic studies of nucleolin complexes in prostate cancer cells treated with novel anticancer agent, AS1411
Authors: Yun Teng, William Pierce, Paula Bates
Journal: Cancer Research (2007)

3275  AS1411 (formerly AGRO100) is a guanosine-rich phosphodiester oligodeoxynucleotide that is currently being tested in clinical trials for the treatment of advanced cancer. This agent has a novel mechanism of action that involves binding as an aptamer to nucleolin, a multifunctional protein that is expressed at high levels by cancer cells. It is our hypothesis that binding of AS1411 alters the molecular interactions of nucleolin leading to pleiotropic biological effects. The goals of this study were to identify nucleolin-associated proteins in DU145 human prostate cancer cells and to investigate the effect of AS1411 on them. Nucleolin-associated proteins were isolated by immunoprecipitation (IP) from human prostate cancer DU145 cells using either anti-nucleolin antibodies to precipitate endogenous protein or anti-FLAG antibodies to capture FLAG-tagged nucleolin. Forty nonribosomal proteins and four ribosomal proteins were identified as candidate nucleolin-associated proteins by MALDI-TOF mass spectrometry. Several of these, including protein arginine methyltransferase 5 (PRMT5), phospholipase C gamma1 (PLCγ1), topoisomerase I, non-muscle myosin IIA/MYH9, heat shock protein 90, kinesin Eg5/KIF 11, NEMO/IKKγ and structure specific recognition protein 1 (SSRP1), were subsequently shown to co-precipitate with endogenous nucleolin from DU145 cells To determine the effect of AS1411 on the molecular interactions of nucleolin, we examined nucleolin complexes in nuclear or cytoplasmic extracts from untreated, AS1411-treated and control-treated DU145 cells using anti-nucleolin IP. Consistently, we found an altered nuclear/cytoplasmic distribution of many nucleolin-precipitated proteins in AS1411-treated cells, although total nucleolin levels were apparently unaffected. Some nucleolin complexes (e.g. with PRMT5, MYH9) exhibited increased cytoplasmic localization in AS1411-treated cells, whereas others (e.g. with PLCγ1, topoisomerase I) displayed increased nuclear localization. In summary, our research has identified nucleolin-associated proteins from human prostate cancer DU145 cells, including several that have not been reported previously. Some of these are also molecular targets for anticancer agents, suggesting possibly novel roles for nucleolin in cancer cell biology. Moreover, the localizations of certain nucleolin complexes were altered in DU145 cells treated with AS1411, which is a new anticancer agent. These results confirm that nucleolin is the primary molecular target of AS1411 and suggest that the trafficking function of nucleolin may be affected by AS1411.
Venetoclax (VEN) Is Active in Chronic Lymphocytic Leukemia (CLL) Relapsed or Refractory to More Than One B-Cell Receptor Pathway Inhibitor (BCRi)
Authors: William G Wierda, Matthew S. Davids, Richard R. Furman, Bruce D. Cheson, Paul M. Barr, Herbert Eradat, Leonard Heffner, Jeffrey Jones, Lang Zhou, Maria Verdugo, Rod A. Humerickhouse, Jalaja Potluri, Michael Choi
Journal: Blood (2017)
Linear and Branching Progression of Chronic Lymphocytic Leukemia (CLL) Under PI3K Inhibition (PI3Ki)
Authors: Julio Delgado, Silvia Bea, Rafael Valdes-Mas, Blanca Gonzalez-Farre, Jesus Gutierrez-Abril, Monica Lopez-Guerra, Alba Navarro, Marta Aymerich, Neus Villamor, Magda Pinyol, Armando Lopez-Guillermo, Carlos Lopez-Otin, Xose Puente, Elias Campo
Journal: Blood (2017)
Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer
Authors: Daniel G. Stover, Heather A. Parsons, Gavin Ha, Samuel S. Freeman, William T. Barry, Hao Guo, Atish D. Choudhury, Gregory Gydush, Sarah C. Reed, Justin Rhoades, Denisse Rotem, Melissa E. Hughes, Deborah A. Dillon, Ann H. Partridge, Nikhil Wagle, Ian E. Krop, Gad Getz, Todd R. Golub, J. Christopher Love, Eric P. Winer, Sara M. Tolaney, Nancy U. Lin, Viktor A. Adalsteinsson
Journal: Journal of Clinical Oncology (2018)

Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.
Presence of bone metastases(BM) at diagnosis is associated with poor prognosis and coagulation disorders (CD) in patients (pts) with advanced gastric cancer (AGC).
Authors: Laura Toppo, Wanda Liguigli, Chiara Senti, Gianluca Tomasello, Michele Ghidini, Margherita Ratti, Andrea Botticelli, Concetta Elisa Onesti, Francesca DI Pietro, Claudio Pizzo, Stefano Panni, Alessandra Curti, Rodolfo Passalacqua
Journal: Journal of Clinical Oncology (2017)

e15538 Background: The presence of BM in AGC is a relatively uncommon finding and has a poor prognosis [Leporini C. 2015]. At diagnosis the presence of BM occurs in approximately 10-15% of pts with AGC.[Park 2011; Silvestris 2013]. Aim of this study is to describe the main features of pts with AGC and BM at diagnosis and the prognostic implications. Methods: A consecutive series of AGC followed at Cremona Oncology Division from November 2004 to Dicember 2016 and included in three consecutive prospective trials [Dalla Chiesa M. 2011; Tomasello G. 2013], were analyzed. All pts were treated with a modified DCF (docetaxel, cisplatin, fluorouracil) given as a dose-dense regimen, every 14 days. We analyzed pts with BM at diagnosis (BMaD) and pts without BMaD. We evaluated baseline clinical and pathological parameters, the presence of coagulation disorders (CD) together with efficacy measures in the two groups. Results:218 pts with AGC were identified (38 with BMaD and 180 without BMaD).Main pts characteristics and results are reported in the Table below. Conclusions: The presence of BM at diagnosis in pts with AGC is not a rare event (21%) and identifies a population with a significantly poorer outcome and a higher incidence of CD, that need a clinical monitoring of coagulation parameters. More efforts are required to understand the reasons of the different prognosis and to find specific treatments to improve the survival. [Table: see text]
Fasting Glucose and All-Cause Mortality by Age in Diabetes: A Prospective Cohort Study
Authors: Sang-Wook Yi, Sangkyu Park, Yong-ho Lee, Beverley Balkau, Jee-Jeon Yi
Journal: Diabetes Care (2018)

OBJECTIVE To examine associations between fasting glucose and mortality and to identify the levels associated with lowest mortality by age in diabetes. RESEARCH DESIGN AND METHODS A total of 359,645 Korean adults with known prevalent diabetes participated in health screening during 2001–2004 and were followed up until 2013. RESULTS U-curve associations were found. Fasting glucose levels associated with the lowest mortality were ∼90–130 mg/dL, except for in those aged 18–44 years (∼80–95 mg/dL). Multivariable-adjusted hazard ratios of fasting glucose &amp;lt;65, 65–74, 75–84, 140–169, 170–199, and ≥200 mg/dL were 1.46, 1.12, 1.09, 1.12, 1.31, and 1.78, respectively, compared with 85–99 mg/dL. CONCLUSIONS Optimal fasting glucose range for survival is higher in adults with than without known prevalent diabetes, except, perhaps, younger adults. Tight glucose control may lessen premature death in younger adults with diabetes. Hypoglycemia (&amp;lt;65 mg/dL) was associated with higher mortality than was fasting glucose 170–199 mg/dL, while fasting glucose 65–84 mg/dL had risks comparable with those at levels 140–169 mg/dL in diabetes.
Surgery in Elderly Patients ( g 70 Years or Older) with Non-Small Lung Cancer (NSCLC). Impact of Adjuvant Chemotherapy
Authors: Hirsh Koyi, Gunnar Hillerdal, Karl Gustav Kolbeck, Olov Andersson, Per Bergman, Lotta Orre, Per Liv, Eva Branden
Journal: Journal of Thoracic Oncology (2015)
Abstract 19243: Late Repolarization During Targeted Temperature Management at 33 Degree C vs. 36 Degree C and Risk of Ventricular Arrhythmia in Post Cardiac Arrest Care
Authors: Jakob H Thomsen, Christian Hassager, Claus Graff, Steen Pehrson, Lars Køber, David Erlinge, John Bro-Jeppesen, Jesper Kjaergaard
Journal: Circulation (2016)

Background:  The T-peak to T-end interval (TPTE) has emerged as a potential clinically useful marker of risk of ventricular arrhythmia. Both the effect of the level of targeted temperature management (TTM) following out-of-hospital cardiac arrest (OHCA) on the TPTE-interval and the importance of the interval in assessing risk of ventricular arrhythmia in post cardiac arrest care is unknown.   Methods:  An ECG-substudy of the TTM-trial which compared TTM at 33C vs. 36C. From 24 sites, serial ECGs (0, 4, 28, 36 and 72 hours after admission) in 682 (94%) patients were analyzed. Bazett’s (TPTE(B)) and Fridericia’s (TPTE(F)) formula were used for heart rate correction. Occurrence of ventricular arrhythmia (VT and VF) was assessed during the first three days of post cardiac arrest care.   Results:  The TPTE-interval remained relatively constant between 92-100 ms from admission and throughout the maintenance phase of TTM in both groups, but decreased after rewarming (Figure 1). A small difference (33C: 100 ms vs. 36C: 93 ms, p=0.04) was found at target temperature, but this was attenuated by both methods of heart rate correction. Ventricular arrhythmia occurred with similar incidences between temperature groups (33C: 61 (18%) vs. 36C: 49 (15%), p=0.30). The uncorrected TPTE-interval at target temperature, were not significantly associated with risk of ventricular arrhythmia (p=0.08), however longer heart rate corrected TPTE-intervals were associated with higher risk of arrhythmia (Odds ratio: TPTE(B): 1.12 (1.02-1.23, p=0.01 TPTE(F): 1.12 (1.02-1.23, p=0.02) per 20 ms), independent of method applied.   Conclusion:  The TPTE-interval is not greatly affected by core temperature, and the small difference found was explained by different heart rates. Corrected TPTE intervals are directly associated with increased risk of ventricular arrhythmia and may represent a clinically useful marker of risk in post cardiac arrest patients treated with TTM at both 33C and 36C.
malERA: An updated research agenda for insecticide and drug resistance in malaria elimination and eradication
Journal: PLoS Medicine (2017)

Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts. Suboptimal responses to drugs and insecticides are both spreading geographically and emerging independently and are being seen at increasing intensities. Whilst resistance is unavoidable, its effects can be mitigated through resistance management practices, such as exposing the parasite or vector to more than one selective agent. Resistance contributed to the failure of the 20th century Global Malaria Eradication Programme, and yet the global response to this issue continues to be slow and poorly coordinated—too often, too little, too late. The Malaria Eradication Research Agenda (malERA) Refresh process convened a panel on resistance of both insecticides and antimalarial drugs. This paper outlines developments in the field over the past 5 years, highlights gaps in knowledge, and proposes a research agenda focused on managing resistance. A deeper understanding of the complex biological processes involved and how resistance is selected is needed, together with evidence of its public health impact. Resistance management will require improved use of entomological and parasitological data in decision making, and optimisation of the useful life of new and existing products through careful implementation, combination, and evaluation. A proactive, collaborative approach is needed from basic science and the development of new tools to programme and policy interventions that will ensure that the armamentarium of drugs and insecticides is sufficient to deal with the challenges of malaria control and its elimination.
Abstract 18186: Restoration of Impaired Diastolic Function in Induced Pluripotent Stem Cell Derived Cardiomyocytes From Hypertrophic Cardiomyopathy Patients by Re-Balancing the Calcium Homeostasis
Authors: Haodi Wu, Huaxiao Yang, Timon Seeger, Chi Keung Lam, Joe Z Zhang, Joseph C Wu
Journal: Circulation (2016)

Introduction: Diastolic dysfunction, defined as the abnormal filling and elevated pressures of ventricles during diastole phase, is commonly seen in patients with hypertrophic cardiomyopathy (HCM)....
Mesenchymal Stromal Cells Inhibit Inflammatory Lymphangiogenesis in the Cornea by Suppressing Macrophage in a TSG-6-Dependent Manner
Authors: Hyun Beom Song, Se Yeon Park, Jung Hwa Ko, Jong Woo Park, Chang Ho Yoon, Dong Hyun Kim, Jeong Hun Kim, Mee Kum Kim, Ryang Hwa Lee, Darwin J. Prockop, Joo Youn Oh
Journal: Molecular Therapy (2017)

The cornea is a transparent tissue devoid of blood and lymphatic vessels. However, various inflammatory conditions can cause hemangiogenesis and lymphangiogenesis in the cornea, compromising transparency and visual acuity. Mesenchymal stem/stromal cells (MSCs) have therapeutic potentials in a variety of diseases because of anti-inflammatory properties. Herein, we investigated the effects of MSCs on corneal angiogenesis using a model of suture-induced inflammatory corneal neovascularization. Data demonstrated that an intravenous administration of MSCs suppressed corneal inflammation and neovascularization, inhibiting both hemangiogenesis and lymphangiogenesis. MSCs reduced the levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, Tek, MRC1, and MRC2 in the cornea, which are expressed by pro-angiogenic macrophages. Moreover, the number of CD11b+ monocytes/macrophages in the cornea, spleen, peripheral blood, and draining lymph nodes was decreased by MSCs. Depletion of circulating CD11b+ monocytes by blocking antibodies replicated the effects of MSCs. Importantly, knockdown of tumor necrosis factor alpha (TNF-α)-stimulated gene/protein 6 (TSG-6) in MSCs abrogated the effects of MSCs in inhibiting corneal hemangiogenesis and lymphangiogenesis and monocyte/macrophage infiltration. Together, the results suggest that MSCs inhibit inflammatory neovascularization in the cornea by suppressing pro-angiogenic monocyte/macrophage recruitment in a TSG-6-dependent manner.
Evaluation of AJCC and an Alternative Tumor Classification System for Primary Vulvar Squamous Cell Carcinoma
Authors: Sarah T. Le, Pritesh S. Karia, Beverley J. Vollenhoven, Robert J. Besaw, Colleen M. Feltmate, Chrysalyne D. Schmults
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Currently, no studies have attempted to validate the AJCC tumor (T) class for vulvar cancer or examine its performance via clinical data. The goal of this study was to identify risk factors associated with poor outcomes in vulvar squamous cell carcinoma (vSCC) and compare prognostic discrimination of these outcomes between the AJCC T-classification system and the newly developed Brigham and Women's Vulvar Tumor Classification system (BWVTC). Methods: A 15-year, 2-center retrospective cohort study of primary vSCCs (N=226) was undertaken. Risk factors for poor outcomes, including local recurrence (LR), nodal and distant metastasis (NM and DM, respectively), disease-specific death (DSD), and overall death (OD) were determined using competing risks models. Poor outcomes were analyzed by T stage with regard to each classification system's distinctiveness, homogeneity, and monotonicity. Results: AJCC T stages were indistinct, with overlapping 95% confidence intervals for 10-year cumulative incidences of poor outcomes. Most poor outcomes occurred in low AJCC T stages: T1a/T1b contained 77% of LR, 79% of NM, 66% of DM/DSD, and 78% of OD, indicating poor homogeneity and monotonicity. Five risk factors were independent predictors of poor outcomes: history of lichen sclerosus, tumor diameter ≥2.0 cm, tumor depth ≥3.0 mm, poor differentiation, and mucosal involvement, and these were used to develop the BWVTC (BWVTC BWT1 = 0 risk factors; BWT2 = 1 risk factor; BWT3 = 2 risk factors; and BWT4 = ≥3 risk factors). The BWVTC displayed superior homogeneity and monotonicity, with most poor outcomes occurring in high T stages: T3/T4 contained 87% of LR, 92% of NM, 91% of DM/DSD, and 78% of OD (P<.001), although not all T stages were statistically distinct in this small cohort. Conclusions: The BWVTC offers improved prognostic discrimination over the AJCC T-classification system. Validation in population-based cohorts and in vulvar cancers other than SCC is needed.
Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase 3 Murano Study
Authors: John F Seymour, Thomas J. Kipps, Barbara F. Eichhorst, Peter Hillmen, James M. D'Rozario, Sarit Assouline, Carolyn Jane Owen, John Gerecitano, Tadeusz Robak, Javier De la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Rod Humerickhouse, Elizabeth Punnoose, Yan Li, Michelle Boyer, Kathryn Humphrey, Mehrdad Mobasher, Arnon P. Kater
Journal: Blood (2017)
Comparison of sensitization to prevalent pollens in two different ethnic populations of children-adolescents born in the same region
Authors: Natalia Blanca-Lopez, Damian López-Sánchez, Elisa Haroun Diaz, Laura Victorio-Puche, Maria Luisa Somoza-Alvarez, Diana Victoria Perez-Alzate, Francisco Javier Ruano, Maria Isabel Garcimartin, Miguel Blanca, María Gabriela Canto
Journal: Journal of Allergy and Clinical Immunology (2018)
VTE Recurrence and Safety of Anticoagulants Among Patients with Cancer Treated for Venous Thromboembolism
Authors: Alok A. Khorana, Keith McCrae, Dejan Milentijevic, Nora McCormick, François Laliberté, Concetta Crivera, Patrick Lefebvre, Dominique Lejeune, Heather Rozjabek, Jeff Schein, Michael B. Streiff
Journal: Blood (2017)
Protective Environment for Hematopoietic Cell Transplant (HSCT) Recipients: The Infectious Diseases Working Party EBMT Analysis of Global Recommendations on Health-Care Facilities
Authors: Jan Styczynski, Simona Iacobelli, Peter Donnelly, Gloria Tridello, Jennifer Hoek, Malgorzata Mikulska, Simone Cesaro
Journal: Blood (2017)
Функциональная диспепсия и хронический гастрит: сходство и различия
Authors: S.M. Tkach
Journal: GASTROENTEROLOGY (2014)

Статья посвящена одному из наиболее частых симптомокомплексов, с которыми приходится сталкиваться врачу общей практики или гастроэнтерологу, — функциональной диспепсии. Изложены ее клинические проявления, уделено внимание вопросам лечения. Подчеркнуто, что первичное лечение функциональной диспепсии в большинстве случаев является эмпирическим, основанным на клинической оценке преобладания кислотозависимых или дисмоторных симптомов, при которых соответственно назначаются ингибиторы протонной помпы, прокинетики или комбинированные препараты, содержащие ингибиторы протонной помпы и прокинетики, например Омез Д или Омез ДСР.
KI Intolerance Study: A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) in Patients with Chronic Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-δ Inhibitor Therapy
Authors: Anthony R. Mato, Bruce D. Cheson, Nicole Lamanna, John M. Pagel, Frederick Lansigan, Paul M. Barr, Jeffrey J. Pu, Colleen Dorsey, Elizabeth T Chatburn, Jakub Svoboda, Stephen J. Schuster, Eline Luning-Prak, Patricia Tsao, Andrea Sitlinger, Chaitra S. Ujjani, Dana Paskalis, Peter Sportelli, Hari P Miskin, Michael S. Weiss, Danielle M. Brander
Journal: Blood (2017)