tbuckley/cabot-search huggingface dataset:
NF-κB upregulation through epigenetic silencing of LDOC1 drives tumor biology and specific immunophenotype in Group A ependymoma
Authors: Andrea M Griesinger, Davis A Witt, Sydney T Grob, Sabrina R Georgio Westover, Andrew M Donson, Bridget Sanford, Jean M Mulcahy Levy, Randall Wong, Daniel C Moreira, John A DeSisto, Ilango Balakrishnan, Lindsey M Hoffman, Michael H Handler, Kenneth L Jones, Rajeev Vibhakar, Sujatha Venkataraman, Nicholas K Foreman
Journal: Neuro-Oncology (2017)

Inflammation has been identified as a hallmark of high-risk Group A (GpA) ependymoma (EPN). Chronic interleukin (IL)-6 secretion from GpA tumors drives an immune suppressive phenotype by polarizing infiltrating monocytes. This study determines the mechanism by which IL-6 is dysregulated in GpA EPN.Twenty pediatric GpA and 21 pediatric Group B (GpB) EPN had gene set enrichment analysis for MSigDB Hallmark gene sets performed. Protein and RNA from patients and cell lines were used to validate transcriptomic findings. GpA cell lines 811 and 928 were used for in vitro experiments performed in this study.The nuclear factor-kappaB (NF-κB) pathway is a master regulator of IL-6 and a signaling pathway enriched in GpA compared with GpB EPN. Knockdown of NF-κB led to significant downregulation of IL-6 in 811 and 928. NF-κB activation was independent of tumor necrosis factor alpha (TNF-α) stimulation in both cell lines, suggesting that NF-κB hyperactivation is mediated through an alternative mechanism. Leucine zipper downregulated in cancer 1 (LDOC1) is a known transcriptional repressor of NF-κB. In many cancers, LDOC1 promoter is methylated, which inhibits gene transcription. We found decreased LDOC1 gene expression in GpA compared with GpB EPN, and in other pediatric brain tumors. EPN cells treated with 5AZA-DC, demethylated LDOC1 regulatory regions, upregulated LDOC1 expression, and concomitantly decreased IL-6 secretion. Stable knockdown of LDOC1 in EPN cell lines resulted in a significant increase in gene transcription of v-rel avian reticuloendotheliosis viral oncogene homolog A, which correlated to an increase in NF-κB target genes.These results suggest that epigenetic silencing of LDOC1 in GpA EPN regulates tumor biology and drives inflammatory immune phenotype.
Long-Term Prognosis of Patients With Intramural Course of Coronary Arteries Assessed With CT Angiography
Authors: Aukelien C. Dimitriu-Leen, Alexander R. van Rosendael, Jeff M. Smit, Tessa van Elst, Nan van Geloven, Teemu Maaniitty, J. Wouter Jukema, Victoria Delgado, Arthur J.H.A. Scholte, Antti Saraste, Juhani Knuuti, Jeroen J. Bax
Journal: JACC. Cardiovascular imaging (2017)
Hepatocyte Growth Factor mediates growth through the activation of ERK5 in mesothelioma cell lines
Authors: Maria E. Ramos-Nino, Steve Blumen, Tara Sabo-Attwood, Joanna Gell, Brooke T. Mossman
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4269 

Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor Met are present in most malignant mesothelioma tumors suggesting that their expression is involved in mesothelioma progression. Previous studies have suggested that Met signaling contributes to chemotaxis, growth, invasion, and angiogenesis. However, the mechanisms through which MET signaling contribute to these events remains unclear. Here we show in six mesothelioma cell lines that signaling by HGF strongly phosphorylates ERK5. Decreased activation of ERK5 by inhibiting its activator, MEK5 with a siRNA construct, reduced the growth effect of HGF in these cells. Additionally, we showed that ERK5 activation by HGF is dependent on the phosphatidylinositol 3-kinase pathway. These results suggest that the ERK5 pathway may be a therapeutic target in mesothelioma. Supported by the Vermont Cancer Center: LCCRO (MERN) and KO1 CA104159-01 (MERN).
Missed Opportunities for Measles, Mumps, Rubella Vaccination Among Departing U.S. Adult Travelers Receiving Pretravel Health Consultations
Authors: Emily P. Hyle, Sowmya R. Rao, Emily S. Jentes, Amy Parker Fiebelkorn, Stefan H.F. Hagmann, Allison Taylor Walker, Rochelle P. Walensky, Edward T. Ryan, Regina C. LaRocque
Journal: Annals of Internal Medicine (2017)

Measles outbreaks continue to occur in the United States and are mostly due to infections in returning travelers.
Soundings: Who measures the Holy Dread?
Authors: Kevin Barraclough
Journal: BMJ (2005)

If you tell patients that a drug is shown in a trial to reduce their absolute risk by 0.2% per year they usually don't want it. They weigh the marginal absolute benefit against the harm of being “medicalised,” and they decline. The opinion forming “experts” who ran the trial take a different view. The experts demonstrate the relative risk reduction with bar charts at a string of lucrative international conferences. They sit on the guidelines committee and see the odd patient between conferences. Their opinion is, they say, evidence based.

Michael Atiyah, a Cambridge mathematician, once described algebra as a Faustian pact with the devil. Mathematicians gained, in algebra, a tool of sublime power but risked losing their soul. While a geometric proof gives patterns that the eye and the soul know to be true, algebra delivers powerful results but does so opaquely, with the magician's sleight of hand. We take the result on the authority of the method rather than “knowing” it to be true.

Evidence based medicine (EBM) is surely a similar pact with the devil. It is a tool of enormous power, but its answers are critically dependent on the validity and subtlety of the questions asked. The temptation is there to treat cohorts rather than people, and people vary not only in their biological responses but also in their aspirations and fears. Those two added years in a nursing home may not be an important benefit to them.

William Osler was once said to have referred the writer Henry James to a colleague. The colleague diagnosed James as having “a dread of the unknown.” I suspect this outcome is rarely measured in the trials. EBM may prove, for example, that we should screen for breast cancer, cervical cancer, and each of our other subliminal nightmares. But who has measured the increase in “the dread of the unknown”? Which variable measures the iatrogenic deceit that we can cheat death? Twenty years ago James McCormick put it thus: “Since death is the inevitable consequence of conception, a morbid preoccupation with its avoidance, and the state of Holy Dread which such a fear engenders, may diminish the quality of life.” In the trials, whose results often advocate medicalising society still further, who measures the “Holy Dread”?
Image Gallery: A case of pemphigus vulgaris following <i>Simulium</i> spp. (Diptera) bites
Authors: C.G. Wambier, T.A. Struecker, L.N. Durski, A.G. de Araújo, S.P.F. Wambier, M.A. Cappel, S. Vernal, A.M. Roselino
Journal: British Journal of Dermatology (2017)
The Clinical Characteristics, Genetic Alterations and Prognostic Significance of De Novo Acute Myeloid Leukemia (AML) with Hyperleukocytosis (HL)
Authors: Feng-Ming Tien, Hsin-An Hou, Chien-Yuan Chen, Wen-Chien Chou, Chi-Cheng Li, Chien-Ting Lin, Ming Yao, Shang-Yi Huang, Bor-Sheng Ko, Szu-Chun Hsu, Shang-Ju Wu, Woei Tsay, Jih-Luh Tang, Hwei-Fang Tien
Journal: Blood (2016)
Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs
Authors: Mikhail Kosiborod, Matthew A. Cavender, Alex Z. Fu, John P. Wilding, Kamlesh Khunti, Reinhard W. Holl, Anna Norhammar, Kåre I. Birkeland, Marit Eika Jørgensen, Marcus Thuresson, Niki Arya, Johan Bodegård, Niklas Hammar, Peter Fenici
Journal: Circulation (2017)

Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class. Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51–0.73; P &lt;0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41–0.57; P &lt;0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48–0.60; P &lt;0.001) with no significant heterogeneity by country. Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02993614.
Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline – Updated January 2017
Authors: Jean-Marc Dumonceau, Pierre Deprez, Christian Jenssen, Julio Iglesias-Garcia, Alberto Larghi, Geoffroy Vanbiervliet, Guruprasad Aithal, Paolo Arcidiacono, Pedro Bastos, Silvia Carrara, László Czakó, Gloria Fernández-Esparrach, Paul Fockens, Àngels Ginès, Roald Havre, Cesare Hassan, Peter Vilmann, Jeanin van Hooft, Marcin Polkowski
Journal: Endoscopy (2017)

MAIN RECOMMENDATIONS For pancreatic solid lesions, ESGE recommends performing endoscopic ultrasound (EUS)-guided sampling as first-line procedure when a pathological diagnosis is required. Alternatively, percutaneous sampling may be considered in metastatic disease. Strong recommendation, moderate quality evidence. In the case of negative or inconclusive results and a high degree of suspicion of malignant disease, ESGE suggests re-evaluating the pathology slides, repeating EUS-guided sampling, or surgery. Weak recommendation, low quality evidence. In patients with chronic pancreatitis associated with a pancreatic mass, EUS-guided sampling results that do not confirm cancer should be interpreted with caution. Strong recommendation, low quality evidence. For pancreatic cystic lesions (PCLs), ESGE recommends EUS-guided sampling for biochemical analyses plus cytopathological examination if a precise diagnosis may change patient management, except for lesions ≤ 10 mm in diameter with no high risk stigmata. If the volume of PCL aspirate is small, it is recommended that carcinoembryonic antigen (CEA) level determination be done as the first analysis. Strong recommendation, low quality evidence. For esophageal cancer, ESGE suggests performing EUS-guided sampling for the assessment of regional lymph nodes (LNs) in T1 (and, depending on local treatment policy, T2) adenocarcinoma and of lesions suspicious for metastasis such as distant LNs, left liver lobe lesions, and suspected peritoneal carcinomatosis. Weak recommendation, low quality evidence. For lymphadenopathy of unknown origin, ESGE recommends performing EUS-guided (or alternatively endobronchial ultrasound [EBUS]-guided) sampling if the pathological result is likely to affect patient management and no superficial lymphadenopathy is easily accessible. Strong recommendation, moderate quality evidence. In the case of solid liver masses suspicious for metastasis, ESGE suggests performing EUS-guided sampling if the pathological result is likely to affect patient management, and (i) the lesion is poorly accessible/not detected at percutaneous imaging, or (ii) a sample obtained via the percutaneous route repeatedly yielded an inconclusive result. Weak recommendation, low quality evidence.
Between a Pod and a Hard Test: The Deep Evolution of Amoebae
Authors: Seungho Kang, Alexander K Tice, Frederick W Spiegel, Jeffrey D Silberman, Tomáš Pánek, Ivan Čepička, Martin Kostka, Anush Kosakyan, Daniel M C Alcântara, Andrew J Roger, Lora L Shadwick, Alexey Smirnov, Alexander Kudryavtsev, Daniel J G Lahr, Matthew W Brown
Journal: Molecular Biology and Evolution (2017)

Amoebozoa is the eukaryotic supergroup sister to Obazoa, the lineage that contains the animals and Fungi, as well as their protistan relatives, and the breviate and apusomonad flagellates. Amoebozoa is extraordinarily diverse, encompassing important model organisms and significant pathogens. Although amoebozoans are integral to global nutrient cycles and present in nearly all environments, they remain vastly understudied. We present a robust phylogeny of Amoebozoa based on broad representative set of taxa in a phylogenomic framework (325 genes). By sampling 61 taxa using culture-based and single-cell transcriptomics, our analyses show two major clades of Amoebozoa, Discosea, and Tevosa. This phylogeny refutes previous studies in major respects. Our results support the hypothesis that the last common ancestor of Amoebozoa was sexual and flagellated, it also may have had the ability to disperse propagules from a sporocarp-type fruiting body. Overall, the main macroevolutionary patterns in Amoebozoa appear to result from the parallel losses of homologous characters of a multiphase life cycle that included flagella, sex, and sporocarps rather than independent acquisition of convergent features.
Eosinophils Are Crucial for Mediating the Anticontractile Capacity of Perivascular Adipose Tissue
Authors: S. Withers, R. Forman, K. Else, S. Meza-Perez, William Winston Agace, S. Cruickshank, A. Heagerty, M. Svensson-Frej
Journal: Circulation (2013)
A New Antibody-Drug Conjugate Composed of an Anti-HLA-DR IgG4 Antibody, IMMU-114, and SN-38, Is Active in Experimental Acute Myelocytic Leukemia (AML), Acute Lymphocytic Leukemia (ALL), and Multiple Myeloma (MM)
Authors: David M Goldenberg, Robert M Sharkey, Serengulam V Govindan, Maria Zalath, Ali Mostafa, Thomas M Cardillo
Journal: Blood (2016)
Abstract 242: Cardiac Remodeling Induced by Chronic β-Adrenergic Simulation Is Blocked by Myocyte-TGF-β Signaling
Authors: Norimichi Koitabashi, Masahiko Kurabayashi, Eiki Takimoto, David A Kass
Journal: Circulation Research (2012)

[Background] Emerging evidence from cell-specific conditional gene manipulation models has revealed complex interactions with differential roles of cardiomyocyte (CM) and non-CM signaling in the evolution of pathological cardiac remodeling. A major factor involved in such cross talk is transforming growth factor-beta (TGFβ), which exists in CM,fibroblasts, and vascular cells. Both mechanical overload and prolonged catecholamine stimulation are critical determinants of hypertensive heart disease. Here, we tested the role of cell-specific TGFβ signaling in chronic pressure-overload or isoproterenol (Iso)-induced cardiac remodeling using CM-specific gene suppression of TGFβ type2 receptor in mice. [Methods and Results] αMHC-driven tamoxifen-inducible Cre (MCM) x Tgfbr2 floxed mice (MCMR2), which achieved CM-specific knockdown of TGFβ signaling, showed a striking suppression of cardiac dilatation and dysfunction induced by chronic pressure-overload. Chronic Iso infusion induced modest cardiac hypertrophy with moderate myocardial fibrosis. Interestingly, in contrast to TAC, myocardial fibrosis induced by the chronic Iso exposure was not inhibited, rather worsened in MCMR2 mice. Systemic treatment with TGFβ neutralizing antibody (NAb) for Chronic Iso significantly inhibited myocardial fibrosis, yet cardiac function and hypertrophy were not improved. In Iso-treated cultured cardiomyocytes, profibrotic genes were up-regulated by TGFβ-receptor inhibition, while they were inhibited in cultured cardiac fibroblasts. [Conclusion] CM-specific TGFβ signaling inhibition has marked protective effect for pressure-overload induced cardiac remodeling but not for Iso-induced cardiac remodeling. These results suggest that the role of TGFβ signaling may be determined by targeted cell types and pathological stresses in a development of heart failure.
Epidemiological foundations for the insurance hypothesis: Methodological considerations
Authors: Joseph M. Boden, Geraldine F. H. McLeod
Journal: Behavioral and Brain Sciences (2017)

Abstract Nettle et al. evaluate evidence for the insurance hypothesis, which links obesity with the perception of food scarcity. Epidemiological findings in this area have generally been weak and inconsistent. The present commentary examines three key methodological issues arising from the literature on the association between obesity and the perception of food scarcity in humans, with suggestions for future epidemiological research.
Randomized Comparison of Antiarrhythmic Drug Therapy With Implantable Defibrillators in Patients Resuscitated From Cardiac Arrest
Authors: Karl-Heinz Kuck, Riccardo Cappato, Jürgen Siebels, Rudolf Rüppel
Journal: Circulation (2000)

Background —We conducted a prospective, multicenter, randomized comparison of implantable cardioverter-defibrillator (ICD) versus antiarrhythmic drug therapy in survivors of cardiac arrest secondary to documented ventricular arrhythmias. Methods and Results —From 1987, eligible patients were randomized to an ICD, amiodarone, propafenone, or metoprolol (ICD versus antiarrhythmic agents randomization ratio 1:3). Assignment to propafenone was discontinued in March 1992, after an interim analysis conducted in 58 patients showed a 61% higher all-cause mortality rate than in 61 ICD patients during a follow-up of 11.3 months. The study continued to recruit 288 patients in the remaining 3 study groups; of these, 99 were assigned to ICDs, 92 to amiodarone, and 97 to metoprolol. The primary end point was all-cause mortality. The study was terminated in March 1998, when all patients had concluded a minimum 2-year follow-up. Over a mean follow-up of 57±34 months, the crude death rates were 36.4% (95% CI 26.9% to 46.6%) in the ICD and 44.4% (95% CI 37.2% to 51.8%) in the amiodarone/metoprolol arm. Overall survival was higher, though not significantly, in patients assigned to ICD than in those assigned to drug therapy (1-sided P =0.081, hazard ratio 0.766, [97.5% CI upper bound 1.112]). In ICD patients, the percent reductions in all-cause mortality were 41.9%, 39.3%, 28.4%, 27.7%, 22.8%, 11.4%, 9.1%, 10.6%, and 24.7% at years 1 to 9 of follow-up. Conclusions —During long-term follow-up of cardiac arrest survivors, therapy with an ICD is associated with a 23% (nonsignificant) reduction of all-cause mortality rates when compared with treatment with amiodarone/metoprolol. The benefit of ICD therapy is more evident during the first 5 years after the index event.
Baseline quality of life (QOL) as a predictor of tolerance to intraperitoneal (IP) chemotherapy for advanced epithelial ovarian cancer (EOC): A Gynecologic Oncology Group (GOG) study
Authors: L. B. Wenzel, H. Q. Huang, D. K. Armstrong, J. L. Walker, D. Cella
Journal: Journal of Clinical Oncology (2006)

5007 Background: A recent GOG randomized phase III trial demonstrated a 16 month improvement in survival for women with optimally debulked stage III EOC. Patients on the IP chemotherapy arm experienced a survival advantage but significantly worse toxicities, worse QOL during treatment, and more neurotoxicity (NTX) one year later, compared to those on the IV arm. We sought to determine whether baseline QOL and NTX and abdominal discomfort (AD) predict severity of IP treatment-related adverse effects and number of cycles completed. Methods: Three self-report QOL measures were utilized: the FACT-O (39 items), and FACT/GOG-NTX (11 items) and FACT/GOG-AD (4 items) subscales. Scoring was on a 5-point scale, with higher scores representing better QOL (FACT-O) whereas higher scores indicated worse symptoms (-NTX and -AD subscales). In addition to NTX and AD, we explored associations with fatigue. A logistic regression model was used for the analyses. Results: Of 205 patients randomly assigned to receive IP chemotherapy, 198 (97%) completed baseline QOL assessments, of whom 83 (42%) completed all 6 cycles and 16 (8%) completed none. Adjusting for age, performance status and residual disease, patients reporting higher baseline FACT-O and lower -NTX and -AD scores were more likely to complete more IP cycles. Categorizing FACT-O scores by quartiles (≤92, 93 to ≤108.8, 109 to ≤121.1, and &gt;121.1), patients in the lowest quartile were significantly less likely to complete 6 cycles of IP therapy (odds ratio [OR] = 4.46; 95% CI: 1.95–10.21, p &lt; 0.001). Higher FACT-O scores were also associated with less grade 3–4 fatigue (OR = 0.81 per 10 points; 95% CI: 0.67–0.99; p = 0.037); however, there was no relationship between baseline NTX and AD subscale scores and severity of physician-rated NTX and AD. Conclusions: Baseline patient-reported QOL and NTX and AD symptoms predict tolerance to IP chemotherapy. Patients with the poorest baseline QOL (FACT-O score &lt;92) were least likely to complete IP therapy. No significant financial relationships to disclose.
Serum Free Light Chain in Waldenstrom Macroglobulinemia.
Authors: Anne-Sophie Moreau, Xavier Leleu, Robert Manning, Valérie Coiteux, Stéphane Darre, Evdoxia Hatjiharisi, Zachary Hunter, Xiaoying Jia, Hai Ngo, Garrett O’Sullivan, Daniel Santos, Steven Treon, Thierry Facon, Kenneth Anderson, Irene Ghobrial
Journal: Blood (2006)