tbuckley/cabot-search huggingface dataset:
Evolution of Hormone Signaling in Elasmobranchs by Exploitation of Promiscuous Receptors
Authors: S. M. Carroll, J. T. Bridgham, J. W. Thornton
Journal: Molecular Biology and Evolution (2008)

Specific interactions among proteins, nucleic acids, and metabolites drive virtually all cellular functions and underlie phenotypic complexity and diversity. Despite the fundamental importance of interactions, the mechanisms and dynamics by which they evolve are poorly understood. Here we describe novel interactions between a lineage-specific hormone and its receptors in elasmobranchs, a subclass of cartilaginous fishes, and infer how these associations evolved using phylogenetic and protein structural analyses. The hormone 1alpha-hydroxycorticosterone (1alpha-B) is a physiologically important steroid synthesized only in elasmobranchs. We show that 1alpha-B modulates gene expression in vitro by activating two paralogous intracellular transcription factors, the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), in the little skate Leucoraja erinacea; MR serves as a high-sensitivity and GR as a low-sensitivity receptor. Using functional analysis of extant and resurrected ancestral proteins, we show that receptor sensitivity to 1alpha-B evolved millions of years before the hormone itself evolved. The 1alpha-B differs from more ancient corticosteroids only by the addition of a hydroxyl group; the three-dimensional structure of the ancestral receptor shows that the ligand pocket contained ample unoccupied space to accommodate this moiety. Our findings indicate that the interactions between 1alpha-B and elasmobranch GR and MR proteins evolved by molecular exploitation: a novel hormone recruited into new functional partnerships two ancient receptors that had previously interacted with other ligands. The ancestral receptor's promiscuous capacity to fortuitously bind compounds that are slight structural variants of its original ligands set the stage for the evolution of this new interaction.
Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β–dependent cancer metastasis
Authors: Jianfei Xue, Xia Lin, Wen-Tai Chiu, Yao-Hui Chen, Guanzhen Yu, Mingguang Liu, Xin-Hua Feng, Raymond Sawaya, René H. Medema, Mien-Chie Hung, Suyun Huang
Journal: Journal of Clinical Investigation (2014)

A key feature of TGF-β signaling activation in cancer cells is the sustained activation of SMAD complexes in the nucleus; however, the drivers of SMAD activation are poorly defined. Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. FOXM1 prevented the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex. Loss of FOXM1 abolished TGF-β-induced SMAD3/SMAD4 formation. Moreover, the interaction of FOXM1 and SMAD3 promoted TGF-β/SMAD3-mediated transcriptional activity and target gene expression. We found that FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. Importantly, the function of FOXM1 in TGF-β-induced invasion was not dependent on FOXM1's transcriptional activity. Knockdown of SMAD3 diminished FOXM1-induced metastasis. Furthermore, FOXM1 levels correlated with activated TGF-β signaling and metastasis in human breast cancer specimens. Together, our data indicate that FOXM1 promotes breast cancer metastasis by increasing nuclear retention of SMAD3 and identify crosstalk between FOXM1 and TGF-β/SMAD3 pathways. This study highlights the critical interaction of FOXM1 and SMAD3 for controlling TGF-β signaling during metastasis.
Sarcoidosis presenting with chylothorax.
Authors: P R Jarman, M K Whyte, I Sabroe, J M Hughes
Journal: Thorax (1995)

A patient in whom chylothorax was the presenting feature of sarcoidosis is reported. Mediastinal lymphadenopathy was shown by computed tomographic scanning. Obstruction of the thoracic duct by enlarged lymph nodes or fibrosis is the probable cause of chylothorax in this case. The association of chylothorax and sarcoidosis is extremely rare.
Landscape of Standing Variation for Tandem Duplications in Drosophila yakuba and Drosophila simulans
Authors: Rebekah L. Rogers, Julie M. Cridland, Ling Shao, Tina T. Hu, Peter Andolfatto, Kevin R. Thornton
Journal: Molecular Biology and Evolution (2014)

We have used whole genome paired-end Illumina sequence data to identify tandem duplications in 20 isofemale lines of D. yakuba, and 20 isofemale lines of D. simulans and performed genome wide validation with PacBio long molecule sequencing. We identify 1,415 tandem duplications that are segregating in D. yakuba as well as 975 duplications in D. simulans, indicating greater variation in D. yakuba. Additionally, we observe high rates of secondary deletions at duplicated sites, with 8% of duplicated sites in D. simulans and 17% of sites in D. yakuba modified with deletions. These secondary deletions are consistent with the action of the large loop mismatch repair system acting to remove polymorphic tandem duplication, resulting in rapid dynamics of gain and loss in duplicated alleles and a richer substrate of genetic novelty than has been previously reported. Most duplications are present in only single strains, suggesting deleterious impacts are common. D. simulans shows larger numbers of whole gene duplications in comparison to larger proportions of gene fragments in D. yakuba. D. simulans displays an excess of high frequency variants on the X chromosome, consistent with adaptive evolution through duplications on the D. simulans X or demographic forces driving duplicates to high frequency. We identify 78 chimeric genes in D. yakuba and 38 chimeric genes in D. simulans, as well as 143 cases of recruited non-coding sequence in D. yakuba and 96 in D. simulans, in agreement with rates of chimeric gene origination in D. melanogaster. Together, these results suggest that tandem duplications often result in complex variation beyond whole gene duplications that offers a rich substrate of standing variation that is likely to contribute both to detrimental phenotypes and disease, as well as to adaptive evolutionary change.
A case of breathlessness:
Authors: Rachelle Shafei, Rowena Goalby, John Hutchinson
Journal: BMJ (2015)

A 62 year old woman was referred to hospital by her general practitioner because of a few days history of progressive shortness of breath. She had associated fever but no cough or sputum production. Her medical history included rheumatoid arthritis, for which she had been taking methotrexate for the past 12 years.

On examination, she was visibly dyspnoeic, with low oxygen saturations. Her respiratory rate was 22 breaths/min, oxygen saturation was 90% on air, heart rate was 100 beats/min, blood pressure was 115/72 mm Hg, and her temperature was 37.4oC. Chronic hand changes, consistent with rheumatoid arthritis, were noted. Bilateral widespread crackles were heard on auscultation of the chest.

Blood tests showed a white blood cell count of 8.8×109/L (reference range 4-10) and a C reactive protein of 1219 nmol/L (<47.6). Further blood tests, including antinuclear antibody (ANA) and extractable nuclear antigen (ENA), were negative. Chest radiography showed diffuse alveolar shadowing throughout both lungs, with possible background fibrotic changes (figure⇓).



Chest radiograph showing diffuse alveolar shadowing throughout both lungs



She was treated with intravenous antibiotics for suspected severe community acquired pneumonia but continued to deteriorate and was transferred to the high dependency unit for closer monitoring and ventilatory support.

In view of the findings on chest radiography, she underwent a high resolution computed tomography scan of the chest. A working diagnosis of interstitial lung disease was made.



### 1. What is the differential diagnosis at presentation?

#### Answer

The differential diagnosis includes infection (including atypical organisms), pulmonary oedema, and interstitial lung disease (ILD), either secondary to rheumatoid arthritis or drug induced.

#### Discussion

The differential diagnosis in a patient with subacute onset of …
Naturally occurring anti–IFN-γ autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans
Authors: Conny Höflich, Robert Sabat, Simone Rosseau, Bettina Temmesfeld, Hortense Slevogt, Wolf-Dietrich Döcke, Gerald Grütz, Christian Meisel, Elke Halle, Ulf B. Göbel, Hans-Dieter Volk, Norbert Suttorp
Journal: Blood (2003)
Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma
Authors: Antoni Ribas, Richard Kefford, Margaret A. Marshall, Cornelis J.A. Punt, John B. Haanen, Maribel Marmol, Claus Garbe, Helen Gogas, Jacob Schachter, Gerald Linette, Paul Lorigan, Kari L. Kendra, Michele Maio, Uwe Trefzer, Michael Smylie, Grant A. McArthur, Brigitte Dreno, Paul D. Nathan, Jacek Mackiewicz, John M. Kirkwood, Jesus Gomez-Navarro, Bo Huang, Dmitri Pavlov, Axel Hauschild
Journal: Journal of Clinical Oncology (2013)

In phase I/II trials, the cytotoxic T lymphocyte-associated antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy.Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine).In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor.This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.
(35) Multiple endocrine adenomatosis (Type i) with cutaneous leiomyomata and cysts of Moll
Authors: J.L. Burton, M. Hartog
Journal: British Journal of Dermatology (1977)

Journal Article (35) Multiple endocrine adenomatosis (Type i) with cutaneous leiomyomata and cysts of Moll Get access J.L. Burton, J.L. Burton Bristol Royal Infirmary Search for other works by this author on: Oxford Academic Google Scholar M. Hartog M. Hartog Bristol Royal Infirmary Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 97, Issue s15, 1 December 1977, Pages 74–75, https://doi.org/10.1111/j.1365-2133.1977.tb14343.x Published: 01 December 1977
Safety and Feasibility of Robotic Percutaneous Coronary Intervention
Authors: Giora Weisz, D. Christopher Metzger, Ronald P. Caputo, Juan A. Delgado, J. Jeffrey Marshall, George W. Vetrovec, Mark Reisman, Ron Waksman, Juan F. Granada, Victor Novack, Jeffrey W. Moses, Joseph P. Carrozza
Journal: Journal of the American College of Cardiology (2013)
Two-Hour Insulin Determination Improves the Ability of Abdominal Fat Measurement to Identify Risk for the Metabolic Syndrome
Authors: Fernando F. Ribeiro-Filho, Alessandra N. Faria, Narcia E.B. Kohlmann, Maria-Teresa Zanella, Sandra R.G. Ferreira
Journal: Diabetes Care (2003)

OBJECTIVE—Visceral obesity is shown to be a predictor of morbidity and mortality. We evaluated the association of measurements of generalized adiposity and visceral fat area (VFA), with abnormalities of metabolic syndrome (MS). RESEARCH DESIGN AND METHODS—Seventy-six women (47.9 ± 9.2 years) with BMI of 38.7 ± 5.4 kg/m2 underwent anthropometric measurements, laboratory procedures, bioeletrical impedance, and abdominal computed tomography (CT) scan. Diagnosis of MS was based on the presence of abdominal obesity and at least two of the following components: hypertension, dyslipidemia, and glucose intolerance and/or hyperinsulinemia. RESULTS—BMI was correlated with both components of adipose tissue—subcutaneous (r = 0.66, P &amp;lt; 0.01) and VFA (r = 0.33, P &amp;lt; 0.02)—and leptin levels (r = 0.38, P &amp;lt; 0.01). In contrast, VFA was correlated with 2-h glucose and insulin levels (r = 0.32 and 0.35, P &amp;lt; 0.05, respectively), triglyceride, HDL cholesterol, and uric acid (r = 0.33, −0.34 and 0.24, P &amp;lt; 0.05, respectively). Subjects with high VFA, matched for BMI, showed greater plasma glucose area under the curve (621 ± 127 vs. 558 ± 129 mg · h−1 · dl−1, P &amp;lt; 0.05), 2-h insulin (804 ± 599 vs. 579 ± 347 pmol/l, P &amp;lt; 0.05), and uric acid levels (0.33 ± 0.07 vs. 0.26 ± 0.06 mmol/l, P &amp;lt; 0.05) than subjects with low VFA. In logistic regression analysis, waist circumference, VFA, and 2-h insulin were identified as independent predictors of MS. Receiver operating characteristic curve analysis pointed out the values of 104 cm for waist circumference (58.1% specificity, 84.1% sensitivity), 158.5 cm2 for VFA (78.1% specificity, 52.3% sensitivity), and 559.8 pmol/l for 2-h insulin (71.9% specificity, 69.8% sensitivity); the presence of at least two of the three variables resulted in a degree of concordance of 76%. CONCLUSIONS—While BMI was unable to differentiate between obese people and those at higher risk for MS, abdominal fat was shown to be associated with its metabolic abnormalities. The usefulness of abdominal fat in the identification of high-risk subjects may be improved when combined with 2-h insulin determination.
Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice.
Authors: A M Jevnikar, M J Grusby, L H Glimcher
Journal: The Journal of Experimental Medicine (1994)

MRL-lpr mice develop aggressive autoimmune kidney disease associated with increased or de novo renal expression of major histocompatibility complex (MHC) class II molecules and a massive systemic expansion of CD4-CD- double negative (DN) T cells. Whereas non-MHC linked genes can have a profound effect on the development of nephritis, lymphadenopathy, and anti-DNA antibody production in MRL-lpr mice, the role of MHC molecules has not been unequivocally established. To study the role of MHC class II in this murine model of systemic lupus erythematosis, class II-deficient MRL-lpr mice (MRL-lpr -/-) were created. MRL-lpr -/- mice developed lymphadenopathy but not autoimmune renal disease or autoantibodies. This study demonstrates that class II expression is critical for the development of autoaggressive CD4+ T cells involved in autoimmune nephritis and clearly dissociates DN T cell expansion from autoimmune disease initiation.
Cell Polarization Defects in Early Heart Development
Authors: Erica E. Davis, Nicholas Katsanis
Journal: Circulation Research (2007)

Cell Polarity defects have been associated with a range of phenotypes in vertebrates, most notably the closure of the neural tube, the orientation of stereociliary bundles in the inner ear, and the orientation of hair and fur.In a new study in this issue of Circulation Research, Phillips and colleagues present data that implicate PCP signaling in the developing mouse heart.Characterized originally as the mechanism governing the polarity of cells in Drosophila, 25 years of genetic and molecular dissection has established Planar Cell Polarity (PCP) as a morphogenetic mechanism in embryonic development that is indispensable for the formation of the body plan.PCP can be defined broadly as a signaling cascade that involves cell/tissue polarity within the plane of the epithelium, which, in Drosophila and to a certain extent in vertebrates, is typically mediated by a small set of "core" proteins.In flies, the best known examples of PCP have been described in relation to the organization of 2 structures: the hexagonal wing cells and their connected hairs, and the omatidia of the compound eye.In each case, the asymmetric distribution of key proteins, such as Strabismus, Prickle, and Flamingo initiates a signaling cascade that passes polarizing information to cells undergoing remodeling. 1 In vertebrates, classic examples of PCP events include convergent extension in zebrafish and xenopus, and neural tube closure, stereociliary bundle organization, hair follicle orientation in the skin, and eyelid closure in mammals (see ref. 2 for a recent representative review of the topic; Figure).Notably, PCP studies in vertebrates (primarily mouse and zebrafish) have unveiled a host of PCP proteins, some of which are functionally conserved with the Drosophila PCP pathway, such as members of the Frizzled (Fz) serpentine receptor family and the Disheveled family of proteins (Dvl), while others seem to have acquired novel PCP functions in the vertebrate lineage, such as the ciliary-associated BBS proteins, Inversin, Inturned and Fuzzy. 2 Circletail (Crc) and Looptail (Lp) are two mouse mutants noted for manifesting the most severe forms of neural tube defects (NTDs).Positional cloning identified the underlying genes for each of these two models as Scribble (Scrib) 3 and Van gogh-like 2 (Vangl2), 4,5 respectively.Importantly,
Pharmacogenetics of Psychotropic Drug Response
Authors: Anil K. Malhotra, Greer M. Murphy, James L. Kennedy
Journal: American Journal of Psychiatry (2004)

Molecular genetic approaches provide a novel method of dissecting the heterogeneity of psychotropic drug response. These pharmacogenetic strategies offer the prospect of identifying biological predictors of psychotropic drug response and could provide the means of determining the molecular substrates of drug efficacy and drug-induced adverse events.The authors discuss methods issues in executing pharmacogenetic studies, review the first generation of pharmacogenetic studies of psychotropic drug response, and consider future directions for this rapidly evolving field.Pharmacogenetics has been most commonly used in studies of antipsychotic drug efficacy, antidepressant drug response, and drug-induced adverse effects. Data from antipsychotic drug studies indicate that polymorphisms within the serotonin 2A and dopamine receptor 2 genes may influence drug efficacy in schizophrenia. Moreover, a growing body of data suggests a relationship between the serotonin transporter gene and clinical effects of the selective serotonin reuptake inhibitors used to treat depression. A significant relationship between genetic variation in the cytochrome P450 system and drug-induced adverse effects may exist for certain medications. Finally, a number of independent studies point to a significant effect of a dopamine D(3) receptor polymorphism on susceptibility to tardive dyskinesia.Initial research into the pharmacogenetics of psychotropic drug response suggests that specific genes may influence phenotypes associated with psychotropic drug administration. These results remain preliminary and will require further replication and validation. New developments in molecular biology, human genomic information, statistical methods, and bioinformatics are ongoing and could pave the way for the next generation of pharmacogenetic studies in psychiatry.
Fungal Zuotin Proteins Evolved from MIDA1-like Factors by Lineage-Specific Loss of MYB Domains
Authors: Edward L. Braun, Erich Grotewold
Journal: Molecular Biology and Evolution (2001)

Proteins are often characterized by the presence of multiple domains, which make specific contributions to their cellular function. While the gain of domains in proteins by duplication and shuffling is well established, domain loss is poorly documented. Here, we provide evidence that domain loss has played an important role in the evolution of protein architecture and function by demonstrating that fungal Zuotin proteins evolved from MIDA1-like proteins, present in animals and plants, by complete loss of the carboxyl-terminal MYB domains. Phylogenetic analyses of the DnaJ motif (the J domain) present in both Zuotin and MIDA1 proteins were complicated by the limited length and profound differences in evolutionary rates exhibited by this domain. To rigorously examine J domain phylogeny, we combined the nonparametric bootstrap with Monte Carlo simulation. This method, which we have designated the resampled parametric bootstrap, allowed us to assess type I and type II error associated with these analyses. These results revealed significant support for domain loss rather than domain gain or gene loss involving paralogs. The absence of sequences related to the MIDA1 MYB domains in Saccharomyces cerevisiae further indicates that the domains have been completely lost, consistent with known functional differences between Zuotin and MIDA1 proteins. These analyses suggest that the description of additional examples of complete domain loss may provide a method to identify orthologous proteins exhibiting functional differences using genomic sequence data.
Intravascular T-cell lymphoma with bowel involvement: Case report and literature review
Authors: Geoffrey Williams, Ann Foyle, Darrell White, Wenda Greer, Steven Burrell, Stephen Couban
Journal: American Journal of Hematology (2005)

Intravascular lymphoma (IVL) is a rare form of non-Hodgkin lymphoma characterized by massive proliferation of large, neoplastic cells in small- and medium-sized blood vessels. Most cases of IVL are of B-cell immunophenotype; fewer than 15 cases of T-cell IVL have been reported. A 23-year-old male presented with acute abdominal pain, fever, and tender lower abdomen. Pathology at laparotomy revealed infiltration of colonic vessels with large lymphoid cells compatible with IVL. We reviewed all cases of IVL diagnosed at the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, from August 1992 to August 2002. A literature review was also performed. Five additional cases of IVL were identified at this institution during a 10-year period. Three patients presented with neurological symptoms, and two with abdominal pain. In 4 of 5 cases, patients died of lymphoma within 3 months of presentation; one patient experienced a 10-month remission. While visceral involvement with IVL is common at autopsy, IVL presenting as an acute abdomen in an immunocompetent patient has not previously been described. Among the 15 cases of T-cell IVL reported in the literature, only two occurred in people under age 30. Given the rarity of T-cell IVL, it is remarkable that three cases of T-cell IVL have been diagnosed at our institution during a 10-year period. Am. J. Hematol. 78:207–211, 2005. © 2005 Wiley-Liss, Inc.