tbuckley/cabot-search huggingface dataset:
Leflunomide Induces Apoptosis in Fludarabine-Resistant and Clinically Refractory CLL Cells
Authors: Sascha Dietrich, Oliver H. Krämer, Esther Hahn, Claudia Schäfer, Thomas Giese, Michael Hess, Theresa Tretter, Michael Rieger, Jennifer Hüllein, Thorsten Zenz, Anthony D. Ho, Peter Dreger, Thomas Luft
Journal: Clinical Cancer Research (2011)

Environmental conditions in lymph node proliferation centers protect chronic lymphocytic leukemia (CLL) cells from apoptotic triggers. This situation can be mimicked by in vitro stimulation with CD40 ligand (CD40L) and interleukin 4 (IL-4). Our study investigates the impact of the drug leflunomide to overcome apoptosis resistance of CLL cells.CLL cells were stimulated with CD40L and IL-4 and treated with fludarabine and the leflunomide metabolite A771726.Resistance to fludarabine-mediated apoptosis was induced by CD40 activation alone stimulating high levels of BCL-XL and MCL1 protein expression. Apoptosis resistance was further enhanced by a complementary Janus-activated kinase (JAK)/STAT signal induced by IL-4. In contrast, CLL proliferation required both a CD40 and a JAK/STAT signal and could be completely blocked by pan-JAK inhibition. Leflunomide (A771726) antagonized CD40L/IL-4-induced proliferation at very low concentrations (3 μg/mL) reported to inhibit dihydroorotate dehydrogenase. At a concentration of 10 μg/mL, A771726 additionally attenuated STAT3/6 phosphorylation, whereas apoptosis of CD40L/IL-4-activated ("resistant") CLL cells was achieved with higher concentrations (IC(50): 80 μg/mL). Apoptosis was also effectively induced by A771726 in clinically refractory CLL cells with and without a defective p53 pathway. Induction of apoptosis involved inhibition of NF-κB activity and loss of BCL-XL and MCL1 expression. In combination with fludarabine, A771726 synergistically induced apoptosis (IC(50): 56 μg/mL).We thus show that A771726 overcomes CD40L/IL-4-mediated resistance to fludarabine in CLL cells of untreated as well as clinically refractory CLL cells. We present a possible novel therapeutic principle for attacking chemoresistant CLL cells.
PNEUMOCOCCAL VACCINE AND OTITIS MEDIA
Authors: P.H. Mäkelä, E. Herva, M. Sibakov, J. Henrichsen, J. Luotonen, M. Leinonen, M. Timonen, M. Koskela, J. Pukander, P. Grönroos, S. Pöntynen, P. Karma
Journal: The Lancet (1980)
Early mortality and morbidity of bilateral versus single internal thoracic artery revascularization: propensity and risk modeling
Authors: John P.A Ioannidis, Othon Galanos, Demosthenes Katritsis, Cliff P Connery, George E Drossos, Daniel G Swistel, Constantine E Anagnostopoulos
Journal: Journal of the American College of Cardiology (2001)
COMPARATIVE IMMUNOGENICITY AND ENHANCEABILITY OF INDIVIDUAL <i>H-2K</i> AND <i>H-2D</i> SPECIFICITIES OF THE MURINE HISTOCOMPATIBILITY-2 COMPLEX
Authors: Ian F. C. McKenzie, George D. Snell
Journal: The Journal of Experimental Medicine (1973)

The immunogenicity of single, private H-2 specificities has been tested. In most cases, the specificity was known to be confined either to H-2K or to H-2D. This was accomplished by the appropriate choice, as donor and recipient, or parent of the F(1) hybrid recipient, of congenic strains differing at H-2 only, and of recombinant haplotypes in donor and/or recipient. By nearly all tests, the H-2K antigen appeared to be a stronger immunogen than the H-2D antigen. Skin grafts with an H-2K difference showed median survival times (MST) of 9.3-14.5 days; for H-2D the values were 13.8-18.6. The difference was also present, though narrowed, for second-set grafts. H-2K grafts regularly engendered a demonstrable cytotoxic antibody response; with H-2D differences the response was absent or very weak. K end cytotoxic titers after multiple immunizations with lymphoid tissues ranged from 1/32 to 1/2,048, D end titers from 0 to 1/128. Hemagglutination titers showed no clear difference. The results of passive enhancement of skin grafts with H-2 alloantibody produced in donor recipient combinations, identical to those used for the skin grafts showed a different pattern. H-2K, despite its greater immunogenic strength was more easily enhanced than H-2D. Prolongation of MST's for H-2K was 2.4-6.7 days, for H-2D grafts, 0.2-1.5 days.
UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma
Authors: Raksha Mudbhary, Yujin Hoshida, Yelena Chernyavskaya, Vinitha Jacob, Augusto Villanueva, M. Isabel Fiel, Xintong Chen, Kensuke Kojima, Swan Thung, Roderick T. Bronson, Anja Lachenmayer, Kate Revill, Clara Alsinet, Ravi Sachidanandam, Anal Desai, Sucharita SenBanerjee, Chinweike Ukomadu, Josep M. Llovet, Kirsten C. Sadler
Journal: Cancer Cell (2014)
How to Use a Noninferiority Trial
Authors: Sohail M. Mulla, Ian A. Scott, Cynthia A. Jackevicius, John J. You, Gordon H. Guyatt
Journal: JAMA (2012)

Clinical investigators are increasingly testing treatments that have the primary benefit of decreased burden or harms relative to an existing standard. The goal of the resulting randomized trials--called noninferiority trials--is to establish that the novel treatment's effectiveness is not substantially less than the existing standard. Conclusions from these trials are, however, based on noninferiority thresholds specified by authors whose judgments may not coincide with those of patients and clinicians. This article highlights issues related to validity, interpretation, and applicability of results specific to noninferiority trials. Suboptimal administration of standard treatment or exclusive reliance on the analyze-as-randomized approach that is standard for conventional superiority trials may produce misleading results in noninferiority trials. Clinicians should judge whether the novel treatment's impact on effectiveness outcomes--the prime reason for wanting to prescribe it--is sufficiently close to that of standard treatment that they are comfortable substituting it for the existing standard. Trading off desirable and undesirable consequences is an individual decision: given the benefits of a novel treatment, some patients may perceive the uncertainty regarding a reduction in treatment effectiveness as acceptable while others may not.
HAb18G/CD147 Promotes pSTAT3-Mediated Pancreatic Cancer Development via CD44s
Authors: Ling Li, Wenhua Tang, Xiaoqing Wu, David Karnak, Xiaojie Meng, Rachel Thompson, Xinbao Hao, Yongmin Li, Xiaotan T. Qiao, Jiayuh Lin, James Fuchs, Diane M. Simeone, Zhi-Nan Chen, Theodore S. Lawrence, Liang Xu
Journal: Clinical Cancer Research (2013)

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 has failed clinically. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate the potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo.The expression of HAb18G/CD147, pSTAT3, and CD44s was determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 were assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot assay, immunofluorescence staining, immunoprecipitation, and in vivo tumor formation using loss or gain-of-function strategies.Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. Cyclophilin A (CyPA), a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147-dependent mechanisms. HAb18G/CD147 was associated and colocalized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high coexpression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer.We identified HAb18G/CD147 as a novel upstream activator of STAT3, which interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest that HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies.
The Bradshaw Lecture
Authors: E. L. Fox
Journal: BMJ (1882)

WHEN you, sir, did me the honour of inviting me to deliver this lec- here to-day, I was tempted to the choice of a subject that is not only a vast one, but also, perhaps, somewhat indefinite.Anyone who has worked for many years in the science and art of medicine must feel some diffidence in expressing views that may be open to controversy, before any body of men so highly educated as are the members of the medical profession at the present time.But this diffidence is necessarily rendered greater, when his immediate audience persons closely connected with this great College; and, although feeling must obtain with reference to all lines of thought connected medical science, it is very specially the case with regard to the subject of this lecture, the Influence of the Sympathetic System on Disease, inasmuch as, without depreciating the earnest investigations carried out in Germany, in France, in Italy, in Russia, on the physiology and pathology of this portion of the nervous system, yet much of the best observation on the subject, much of the best reasoning on may be called sympathetic phenomena, based on clinical and pathological data, has been placed before the profession at large by Fellows and Members of this College of Physicians.And if to-day the mention by name of any observer be perchance omitted, it will not be from want of due recognition on my part, but either because independent observations have been made in this, as in other scientific questions, almost synchronously in different countries, but chiefly that the results many investigations have become, like those of Claude Bernard, household
Effects of Cytosolic ATP on Ca <sup>2+</sup> Sparks and SR Ca <sup>2+</sup> Content in Permeabilized Cardiac Myocytes
Authors: Zhaokang Yang, Derek S. Steele
Journal: Circulation Research (2001)

Abstract— Confocal imaging was used to study the influence of cytosolic ATP on the properties of spontaneous Ca 2+ sparks in permeabilized ventricular myocytes. Cells were perfused with mock intracellular solutions containing fluo 3. Reducing [ATP] to &lt;0.5 mmol/L decreased the frequency but increased the amplitude of spontaneous Ca 2+ sparks. In the presence of 20 μmol/L ATP, the amplitude increased by 48.7±10.9%, and the frequency decreased by 77.07±3.8%, relative to control responses obtained at 5 mmol/L ATP. After exposure to a solution containing zero ATP, the frequency of Ca 2+ sparks decreased progressively and approached zero within 90 seconds. As ATP washed out of the cell, the sarcoplasmic reticulum (SR) Ca 2+ content increased, until reaching a maximum after 3 minutes. Subsequent introduction of adenylyl imidodiphosphate precipitated a burst of large-amplitude Ca 2+ sparks. This was accompanied by a rapid decrease in SR Ca 2+ content to 80% to 90% of the steady-state value obtained in the presence of 5 mmol/L ATP. Thereafter, the SR Ca 2+ content declined much more slowly over 5 to 10 minutes. The effects of ATP withdrawal on Ca 2+ sparks may reflect reduced occupancy of the adenine nucleotide site on the SR Ca 2+ channel. These effects may contribute to previously reported changes in SR function during myocardial ischemia and reperfusion, in which ATP depletion and Ca 2+ overload occur.
Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy
Authors: Yuan-Yuan Wang, Sachio Morimoto, Cheng-Kun Du, Qun-Wei Lu, Dong-Yun Zhan, Takaki Tsutsumi, Tomomi Ide, Yosikazu Miwa, Fumi Takahashi-Yanaga, Toshiyuki Sasaguri
Journal: Cardiovascular Research (2010)

Thyroid hormone (TH) has prominent effects on the heart, and hyperthyroidism is occasionally found to be a cause of dilated cardiomyopathy (DCM). We aim to explore the potential role of TH in the pathogenesis of DCM.The pathophysiological role of TH in the heart was investigated using a knock-in mouse model of inherited DCM with a deletion mutation DeltaK210 in the cardiac troponin T gene. Serum tri-iodothyronine (T(3)) levels showed no significant difference between wild-type (WT) and DCM mice, whereas cardiac T(3) levels in DCM mice were significantly higher than those in WT mice. Type 2 iodothyronine deiodinase (Dio2), which produces T(3) from thyroxin, was up-regulated in the DCM mice hearts. The cAMP levels were increased in DCM mice hearts, suggesting that transcriptional up-regulation of Dio2 gene is mediated through the evolutionarily conserved cAMP-response element site in its promoter. Propylthiouracil (PTU), an anti-thyroid drug, prevented the hypertrophic remodelling of the heart in DCM mice and improved their cardiac function and life expectancy. Akt and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation increased in the DCM mice hearts and PTU treatment significantly reduced the phosphorylation levels, strongly suggesting that Dio2 up-regulation is involved in cardiac remodelling in DCM through activating the TH-signalling pathways involving Akt and p38 MAPK. Dio2 gene expression was also markedly up-regulated in the mice hearts developing similar eccentric hypertrophy after myocardial infarction.Local hyperthyroidism via transcriptional up-regulation of the Dio2 gene may be an important underlying mechanism for the hypertrophic cardiac remodelling in DCM.
Early Hepatic Histologic Alterations Among Chemical (Vinyl Monomer) Workers
Authors: Carlo H. Tamburro, Laszlo Mark, Hans Popper
Journal: Hepatology (1984)

Focal hepatocellular hyperplasia and focal mixed (hepatocytes and sinusoidal cells) hyperplasia are early histological alterations indicative of vinyl monomer exposure. To evaluate their uses in screening chemical workers, 93 liver biopsy specimens from 78 persons were examined in double-blind duplicative fashion. Forty-eight specimens were from exposed chemical workers, 35 of them having liver biopsy(ies) for hepatic test abnormalities and 13 for nonliver-related reasons. A comparison group consisted of 30 nonchemical workers who had undergone liver biopsy for nonliver related reasons. Twenty-three of the exposed workers (48%) had hepatic lesions consistent with exposure: 17 (35%) of these had focal hepatocytic hyperplasia, while 6 (13%) had focal mixed hyperplasia or more advanced lesions. Only five of the comparison group had like findings: four (13%) had focal hepatocytic hyperplasia; one had focal mixed hyperplasia and sinusoidal dilatation. This individual had persistent hepatic test abnormalities with the focal mixed hyperplasia and a sinusoidal dilatation, and on subsequent biopsy, angiosarcoma (and a history of using hair spray containing vinyl chloride propellant). Ten individuals had 25 multiple biopsies also read double-blindly; 10 had two or more readings of the same biopsy. Duplicate 21 of 23 (91%) and multiple 27 of 28 (96%) biopsy interpretations in the same individual were identical. Only 6% of either duplicate and/or multiple readings disagreed. Both focal hepatocellular and mixed hyperplasia were always associated with abnormalities in hepatic test results of which indocyanine green clearance was the most sensitive and γ-glutamyl transpeptidase the least specific. Focal hepatocellular hyperplasia is a more common finding and occurs earlier than the focal mixed hyperplasia among vinyl monomer exposed workers. Follow-up for 5 to 7 years yielded no biochemical or histological evidence of spontaneous progression of this lesion in a work environment where vinyl chloride levels were 10 ppm with time-weighted averages of 1 to 2 ppm. Focal mixed hyperplasia is, as noted, a later and less frequent finding among vinyl monomer-exposed workers. Some individuals with this lesion develop hepatic angiosarcoma independent of subsequent vinyl monomer exposure. In screening for chemical liver injury, indocyanine green clearance supplementary to routine tests is recommended with confirmation by liver biopsy.
Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment
Authors: Benoît P. Guery, Maiken C. Arendrup, Georg Auzinger, Élie Azoulay, Márcio Borges Sá, Elizabeth M. Johnson, Eckhard Müller, Christian Putensen, Coleman Rotstein, Gabriele Sganga, Mario Venditti, Rafael Zaragoza Crespo, Bart Jan Kullberg
Journal: Intensive Care Medicine (2008)

Invasive candidiasis and candidemia are frequently encountered in the nosocomial setting particularly in the intensive care unit (ICU). To review the current management of invasive candidiasis and candidemia in non-neutropenic adult ICU patients based on a review of the literature and an European expert panel discussion. Empiric and directed treatment for invasive candidiasis are predicated on the hemodynamic status of the patient. Unstable patients may benefit from broad-spectrum antifungal agents, which can be narrowed once the patient has stabilized and the identity of the infecting species is established. In stable patients, a more classical approach using fluconazole may be satisfactory provided that the patient is not colonized with fluconazole resistant strains or there has been recent past exposure to an azole (<30 days). In contrast, pre-emptive therapy is based on the presence of surrogate markers.
The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation
Authors: Alexa S. Green, Nicolas Chapuis, Thiago Trovati Maciel, Lise Willems, Mireille Lambert, Christophe Arnoult, Olivier Boyer, Valerie Bardet, Sophie Park, Marc Foretz, Benoit Viollet, Norbert Ifrah, François Dreyfus, Olivier Hermine, Ivan Cruz Moura, Catherine Lacombe, Patrick Mayeux, Didier Bouscary, Jerome Tamburini
Journal: Blood (2010)
Five-year follow-up of a prospective randomized trial of hepatitis B recombinant DNA yeast vaccine vs. plasma-derived vaccine in children: Immunogenicity and anamnestic responses
Authors: Ching-Lung Lai, Benjamin Chun-Yu Wong, Eng-Kiong Yeoh, Wai-Ling Lim, Wai-Kwan Chang, Hsiang-Ju Lin
Journal: Hepatology (1993)

In a prospective randomized trial, 318 children aged between 3 mo and 11 yr who were negative for all hepatitis B markers were randomized to receive two 5-μg doses of hepatitis B recombinant DNA yeast vaccine at 0 and 1 mo (group 1), three 5-μg doses of hepatitis B recombinant DNA yeast vaccine at 0, 1 and 6 mo (group 2) or three 10-μg doses of plasma-derived hepatitis B vaccine (group 3). The HBs antibody response rate at 8 mo was between 93% and 99%; it was still 75% to 87% at 5 yr in all three groups. Geometric mean titers at 1 yr were 83, 1,085 and 858 mIU/ml in groups 1, 2 and 3, respectively. These values had decreased after 5 yr to 47, 131 and 250 mIU/ml. Subjects in group 1 showed a significantly less proportional drop in geometric mean titer at the fifth year than did subjects in group 2 (p = 0.05) or group 3 (p = 0.015). None of the children developed HBc antibody, even after 5 yr of follow-up. We noted 42 episodes of significantly increased HBs antibody titers, probably due to anamnestic response, even when the titers had dropped to low levels. The mean age at which anamnestic response occurred was 8.7 yr. We conclude that (a) the recombinant vaccine and plasma-derived vaccine are comparable in safety and immunogenicity; (b) two doses of vaccine was as effective in protecting hepatitis B infection as three doses, despite lower HBs antibody titers; (c) anamnestic responses occurred most frequently around 4 yr after a child began attending school; and (d) a booster dose was not necessary at 5 yr, probably because of ability of healthy child vaccinees to mount good anamnestic responses. (HEPATOLOGY 1993;18:763-767).
CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment
Authors: Niklas Mattsson
Journal: JAMA (2009)

Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted.To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI.The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia.Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD.During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%.This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.
Effect of alginate encapsulation on the cellular transcriptome of human islets
Authors: Vijayaganapathy Vaithilingam, Nayeem Quayum, Mugdha V. Joglekar, Jan Jensen, Anandwardhan A. Hardikar, Jose Oberholzer, Gilles J. Guillemin, Bernard E. Tuch
Journal: Biomaterials (2011)