tbuckley/cabot-search huggingface dataset:
Computer extracted nuclear features from tumor and benign regions of Feulgen and H&E images to help predict recurrence in prostate cancer patients following radical prostatectomy.
Authors: Anna Gawlik, George Lee, Michael D Feldman, Guangjing Zhu, Robert W. Veltri, Anant Madabhushi
Journal: Journal of Clinical Oncology (2017)

e16556 Background: Following radical prostatectomy, around 30% of prostate cancer (PCa) patients experience biochemical recurrence (BCR). H&amp;E highlights nuclear morphology and Feulgen reflects nuclear DNA content, a feature linked to PCa presence and aggressiveness. In this work we sought to explore whether computer extracted measurements of tumor morphology and tumor adjacent benign regions on H&amp;E and Feulgen tissue images could predict BCR. Methods: We used 108 patients (59 BCR and 49 non-recurrence (NR)) and each patient had 242 QH features calculated from both the tumor and benign region of stained TMA core images. Feature selection was performed on a training set (30 BCR, 24 NR) to select the 10 most discriminating tumor and tumor adjacent benign features of each stain. A random forest classifier was trained with features so identified and validated on a test set (29 BCR, 25 NR) to predict BCR. Predictions were displayed using Kaplan-Meier analysis and area under the ROC curve (AUC). Results: The most discriminating feature from the tumor regions of the H&amp;E stain was Fourier descriptors of nuclear shape and from the Feulgen stain was texture intensity while from the benign regions it was invariant moments of nuclear shape and texture contrast energy. Combining the significant features from tumor and tumor adjacent benign regions from H&amp;E and Feulgen resulted in the highest accuracy and a statistically significant difference (p &lt; 0.05) via a log-rank test (Table 1). Gleason score did not show statistically significant differences and had the lowest AUC. Conclusions: Combining nuclear morphology and DNA related features of the tumor and tumor adjacent benign regions enabled accurate prediction of BCR. With additional multi-site validation, the combined H&amp;E + Feulgen classifier could allow better risk stratification and post-surgical patient management. [Table: see text]
ACC/AHA/ASE 2003 Guideline Update for the Clinical Application of Echocardiography: Summary Article
Authors: Melvin D. Cheitlin, William F. Armstrong, Gerard P. Aurigemma, George A. Beller, Fredrick Z. Bierman, Jack L. Davis, Pamela S. Douglas, David P. Faxon, Linda D. Gillam, Thomas R. Kimball, William G. Kussmaul, Alan S. Pearlman, John T. Philbrick, Harry Rakowski, Daniel M. Thys, Elliott M. Antman, Sidney C. Smith, Joseph S. Alpert, Gabriel Gregoratos, Jeffrey L. Anderson, Loren F. Hiratzka, David P. Faxon, Sharon Ann Hunt, Valentin Fuster, Alice K. Jacobs, Raymond J. Gibbons, Richard O. Russell
Journal: Circulation (2003)

The ACC/AHA Task Force on Practice Guidelines makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or personal interest of a member of the writing panel.Specifically, all members of the writing panel are asked to provide disclosure statements of all such relationships that might be perceived
Endobronchial Optical Coherence Tomography for Low-Risk Microscopic Assessment and Diagnosis of Idiopathic Pulmonary Fibrosis <i>In Vivo</i>
Authors: Lida P. Hariri, David C. Adams, John C. Wain, Michael Lanuti, Ashok Muniappan, Amita Sharma, Thomas V. Colby, Mari Mino-Kenudson, Eugene J. Mark, Richard L. Kradin, Hannah Goulart, Andrew M. Tager, Melissa J. Suter
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis
Authors: Oliver Krenkel, Tobias Puengel, Olivier Govaere, Ali T. Abdallah, Jana C. Mossanen, Marlene Kohlhepp, Anke Liepelt, Eric Lefebvre, Tom Luedde, Claus Hellerbrand, Ralf Weiskirchen, Thomas Longerich, Ivan G. Costa, Quentin M. Anstee, Christian Trautwein, Frank Tacke
Journal: Hepatology (2017)

Macrophages are key regulators of liver fibrosis progression and regression in nonalcoholic steatohepatitis (NASH). Liver macrophages comprise resident phagocytes, Kupffer cells, and monocyte‐derived cells, which are recruited through the chemokine receptor C‐C motif chemokine receptor 2 (CCR2). We aimed at elucidating the therapeutic effects of inhibiting monocyte infiltration in NASH models by using cenicriviroc (CVC), an oral dual chemokine receptor CCR2/CCR5 antagonist that is under clinical evaluation. Human liver tissues from NASH patients were analyzed for CCR2+ macrophages, and administration of CVC was tested in mouse models of steatohepatitis, liver fibrosis progression, and fibrosis regression. In human livers from 17 patients and 4 controls, CCR2+ macrophages increased parallel to NASH severity and fibrosis stage, with a concomitant inflammatory polarization of these cluster of differentiation 68+, portal monocyte‐derived macrophages (MoMF). Similar to human disease, we observed a massive increase of hepatic MoMF in experimental models of steatohepatitis and liver fibrosis. Therapeutic treatment with CVC significantly reduced the recruitment of hepatic Ly‐6C+ MoMF in all models. In experimental steatohepatitis with obesity, therapeutic CVC application significantly improved insulin resistance and hepatic triglyceride levels. In fibrotic steatohepatitis, CVC treatment ameliorated histological NASH activity and hepatic fibrosis. CVC inhibited the infiltration of Ly‐6C+ monocytes, without direct effects on macrophage polarization, hepatocyte fatty acid metabolism, or stellate cell activation. Importantly, CVC did not delay fibrosis resolution after injury cessation. RNA sequencing analysis revealed that MoMF, but not Kupffer cells, specifically up‐regulate multiple growth factors and cytokines associated with fibrosis progression, while Kupffer cells activated pathways related to inflammation initiation and lipid metabolism. Conclusion: Pharmacological inhibition of CCR2+ monocyte recruitment efficiently ameliorates insulin resistance, hepatic inflammation, and fibrosis, corroborating the therapeutic potential of CVC in patients with NASH. (Hepatology 2018;67:1270‐1283)
Abstract P081: Voltage-Gated TTX-Sensitive Nav1.1 Brain Sodium Channels Are Important for Cardiac Contractile Function
Authors: Susan T Varghese, Stephanie Humphrey, An Xie, Andrew P Escayg, Samuel C Dudley
Journal: Circulation Research (2011)

Background: Mutations in voltage gated brain sodium channel Nav1.1 have been linked to many disorders, including Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI). Recent studies have identified TTX- sensitive Nav1.1 brain sodium channels in the SA node and ventricular T-tubules of the heart, though their role in cardiac function is still controversial. We tested the functional significance of Nav1.1 sodium channels in the heart by creating a novel knock-in of human epilepsy GEFS+ mutation SCN1A-R1648H at the Scn1a locus of a C57BL/6J X 129 mouse. Method: In vivo 2-D echocardiography was performed on 2 week old (juvenile) and 8 week old (adult) wild-type and heterozygote (Scn1aRH/+) mice after extracardiac neuronal block through intraperitoneal injections of atropine and propranolol (2.5mg/kg each). Calcium and contractility studies on adult ventricular cardiomyocytes isolated from the wild type and Scn1aRH/+ mice paced at 0.5Hz were followed by administration of TTX (100nM, a brain sodium channel inhibitor) and pacing at 2Hz. qRT-PCR and Western blot of the isolated cells and whole heart samples was also done. Results: A decrease in Nav1.1 gene expression in the Scn1aRH/+ juvenile (by 31%, 0.69 of 1) and adult (by 60%, 0.4 of 1) whole heart samples and isolated cells (p&lt;0.05) was seen. Echocardiography revealed concentric hypertrophy in the juvenile Scn1aRH/+ mice by a significant increase in LV mass, LV mass/body weight ratio, and relative wall thickness (p&lt;0.05). In the adult Scn1aRH/+ mice, systolic isovolumic contraction time (IVCT) was reduced (p=0.03) and decrease in diastolic function was evident through significant decreases in isovolumic relaxation time (IVRT) and E’/A’ ratio, and increase in E/E’ ratio. Isolated adult ventricular Scn1aRH/+ cardiomyocytes showed significant reduction in percent sarcomere shortening, maximum rate of contraction and relaxation, and time to peak contraction, exaggerated with TTX and pacing at 2Hz (p&lt;0.5). Conclusions: Our study demonstrates the importance of voltage gated TTX-sensitive Nav1.1 brain sodium channels in cardiac contractile function and their possible role in cardiac complications in epilepsy.
Cardiovascular disease in the Eastern Mediterranean region: epidemiology and risk factor burden
Authors: Karam Turk-Adawi, Nizal Sarrafzadegan, Ibtihal Fadhil, Kathryn Taubert, Masoumeh Sadeghi, Nanette K. Wenger, Nigel S. Tan, Sherry L. Grace
Journal: Nature Reviews Cardiology (2017)
Phase II trial of pembrolizumab in patients (pts) with incurable platinum refractory germ cell tumors (GCT).
Authors: Nabil Adra, Sandra K. Althouse, Natraj Reddy Ammakkanavar, Milan Radovich, Costantine Albany, David J. Vaughn, Lawrence H. Einhorn, Nasser H. Hanna
Journal: Journal of Clinical Oncology (2017)

4520 Background: Despite remarkable results with salvage standard-dose (SDCT) or high-dose chemotherapy (HDCT), about 15% of pts with relapsed GCT are incurable. Immune therapy with Pembrolizumab is a novel approach for salvage in pts with metastatic GCT. Methods: Single arm phase 2 trial investigating pembrolizumab 200mg IV Q3weeks until disease progression in pts with relapsed GCT and no curable options. Pts age≥18 with metastatic GCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (HDCT or SDCT) were eligible. Centrally assessed PD-L1 on tumor infiltrating immune cells using PD-L1 (22C3) assay was scored as 0, 1, 2, 3 along with PD-L1 expression score (H-score) incorporating intensity of staining. Pts were eligible irrespective of PD-L1 expression status. The primary endpoint was overall response rate using immune-related response criteria. Simon’s 2-stage design required response in ≥ 1/12 pts to proceed to stage 2 enrolling 8 more pts for a total of 20. Results: 12 male pts were enrolled. Median age 38 (range, 27-55). All pts had non-seminoma. Primary tumor site was testis in 11 pts and mediastinum in 1. Median AFP 615 (range, 1-32,760) and hCG 4 (range, 0.6-37,096). 5 pts had late relapse ( &gt; 2years). Median number of previous chemotherapy regimens was 3 (range, 1-6). 6 pts received prior HDCT. 2 pts had positive PD-L1 staining (H-score 90 and 170). Median number of deliverable pembrolizumab doses was 2 (range, 1-8). There were 5 grade 3 adverse events, with 3 events possibly related to study treatment (chest pain, hyperglycemia, abdominal pain). No partial or complete responses were observed. 2 pts achieved stable disease for 12 and 9 weeks respectively; 10 pts had progression of disease as their best response. The 2 pts with stable disease had continued rising AFP level despite radiographic stability; both had negative PD-L1 staining. Conclusions: This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Although 2 pts had stable disease, each had rising tumor markers suggesting continued treatment resistance. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. Clinical trial information: NCT02499952.
KIT Suppresses BRAFV600E-Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling
Authors: James V. Neiswender, Robert L. Kortum, Caitlin Bourque, Melissa Kasheta, Leonard I. Zon, Deborah K. Morrison, Craig J. Ceol
Journal: Cancer Research (2017)

The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF- or NRAS-activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation into a strain of Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone zebrafish. Melanoma onset was accelerated in kit(lf); Tg(mitfa:BRAFV600E); p53(lf) fish. Tumors from kit(lf) animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAFV600E-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAFV600E could paradoxically reduce signaling downstream of BRAFV600E, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAFV600E signaling. In vivo, expression of wild-type BRAF delayed melanoma onset, but only in a kit-dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAFV600E-driven melanoma formation. Cancer Res; 77(21); 5820-30. ©2017 AACR.
Abstract 155: TGF-β1 Positively Modulates Cell-Metal Interaction in Cardiovascular Applications
Authors: S Hamed Alavi, Arash Kheradvar
Journal: Circulation Research (2012)

Introduction: The interaction between a metallic implant and local cells in the cardiovascular system determines the fate of the implant. We have recently developed a hybrid scaffold for tissue engineering of valves, which consists of an extra thin layer of Stainless Steel mesh tightly enclosed by three distinct layers of cells. We have examined the effect of TGF-β1 on degree of cell attachment to the metal mesh. Methods and Results: By using a 3D cell culture method a Stainless Steel mesh with desired size and thickness was enclosed through cultured layers of cells similar to a heart valve leaflet pattern. Human aortic smooth muscle cells and adventitial fibroblast/myofibroblast cells were used to fulfill the role of valvular interstitial cells, and human umbilical vascular endothelial cells were used to cover the construct in place of the valvular endothelial cells. The layers were seeded in sequence on a three dimensional, porous biological scaffold comprised of bovine type I collagen gel mixture. The effect of TGF-β1 supplementation at proper time-steps on the cultured hybrid tissue after two months of cell culture was determined. TGF-β supplementation resulted in significant increase in proliferation, and extra ingrowths into the outer portions of the tissue. DAPI staining of nuclei showed that the number of cells at the surface of the mesh progressively increased due to TGF-β, and eventually formed a thicker tissue around the mesh Conclusions: We have demonstrated the effects of TGF-β1 on cell attachment and tissue development by using a hybrid tissue material that helped us study the direct cell-metal interactions in-vitro.
Skin infections are eliminated by cooperation of the fibrinolytic and innate immune systems
Authors: William Santus, Simona Barresi, Francesca Mingozzi, Achille Broggi, Ivan Orlandi, Giulia Stamerra, Marina Vai, Alessandra M. Martorana, Alessandra Polissi, Julia R. Köhler, Ningning Liu, Ivan Zanoni, Francesca Granucci
Journal: Science Immunology (2017)

Nuclear factor of activated T cells (NFAT) is activated in innate immune cells downstream of pattern recognition receptors, but little is known about NFAT's functions in innate immunity compared with adaptive immunity. We show that early activation of NFAT balances the two major phases of the innate response to Candida albicans skin infections: the protective containment (abscess) and the elimination (expulsion) phases. During the early containment phase, transforming growth factor-β (TGF-β) induces the deposit of collagen around newly recruited polymorphonuclear cells to prevent microbial spreading. During the elimination phase, interferon-γ (IFN-γ) blocks differentiation of fibroblasts into myofibroblasts by antagonizing TGF-β signaling. IFN-γ also induces the formation of plasmin that, in turn, promotes abscess capsule digestion and skin ulceration for microbial discharge. NFAT controls innate IFN-γ production and microbial expulsion. This cross-talk between the innate immune and the fibrinolytic systems also occurs during infection with Staphylococcus aureus and is a protective response to minimize tissue damage and optimize pathogen elimination.
Abstract 18760: Resident c-kit-positive Cardiac Stem Cells Replenish Cardiomyocytes During Physiological Cardiac Growth
Authors: Daniele Torella, Iolanda Aquila, Carla Vicinanza, Angelo Leone, Angela Bochicchio, Christelle Correale, Cheryl D Waring, Ciro Indolfi, Bernardo Nadal-Ginard, Georgina M Ellison
Journal: Circulation (2012)

How cell diversity is maintained within the adult heart through normal wear and tear and physio-pathologic remodeling remains an unanswered question. Intriguingly, exercise training produces physiological growth of the myocardium encompassing both myocyte hypertrophy and new myocyte formation. We assessed whether new myocyte formation during exercise training is the direct progeny of resident c-kit-positive (c-kit-pos) cardiac stem/progenitor cells (CSCs). Mice underwent a program of controlled swimming for 28 days. Untrained mice acted as sedentary controls. To distinguish new myocyte formation (detected by BrdU in vivo labeling) due to unexpected myocyte division or to stem cell differentiation, we used double-transgenic mice by crossbreeding the myocyte-specific Myh6-MerCreMer mice with p-lox-LacZ-Stop-lox/eYFP (ZYP) mice. To ascertain a direct relationship between c-kit-pos CSCs and new myocyte generation, we released into the myocardium of ZYP mice a lentiviral vector carrying Cre-Recombinase under the control of the c-kit promoter (Lenti-c-kit/Cre). This strategy permanently labels with YFP only resident c-kit-pos CSCs and allows to track their cell fate. Physical exercise produced rapid myogenic differentiation in c-kit-pos CSCs during the 28 days swimming program, which was followed by an increased number of new myocytes. The inducible myocyte-specific genetic fate-mapping strategy shows that new myocytes are not generated through the division of pre-existing myocytes but rather are replenished by stem/progenitor cells. Importantly, when chimeric GFP bone marrow-transplanted mice were enrolled in the training program, all new myocytes were GFP-negative, thus confirming they were not derived from cardiac homed bone marrow stem cells. Finally, through the Cre/YFP c-kit-pos CSC specific genetic recombination in vivo, we demonstrated that new myocyte formation during exercise training is the direct progeny of c-kit-pos CSC differentiation. These data based on genetic cell fate mapping provide the convincing direct evidence that cardiac workload triggers the in situ cardiac regenerative capacity of c-kit-pos CSCs. This property of the myocardium could be meaningfully exploited for cardiac regenerative therapies.
Particulate Matter Air Pollution and the Risk of Incident CKD and Progression to ESRD
Authors: Benjamin Bowe, Yan Xie, Tingting Li, Yan Yan, Hong Xian, Ziyad Al-Aly
Journal: Journal of the American Society of Nephrology (2017)

Elevated levels of fine particulate matter &lt;2.5 µ m in aerodynamic diameter (PM 2.5 ) are associated with increased risk of cardiovascular outcomes and death, but their association with risk of CKD and ESRD is unknown. We linked the Environmental Protection Agency and the Department of Veterans Affairs databases to build an observational cohort of 2,482,737 United States veterans, and used survival models to evaluate the association of PM 2.5 concentrations and risk of incident eGFR &lt;60 ml/min per 1.73 m 2 , incident CKD, eGFR decline ≥30%, and ESRD over a median follow-up of 8.52 years. County-level exposure was defined at baseline as the annual average PM 2.5 concentrations in 2004, and separately as time-varying where it was updated annually and as cohort participants moved. In analyses of baseline exposure (median, 11.8 [interquartile range, 10.1–13.7] µ g/m 3 ), a 10- µ g/m 3 increase in PM 2.5 concentration was associated with increased risk of eGFR&lt;60 ml/min per 1.73 m 2 (hazard ratio [HR], 1.21; 95% confidence interval [95% CI], 1.14 to 1.29), CKD (HR, 1.27; 95% CI, 1.17 to 1.38), eGFR decline ≥30% (HR, 1.28; 95% CI, 1.18 to 1.39), and ESRD (HR, 1.26; 95% CI, 1.17 to 1.35). In time-varying analyses, a 10- µ g/m 3 increase in PM 2.5 concentration was associated with similarly increased risk of eGFR&lt;60 ml/min per 1.73 m 2 , CKD, eGFR decline ≥30%, and ESRD. Spline analyses showed a linear relationship between PM 2.5 concentrations and risk of kidney outcomes. Exposure estimates derived from National Aeronautics and Space Administration satellite data yielded consistent results. Our findings demonstrate a significant association between exposure to PM 2.5 and risk of incident CKD, eGFR decline, and ESRD.
Therapeutic targeting of CK2 in acute and chronic leukemias
Authors: F Buontempo, J A McCubrey, E Orsini, M Ruzzene, A Cappellini, A Lonetti, C Evangelisti, F Chiarini, C Evangelisti, J T Barata, A M Martelli
Journal: Leukemia (2017)

CK2 is a ubiquitously expressed, constitutively active Ser/Thr protein kinase, which is considered the most pleiotropic protein kinase in the human kinome. Such a pleiotropy explains the involvement of CK2 in many cellular events. However, its predominant roles are stimulation of cell growth and prevention of apoptosis. High levels of CK2 messenger RNA and protein are associated with CK2 pathological functions in human cancers. Over the last decade, basic and translational studies have provided evidence of CK2 as a pivotal molecule driving the growth of different blood malignancies. CK2 overexpression has been demonstrated in nearly all the types of hematological cancers, including acute and chronic leukemias, where CK2 is a key regulator of signaling networks critical for cell proliferation, survival and drug resistance. The findings that emerged from these studies suggest that CK2 could be a valuable therapeutic target in leukemias and supported the initiation of clinical trials using CK2 antagonists. In this review, we summarize the recent advances on the understanding of the signaling pathways involved in CK2 inhibition-mediated effects with a particular emphasis on the combinatorial use of CK2 inhibitors as novel therapeutic strategies for treating both acute and chronic leukemia patients.