tbuckley/cabot-search huggingface dataset:
Abstract P049: Molecular Mechanisms of PARP1-Mediated Necrosis
Authors: Diana L Douglas, Christopher P Baines
Journal: Circulation Research (2011)

Poly(ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme associated with DNA replication, transcription, repair, and cell death. Although, PARP1 is most commonly associated with apoptosis, a specific PARP1-mediated caspase-independent necrosis pathway has recently been described. Two main models for this pathway have been proposed: one involving RIP1 and JNK kinases and mitochondrial permeability transition (MPT), the other involving activation of Bax and subsequent release of apoptosis inducing factor (AIF) from mitochondria. However, these models still remain untested. Consequently, the purpose of this study was to determine which (if any) of these molecules are truly involved in PARP1-mediated necrosis. Murine embryonic fibroblasts (MEFs) were treated with either N-Methyl-N’-Nitro-N-Nitrosoguanidine (MNNG) or β-Lapachone, 2 chemically distinct PARP1 activators. To inhibit RIP1, CypD, and AIF, MEFs were transfected with specific siRNAs for 48 hrs prior to treatment. RIP1 and CypD-null cells were also used. To block JNK activity, cells were incubated with the JNK-specific inhibitor SP600125. Inhibition of Bax was achieved using either Bax/Bak-null MEFs or Bcl2 overexpression. Necrosis, MPT, JNK activation, and AIF translocation were then analyzed using a combination of cell death assays, western blotting, and immunocytochemistry. Treatment of MEFs with MNNG and β-Lapachone induced translocation of AIF from the mitochondria to nucleus, and necrotic cell death. However, inhibition of RIP1, CypD, and Bax had no significant effect on MNNG or β-Lapachone- induced necrotic cell death. Moreover, neither PARP1 activator induced MPT. In contrast, the JNK inhibitor SP600125 significantly reduced MNNG- and β-Lapachone-induced JNK activation, AIF translocation, and necrosis. This suggests that JNK plays a key role in the pathway and that it is upstream of AIF. To our surprise, however, depletion of AIF did not influence PARP1-mediated cell death, thus indicating that AIF is more of a marker, rather than a key mediator, of this particular process. We conclude that JNK plays a significant signaling role in PARP1-mediated necrosis. However, RIP1, Bax, CypD, and AIF do not appear to be essential components of the PARP1 death pathway.
Abstract 401: The γ2-AMPK Regulates Glucose and Glycogen Metabolism in the Heart by Modulating Cytosolic Hexokinase II Level
Authors: Maengjo Kim, Lorena Garcia-Menendez, Yong Seon Choi, Birthe Roos, Mirjam M Wamelink, Haiwei Gu, Lauren Abell, Daniel Raftery, Richard D Palmiter, Rong Tian
Journal: Circulation Research (2016)

Mutations in the γ2-subunit of AMPK (encoded by PRKAG2 gene) cause glycogen storage cardiomyopathy. We generated a mouse model with cardiac specific deletion of γ2-AMPK (cKO) to define its function in the heart. The cKO mice were born normal and remained indistinguishable from control mice under baseline conditions but developed greater cardiac hypertrophy and dysfunction after transverse aortic constriction (TAC). The total AMPK activity was normal in cKO hearts and it increased after TAC to the same extent as that of the controls. However, the γ2-AMPK activity was abolished in the cKO and the overall AMPK activity was maintained by a compensatory increase in the γ1-AMPK activity. The lack of γ2-AMPK selectively reduced hexokinase II in the cytosol resulting in decreases in glycogen content and NADPH levels. Knock-down of γ2-AMPK subunit in neonatal rat ventricle cardiomyocytes resulted in increased oxidative stress and exacerbated response to phenylephrine and H 2 O 2 , both were rescued by HKII overexpression. Taken together, these data identify isoform-specific functions of γ2-AMPK in regulating glucose and glycogen metabolism that are critical for cardiac response to stress. The results also indicate that the specific activation of γ2-AMPK is responsible for the glycogen storage cardiomyopathy associated with PRKAG2 mutations.
MicroRNA-155 regulates casein kinase 1 gamma 2: a potential pathogenetic role in chronic lymphocytic leukemia
Authors: T Zhang, J K Davidson-Moncada, P Mukherjee, R R Furman, E Bhavsar, Z Chen, P Hakimpour, N Papavasiliou, W Tam
Journal: Blood Cancer Journal (2017)

Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in Western countries. There are approximately 19 000 new cases diagnosed in the United States in 2016 (https://seer.cancer.gov/statfacts/html/clyl.html). MicroRNAs (miRs) have been implicated as one of the key contributors in the pathogenesis of CLL. One of these miRNAs is miR-155, which is probably the best-characterized miRNA involved in B-cell maturation and function. MiR-155 has a critical role in normal immune function,1 including innate response, regulation of the germinal center response and formation of class-switched plasma cells and negative regulation of activation-induced cytidine deaminase. However, miR-155 is also an oncogenic miRNA overexpression of miR-155 in mice or its precursor BIC in chickens led to the development of lymphomas. Furthermore, abnormal expression of miR-155 has been observed in a number of lymphoid malignancies, including diffuse large B-cell lymphoma, classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma and CLL.2 In various studies, miR-155 has been found consistently overexpressed in CLL cells compared with normal B cells. Although there does not appear to be definitive correlations between miR-155 expression levels and individual CLL prognostic factors, high pretreatment levels of miR-155 in CLL cells or in plasma have been demonstrated to be associated with shorter need-for-treatment interval and failure to achieve complete response, respectively.3, 4 The association of adverse clinical outcome in CLL with high miR-155 levels appears to be linked to the capacity of miR-155 to enhance the sensitivity of CLL cells to B-cell receptor ligation.5 Thus it is likely that miR-155 has important roles in the pathobiology of CLL.
Prostate tumors preferentially express Th2 cytokines and chemokines: Implications in prostate cancer immunotherapy.
Authors: Kereen Gordon, Godwin Ifere, LaTonia Taliaferro-Smith, Eno Ekong, Francis Eko, Joseph Igietseme, Natalya Klueva, Godwin Ananaba
Journal: Clinical Cancer Research (2007)

A50  Cytokines and chemokines and their cognate receptors are essential immune effector molecules that are known to be involved in tumor progression. Th2 specific cytokines are generally immunosuppressive and have been reported to be elevated in a large number of advanced tumors and correlated with poor prognosis. In this study, we investigated the hypothesis that Th2 specific cytokines IL-4, IL-10 and Th2 specific chemokine CCL17(TARC) and cognate receptor CCR4 are upregulated in prostate adenocarcinoma cell lines relative to immortalized normal prostate epithelial cells. Standard PCR showed that IL-4 and IL-10 are expressed in DU145, PC3 and LNCaP prostate tumor cells. Real time PCR(qRT-PCR) and proteomic analysis indicated that CCL17 and receptor CCR4 are significantly upregulated in DU145 and PC3 prostate tumor cell lines relative to immortalized normal prostate epithelial cell line. The production of Th2 specific cytokines and chemokines by tumor cell lines explains a possible mechanism for them to negatively modulate the immune response and support their metastatic potential. Th2 specific cytokines may be used as potential diagnostic biomarkers for disease progression. In addition, an efficacious vaccine will depend on its ability to inhibit the recruitment of known distinct functional Th2 subsets, implicated in prostate cancer progression. Supported by NIH grants GM08247 and AI41231.
Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells
Authors: Marco Ruella, Michael Klichinsky, Saad S Kenderian, Olga Shestova, Amy Ziober, Michael D Feldman, Mariusz A Wasik, Carl H June, Saar I Gill
Journal: Blood (2016)
Quality of life in people with vitiligo: a systematic review and meta-analysis
Authors: B. Morrison, E. Burden-Teh, J.M. Batchelor, E. Mead, D. Grindlay, S. Ratib
Journal: British Journal of Dermatology (2017)

Vitiligo is cosmetically disfiguring and has profound psychosocial effects due to stigmatization, problems in sexual function, anxiety, self-esteem and difficulty finding employment. Previous studies suggest a reduction in quality of life (QoL) due to vitiligo, but to date no systematic review has quantified this in comparison to people without vitiligo. Therefore, the aim of this review was to compare QoL in people with and without vitiligo.
代謝チェックポイントキナーゼmTORC1を介する慢性的シグナル伝達は,マクロファージ肉芽形成を誘導し,サルコイドーシスの進行を知らせる
Authors: Linke Monika, Pham Ha Thi Thanh, Katholnig Karl, Schnoeller Thomas, Miller Anne, Demel Florian, Schuetz Birgit, Rosner Margit, Kovacic Boris, Sukhbaatar Nyamdelger, Niederreiter Birgit, Blueml Stephan, Kuess Peter, Sexl Veronika, Mueller Mathias, Mikula Mario, Weckwerth Wolfram, Haschemi Arvand, Susani Martin, Hengstschlaeger Markus, Gambello Michael J, Weichhart Thomas
Journal: Nature Immunology (2017)
Cutaneous T‐cell lymphoma: 2017 update on diagnosis, risk‐stratification, and management
Authors: Ryan A. Wilcox
Journal: American Journal of Hematology (2017)

Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS).The diagnosis of MF or SS requires the integration of clinical and histopathologic data.TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
Cyclooxygenase inhibition and response to anti-PD1/L1 in advanced melanoma.
Authors: Romany Anne Nilanthi Johnpulle, Megan Lynn Hames Pollack, Kelsie Riemenschneider, Igor Puzanov, Jeffrey Alan Sosman, Douglas Buckner Johnson
Journal: Journal of Clinical Oncology (2016)

e21023 Background: The advent of agents blocking programmed death 1/ligand (PD-1/PD-L1) has transformed the treatment of melanoma and other malignancies. A recent study suggested that suppression of the cyclooxygenase (COX) pathway, remodels the tumor microenvironment and can act synergistically with PD-1 blockade. We hypothesized that patients (pts) with advanced melanoma treated with anti-PD-1/PD-L1, who were concomitantly receiving a non-steroidal anti-inflammatory agent (NSAID) or aspirin (ASA) may have improved clinical outcomes compared to pts not using these agents. Methods: We performed a retrospective, single-institution review of 167 pts with metastatic melanoma, who were treated with anti-PD-1/PD-L1. We characterized prognostic features (prior therapies, disease stage, lactate dehydrogenase (LDH)), NSAID/ASA use and dose, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). Results: 167 pts with advanced melanoma received either nivolumab, pembrolizumab, or atezolizumab monotherapy. Seventy-two (43%) of these pts concomitantly received NSAIDs/ASA. Baseline characteristics were similar between the two groups. An NSAID or ASA alone was used by 34 (47%) and 28 (39%) pts, respectively, while 10 (14%) pts received both agents. Of the 44 pts on NSAIDs, 36 received them as needed (prn). Of the 38 pts who were on ASA, all but 2 received ≤ 81mg daily. ORR in the NSAID/ASA group was 43% (31/72) vs. 34% (32/95) in pts not on either of these agents (p = 0.21). When comparing pts on NSAID/ASA with those not on these agents, the median PFS and OS were 6.7 vs. 5.3 months (p = 0.065) and 25.7 vs. 14 months (p = 0.09), respectively. No difference in grade 3+ irAEs was observed between groups. No pts on NSAIDs developed immune-related nephritis. Conclusions: In this small cohort of pts with melanoma treated with anti-PD1/L1 and receiving NSAIDs/ASA, there was no statistically significant improvement in outcomes compared to those not taking these medications. However, the predominance of low-dose/prn dosing in this study and the numerical trends towards improved ORR, PFS and OS suggest that this should be studied in a larger and prospective fashion using various doses.
Brief Report: A Novel <i>ELANE</i> Mutation Associated With Inflammatory Arthritis, Defective NETosis, and Recurrent Parvovirus Infection
Authors: Uma Thanarajasingam, Mark A. Jensen, Jessica M. Dorschner, Theresa Wampler Muskardin, Yogita Ghodke‐Puranik, Monica Purmalek, Elias Eliopoulos, Maria I. Zervou, George N. Goulielmos, Matthew Howard, Mariana J. Kaplan, Timothy B. Niewold
Journal: Arthritis & Rheumatology (2017)

Objective We describe a 38‐year‐old woman who presented with a history of inflammatory arthritis, rash, and daily fevers. She was noted to have chronic parvovirus infection with persistently detectable viral titers and a novel mutation in the ELANE gene. ELANE encodes neutrophil elastase, a neutrophil serine protease with important antimicrobial effects, and is found as part of neutrophil extracellular trap (NET) complexes. Pathogenic ELANE mutations have been identified in forms of hereditary neutropenia. However, our patient never had neutropenia. Because of the striking clinical scenario, we investigated this mutation functionally. Methods NET formation by neutrophils was assessed by scanning electron microscopy. Neutrophil activation and neutrophil elastase production were evaluated by flow cytometry and fluorescent substrate–based functional assay, respectively. A multiplex assay was used to quantitate neutrophil inflammatory cytokine production. PyMOL software was used to generate 3‐dimensional models of mutant elastase. Results Activated neutrophils from the patient demonstrated a significantly decreased ability to form NETs on scanning electron microscopy, as well as quantitative defects in neutrophil activation and neutrophil elastase activity. The patient's neutrophils showed altered levels of interleukin‐12 (IL‐12) and IL‐8, which are key cytokines for antiviral immunity and neutrophil chemotaxis. Three‐dimensional mapping revealed that the mutation could alter protein folding and surface charge distribution, potentially perturbing protein trafficking. Thus, the mutation could affect neutrophil function by decreasing NETosis and altering key antiviral activities of neutrophils. Conclusion This is the first report of a human pathogenic ELANE mutation associated with a defect in NETosis and a distinct syndrome of recurrent viral infection and chronic inflammation.
A Collaborative Cardiologist-Intensivist Management Model Improves Cardiac Intensive Care Unit Outcomes
Authors: Karan Kapoor, Avelino C. Verceles, Giora Netzer, Amal Chaudhry, Mary Bolgiano, Sandeep Devabhakthuni, Jonathan Ludmir, Jeremy S. Pollock, Gautam V. Ramani, Michael T. McCurdy
Journal: Journal of the American College of Cardiology (2017)
Liraglutide and Renal Outcomes in Type 2 Diabetes
Authors: Johannes F E Mann, David D Ørsted, Kirstine Brown-Frandsen, Steven P Marso, Neil R Poulter, Søren Rasmussen, Karen Tornøe, Bernard Zinman, John B Buse
Journal: New England Journal of Medicine (2017)

In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown.We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed.A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively).This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .).
Co-expression of an EGFR mutant with ErbB-2 enhanced motility and invasion
Authors: Karin D. Rodland, Nikki Bollinger, Lee Opresko, Steven Wiley
Journal: Cancer Research (2005)

4508  Cells are confronted with a variety of extracellular signals, including peptide ligands, amino acids, nucleotides, small organic molecules, and even specific ions. In order for cells to integrate information from multiple distinct signals, it is necessary that there be some mechanism for the signal from one receptor pathway to modify cell responsiveness to a second receptor type. Using human mammary epithelial cells as a model system, we have investigated the ability of multiple distinct receptor subclasses to transactivate the EGFR. We found that G-protein coupled receptors (the LPA receptor and the Calcium-sensing receptor), cytokine receptors (VEGF receptors and GH receptors), the TNF alpha receptor, and the IGF receptor were all capable of transactivating the EGFR as determined by increased phosphorylation of ERK1/2 that was dependent on EGFR kinase activity and on the metalloprotease-mediated release of EGFR ligands. ERK phosphorylation in response to general stressors (sorbitol or anisomycin) was also dependent on EGFR kinase activity. In contrast, Met, the receptor for HGF/scatter factor, acted independently from the EGFR in increasing ERK phosphorylation. The signaling pathways linking each of these receptor classes to ligand shedding are currently under investigation.
Vision Screening in Children Aged 6 Months to 5 Years
Authors: David C. Grossman, Susan J. Curry, Douglas K. Owens, Michael J. Barry, Karina W. Davidson, Chyke A. Doubeni, John W. Epling, Alex R. Kemper, Alex H. Krist, Ann E. Kurth, C. Seth Landefeld, Carol M. Mangione, Maureen G. Phipps, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng
Journal: JAMA (2017)

<h3>Importance</h3> One of the most important causes of vision abnormalities in children is amblyopia (also known as "lazy eye"). Amblyopia is an alteration in the visual neural pathway in a child's developing brain that can lead to permanent vision loss in the affected eye. Among children younger than 6 years, 1% to 6% have amblyopia or its risk factors (strabismus, anisometropia, or both). Early identification of vision abnormalities could prevent the development of amblyopia. <h3>Subpopulation Considerations</h3> Studies show that screening rates among children vary by race/ethnicity and family income. Data based on parent reports from 2009-2010 indicated identical screening rates among black non-Hispanic children and white non-Hispanic children (80.7%); however, Hispanic children were less likely than non-Hispanic children to report vision screening (69.8%). Children whose families earned 200% or more above the federal poverty level were more likely to report vision screening than families with lower incomes. <h3>Objective</h3> To update the 2011 US Preventive Services Task Force (USPSTF) recommendation on screening for amblyopia and its risk factors in children. <h3>Evidence Review</h3> The USPSTF reviewed the evidence on the accuracy of vision screening tests and the benefits and harms of vision screening and treatment. Surgical interventions were considered to be out of scope for this review. <h3>Findings</h3> Treatment of amblyopia is associated with moderate improvements in visual acuity in children aged 3 to 5 years, which are likely to result in permanent improvements in vision throughout life. The USPSTF concluded that the benefits are moderate because untreated amblyopia results in permanent, uncorrectable vision loss, and the benefits of screening and treatment potentially can be experienced over a child's lifetime. The USPSTF found adequate evidence to bound the potential harms of treatment (ie, higher false-positive rates in low-prevalence populations) as small. Therefore, the USPSTF concluded with moderate certainty that the overall net benefit is moderate for children aged 3 to 5 years. <h3>Conclusions and Recommendations</h3> The USPSTF recommends vision screening at least once in all children aged 3 to 5 years to detect amblyopia or its risk factors. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of vision screening in children younger than 3 years. (I statement)
Validity, responsiveness and minimum clinically important difference of the incremental shuttle walk in idiopathic pulmonary fibrosis: a prospective study
Authors: Claire M Nolan, Veronica Delogu, Matthew Maddocks, Suhani Patel, Ruth E Barker, Sarah E Jones, Samantha S C Kon, Toby M Maher, Paul Cullinan, William D-C Man
Journal: Thorax (2017)

The incremental shuttle walk (ISW) is well validated in COPD but limited psychometric data restrict its use in idiopathic pulmonary fibrosis (IPF). Study 1: 50 patients performed the ISW and 6 min walk test (6MWT). Study 2: 72 patients completed the ISW before and after pulmonary rehabilitation (PR). The ISW correlated strongly with 6MWT distance (r=0.81,p<0.0001). Mean (95% confidence interval) improvement in ISW with PR was 54 (38 to 70) m with an effect size of 0.29. Distribution-based and anchor-based minimum clinically important difference (MCID) estimates ranged from 31 to 46 m. The ISW is valid and responsive in IPF, with an anchor-based MCID estimate similar to that observed in chronic obstructive pulmonary disease.
骨格筋由来幹細胞は腹壁再建のための生分解性エラストマへのmicrointegrated【Powered by NICT】
Authors: Takanari Keisuke, Hashizume Ryotaro, Hong Yi, J Amoroso Nicholas, Yoshizumi Tomo, Gharaibeh Burhan, Yoshida Osamu, Nonaka Kazuhiro, Sato Hideyoshi, Huard Johnny, R Wagner William
Journal: Biomaterials (2017)