tbuckley/cabot-search huggingface dataset:
Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases
Authors: Antonio C. Bianco, Domenico Salvatore, Balázs Gereben, Marla J. Berry, P. Reed Larsen
Journal: Endocrine Reviews (2002)

The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T3 production. We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium.
Combination mTOR and IGF-1R Inhibition: Phase I Trial of Everolimus and Figitumumab in Patients with Advanced Sarcomas and Other Solid Tumors
Authors: Richard Quek, Qian Wang, Jeffrey A. Morgan, Geoffrey I. Shapiro, James E. Butrynski, Nikhil Ramaiya, Tarsha Huftalen, Nicole Jederlinic, Judith Manola, Andrew J. Wagner, George D. Demetri, Suzanne George
Journal: Clinical Cancer Research (2010)

Preclinical models demonstrate synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling. We aimed to determine the safety, tolerability, and recommended phase II dose (RP2D) of the combination of figitumumab, a fully human IgG(2) anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination were evaluated.Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Intercohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1.No DLTs were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17-300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and, stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab.Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting antitumor activity warranting further investigation.
The Bcl-2/xL inhibitor ABT-263 increases the stability of Mcl-1 mRNA and protein in hepatocellular carcinoma cells
Authors: Bin Wang, Zhenhong Ni, Xufang Dai, Liyan Qin, Xinzhe Li, Liang Xu, Jiqin Lian, Fengtian He
Journal: Molecular Cancer (2014)

Hepatocellular carcinoma (HCC) is one of the major causes of mortality. ABT-263 is a newly synthesized, orally available Bcl-2/xL inhibitor that shows promising efficacy in HCC therapy. ABT-263 inhibits the anti-apoptotic activity of Bcl-2 and Bcl-xL, but not Mcl-1. Previous reports have shown that ABT-263 upregulates Mcl-1 in various cancer cells, which contributes to ABT-263 resistance in cancer therapy. However, the associated mechanisms are not well known. Western blot, RNAi and CCK-8 assays were used to investigate the relationship between Mcl-1 upregulation and ABT-263 sensitivity in HCC cells. Real-time PCR and Western blot were used to detect Mcl-1 mRNA and protein levels. Luciferase reporter assay and RNA synthesis inhibition assay were adopted to analyze the mechanism of Mcl-1 mRNA upregulation. Western blot and the inhibition assays for protein synthesis and proteasome were used to explore the mechanisms of ABT-263-enhanced Mcl-1 protein stability. Trypan blue exclusion assay and flow cytometry were used to examine cell death and apoptosis. ABT-263 upregulated Mcl-1 mRNA and protein levels in HCC cells, which contributes to ABT-263 resistance. ABT-263 increased the mRNA level of Mcl-1 in HCC cells by enhancing the mRNA stability without influencing its transcription. Furthermore, ABT-263 increased the protein stability of Mcl-1 through promoting ERK- and JNK-induced phosphorylation of Mcl-1Thr163 and increasing the Akt-mediated inactivation of GSK-3β. Additionally, the inhibitors of ERK, JNK or Akt sensitized ABT-263-induced apoptosis in HCC cells. ABT-263 increases Mcl-1 stability at both mRNA and protein levels in HCC cells. Inhibition of ERK, JNK or Akt activity sensitizes ABT-263-induced apoptosis. This study may provide novel insights into the Bcl-2-targeted cancer therapeutics.
Prediction of Mortality in Type 2 Diabetes From Health-Related Quality of Life (ZODIAC-4)
Authors: Nanne Kleefstra, Gijs W.D. Landman, Sebastiaan T. Houweling, Lielith J. Ubink-Veltmaat, Susan J.J. Logtenberg, Betty Meyboom-de Jong, James C. Coyne, Klaas H. Groenier, Henk J.G. Bilo
Journal: Diabetes Care (2008)

OBJECTIVE—To investigate the relationship between health-related quality of life (HRQOL) and mortality in type 2 diabetes. RESEARCH DESIGN AND METHODS—In 1998, 1,143 primary care patients with type 2 diabetes participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study. At baseline, HRQOL was assessed with the RAND-36 and, after almost 6 years, life status was retrieved. Cox proportional hazards modeling was used to investigate the association between HRQOL (continuous data) and mortality with adjustment for selected confounders (smoking, age, sex, diabetes duration, A1C, renal function, BMI, blood pressure, HDL cholesterol, and macrovascular complications). RESULTS—The Physical Component Summary of the RAND-36 was inversely associated with mortality (hazard ratio [HR] 0.979 [95% CI 0.966–0.992]), as were two separate RAND-36 dimensions. CONCLUSIONS—This study found that HRQOL is an independent marker of mortality and emphasizes the importance of looking beyond clinical parameters in patients with type 2 diabetes.
The Influence of a Human Embryonic Stem Cell–Derived Microenvironment on Targeting of Human Solid Tumor Xenografts
Authors: Maty Tzukerman, Tzur Rosenberg, Irena Reiter, Shoshana Ben-Eliezer, Galit Denkberg, Raymond Coleman, Yoram Reiter, Karl Skorecki
Journal: Cancer Research (2006)

Abstract The awareness of the important role that the surrounding tissue microenvironment and stromal response play in the process of tumorigenesis has grown as a result of in vivo models of tumor xenograft growth in immunocompromised mice. In the current study, we used human embryonic stem cells in order to study the interactions of tumor cells with the surrounding microenvironment of differentiated human cell tissues and structures. Several cancer cell types stably expressing an H2A-green fluorescence protein fusion protein, which allowed tracking of tumor cells, were injected into mature teratomas and developed into tumors. The salient findings were: (a) the observation of growth of tumor cells with high proliferative capacity within the differentiated microenvironment of the teratoma, (b) the identification of invasion by tumor cells into surrounding differentiated teratoma structures, and (c) the identification of blood vessels of human teratoma origin, growing adjacent to and within the cancer cell–derived tumor. Mouse embryonic stem cell–derived teratomas also supported cancer cell growth, but provided a less suitable model for human tumorigenesis studies. Anticancer immunotherapy treatment directed against A431 epidermoid carcinoma cell–related epitopes induced the complete regression of A431-derived tumor xenografts following direct i.m. injection in immunocompromised mice, as opposed to corresponding tumors growing within a human embryonic stem cell–derived microenvironment, wherein remnant foci of viable tumor cells were detected and resulted in tumor recurrence. We propose using this novel experimental model as a preclinical platform for investigating and manipulating the stromal response in tumor cell growth as an additional tool in cancer research. (Cancer Res 2006; 66(7): 3792-801)
<i>DNAH5</i> Mutations Are a Common Cause of Primary Ciliary Dyskinesia with Outer Dynein Arm Defects
Authors: Nada Hornef, Heike Olbrich, Judit Horvath, Maimoona A. Zariwala, Manfred Fliegauf, Niki Tomas Loges, Johannes Wildhaber, Peadar G. Noone, Marcus Kennedy, Stylianos E. Antonarakis, Jean-Louis Blouin, Lucia Bartoloni, Thomas Nüsslein, Peter Ahrens, Matthias Griese, Heiner Kuhl, Ralf Sudbrak, Michael R. Knowles, Richard Reinhardt, Heymut Omran
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Primary ciliary dyskinesia (PCD) is characterized by recurrent airway infections and randomization of left-right body asymmetry. To date, autosomal recessive mutations have only been identified in a small number of patients involving DNAI1 and DNAH5, which encode outer dynein arm components.We screened 109 white PCD families originating from Europe and North America for presence of DNAH5 mutations by haplotype analyses and/or sequencing.Haplotype analyses excluded linkage in 26 families. In 30 PCD families, we identified 33 novel (12 nonsense, 8 frameshift, 5 splicing, and 8 missense mutations) and two known DNAH5 mutations. We observed clustering of mutations within five exons harboring 27 mutant alleles (52%) of the 52 detected mutant alleles. Interestingly, 6 (32%) of 19 PCD families with DNAH5 mutations from North America carry the novel founder mutation 10815delT. Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects. High-resolution immunofluorescence imaging of respiratory epithelial cells from eight patients with DNAH5 mutations showed mislocalization of mutant DNAH5 and accumulation at the microtubule organizing centers. Mutant DNAH5 was absent throughout the ciliary axoneme in seven patients and remained detectable in the proximal ciliary axoneme in one patient carrying compound heterozygous splicing mutations at the 3'-end (IVS75-2A>T, IVS76+5G>A). In a preselected subpopulation with documented outer dynein arm defects (n = 47), DNAH5 mutations were identified in 53% of patients.DNAH5 is frequently mutated in patients with PCD exhibiting outer dynein arm defects and mutations cluster in five exons.
Gastro-oesophageal reflux and nocturnal asthma
Authors: T Ekström, L Tibbling
Journal: European Respiratory Journal (1988)

Gastro-oesophageal (GO) reflux is believed to be a possible cause of nocturnal asthma. The aim of this study was to see if there is any correlation between the incidence of GO-reflux at night and nocturnal asthma. Thirty-seven adult patients with a history of nocturnal asthma for more than one hundred days a year and of reflux disease were evaluated using 24 h pH-monitoring of the oesophagus and measurement of peak expiratory flow (PEF) rate every hour when awake. Half of the patients suffered from severe GO-reflux at night, whilst the other half had no nocturnal reflux. Respiratory symptoms and inhalation of beta-2 agonists were recorded during the night and PEF was recorded when the patients awoke in the morning. A significant correlation was found between reflux at night and the degree of bronchial obstruction in the early morning, but not between night-time reflux and nocturnal respiratory symptoms. It would appear that GO-reflux in most asthmatics is neither a strong nor immediate trigger factor in nocturnal asthma, although it does seem to influence bronchial obstruction during the night as was demonstrated by a low morning-PEF value.
Insurance Status, Comorbidity Level, and Survival Among Colorectal Cancer Patients Age 18 to 64 Years in the National Cancer Data Base From 2003 to 2005
Authors: Anthony S. Robbins, Alexandre L. Pavluck, Stacey A. Fedewa, Amy Y. Chen, Elizabeth M. Ward
Journal: Journal of Clinical Oncology (2009)

Previous analyses have found that insurance status is a strong predictor of survival among patients with colorectal cancer aged 18 to 64 years. We investigated whether differences in comorbidity level may account in part for the association between insurance status and survival.We used 2003 to 2005 data from the National Cancer Data Base, a national hospital-based cancer registry, to examine the relationship between baseline characteristics and overall survival at 1 year among 64,304 white and black patients with colorectal cancer. In race-specific analyses, we used Cox proportional hazards models to assess 1-year survival by insurance status, controlling first for age, stage, facility type, and neighborhood education level and income, and then further controlling for comorbidity level. RESULTS; Comorbidity level was lowest among those with private insurance, higher for those who were uninsured or insured by Medicaid, and highest for those insured by Medicare. Survival at 1 year was significantly poorer for patients without private insurance, even after adjusting for important covariates. In these multivariate models, risk of death at 1 year was approximately 50% to 90% higher for white and black patients without private insurance. Further adjustment for number of comorbidities had only a modest impact on the association between insurance status and survival. In multivariate analyses, patients with > or = three comorbid conditions had approximately 40% to 50% higher risk of death at 1 year. CONCLUSION Among white and black patients aged 18 to 64 years, differences in comorbidity level do not account for the association between insurance status and survival in patients with colorectal cancer.
Anti-RNA polymerase I antibodies in sera of MRL lpr/lpr and MRL +/+ autoimmune mice. Correlation of antibody production with delayed onset of lupus-like disease in MRL +/+ mice.
Authors: D A Stetler, D E Sipes, S T Jacob
Journal: The Journal of Experimental Medicine (1985)

Sera from individual MRL/lpr and MRL/++ mice, which develop an autoimmune disease similar to human systemic lupus erythematosus (SLE), were screened over a period of approximately 30 wk for the presence of anti-RNA polymerase I and anti-ssDNA antibodies. Even though onset of the disease is delayed in MRL/++ as compared to MRL/lpr mice, anti-ssDNA antibodies were present in comparable concentrations in the sera of all mice by the age of 6 wk. As observed in sera of human SLE patients, anti-RNA polymerase I antibodies were detected in the sera of all MRL mice. However, unlike the anti-ssDNA antibodies, anti-RNA polymerase I antibodies were detected much later in MRL/++ mice (mean age, 22.8 wk) as compared to MRL/lpr mice (mean age, 9.6 wk). The presence of anti-RNA polymerase I antibodies in sera of MRL mice was thus a much better indicator of disease status than the presence of anti-ssDNA antibodies. The appearance and increase in anti-RNA polymerase I antibodies in the sera of MRL/++ mice correlated (R2 = 0.964) with a precipitous decrease in anti-ssDNA antibodies, starting at about 20 wk of age. These results suggest a possible relationship between the RNA polymerase I and DNA autoimmune reactions.
MOZ-TIF2 repression of nuclear receptor-mediated transcription requires multiple domains in MOZ and in the CID domain of TIF2
Authors: Hong Yin, Jonathan Glass, Kerry L Blanchard
Journal: Molecular Cancer (2007)

Fusion of the MOZ and TIF2 genes by an inv (8) (p11q13) translocation has been identified in patients with acute mixed-lineage leukemia. Characterization of the molecular structure of the MOZ-TIF2 fusion protein suggested that the fusion protein would effect on nuclear receptor signaling. A series of deletions from the N-terminus of the MOZ-TIF2 fusion protein demonstrated that the MOZ portion is essential for nuclear localization of the fusion protein. Transient expression of MOZ-TIF2 dramatically decreased both basal and estradiol inducible reporter gene activity in an estrogen receptor element (ERE) driven luciferase reporter system and decreased androgen-inducible reporter gene activity in an androgen receptor element (ARE) luciferase reporter system. Deletions in the MOZ portion of the MOZ-TIF2 fusion protein reduced the suppression in the ER reporter system. Stable expression of MOZ-TIF2 inhibited retinoic acid (RA) inducible endogenous CD11b and C/EBPβ gene response. The suppression of the reporter systems was released with either a CID domain deletion or with mutations of leucine-rich repeats in the TIF2 portion of MOZ-TIF2. The co-expression of TIF2, but not CBP, with MOZ-TIF2 partially restored the inhibition of the reporter systems. In addition, analysis of protein interactions demonstrated MOZ-TIF2 interaction with the C-terminus of CBP through both the MOZ and TIF2 portions of the fusion protein. MOZ-TIF2 inhibited nuclear receptor-mediated gene response by aberrant recruitment of CBP and both the MOZ and TIF2 portions are required for this inhibition.
Cardiac Hypertrophy Is Inhibited by a Local Pool of cAMP Regulated by Phosphodiesterase 2
Authors: Anna Zoccarato, Nicoletta C. Surdo, Jan M. Aronsen, Laura A. Fields, Luisa Mancuso, Giuliano Dodoni, Alessandra Stangherlin, Craig Livie, He Jiang, Yuan Yan Sin, Frank Gesellchen, Anna Terrin, George S. Baillie, Stuart A. Nicklin, Delyth Graham, Nicolas Szabo-Fresnais, Judith Krall, Fabrice Vandeput, Matthew Movsesian, Leonardo Furlan, Veronica Corsetti, Graham Hamilton, Konstantinos Lefkimmiatis, Ivar Sjaastad, Manuela Zaccolo
Journal: Circulation Research (2015)

Rationale : Chronic elevation of 3′-5′-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodeling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A signaling seems to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signaling microdomains. Objective : How individual cAMP microdomains affect cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. Methods and Results : Using pharmacological and genetic manipulation of PDE activity, we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy, whereas increasing cAMP levels via PDE2 inhibition is antihypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of protein kinase A isoforms, we demonstrate that the antihypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a protein kinase A type II subset, leading to phosphorylation of the nuclear factor of activated T cells. Conclusions : Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo, and its inhibition may have therapeutic applications.
Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
Authors: Alexandra Snyder, Vladimir Makarov, Taha Merghoub, Jianda Yuan, Jesse M. Zaretsky, Alexis Desrichard, Logan A. Walsh, Michael A. Postow, Phillip Wong, Teresa S. Ho, Travis J. Hollmann, Cameron Bruggeman, Kasthuri Kannan, Yanyun Li, Ceyhan Elipenahli, Cailian Liu, Christopher T. Harbison, Lisu Wang, Antoni Ribas, Jedd D. Wolchok, Timothy A. Chan
Journal: New England Journal of Medicine (2014)

Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.).
Acute pancreatitis reclassified: Table 1
Authors: John A Windsor, Maxim S Petrov
Journal: Gut (2012)

Science is founded on observation and classification. The taxonomist's task to classify is both dependent and limited by what has been observed and is known. Progress in science is made by classifying seeming disorder, highlighting gaps and contradictions in knowledge and addressing them by experimentation. Classifications are stepping-stones, sign-posting current understanding, promoting hypotheses and enabling comparisons. Such is the iterative nature of science.

Progress has been made in the management of acute pancreatitis, evidenced by a decreasing overall mortality rate. And even though our understanding of the pathophysiology is more complete, specific treatments for acute pancreatitis remain elusive and our classifications have been simplistic. For more than a century we have relied on a binary classification of acute pancreatitis severity.1 Patients had either mild or severe disease, and this approach was enshrined in the original Atlanta Classification 20 years ago. Classification has not kept pace with our understanding of this disease and has hindered studies of potential treatments.2 When misclassification error runs to a quarter or a third of those enrolled, it is little wonder that the clinical trials of potential treatments for acute pancreatitis have been described as a ‘litany of failure’. And maybe we have discarded certain treatments prematurely.2 But the …