tbuckley/cabot-search huggingface dataset:
The structure of the Adh locus of Drosophila mettleri: an intermediate in the evolution of the Adh locus in the repleta group of Drosophila.
Authors: J S Yum, W T Starmer, D T Sullivan
Journal: Molecular Biology and Evolution (1991)

Members of species of the mulleri and hydei subgroups of the repleta group of Drosophila have duplicate Adh genes. The Adh regions of D. mojavensis, D. mulleri, and D. hydei contain three genes--a pseudogene, Adh-2, and Adh-1--arranged 5' to 3'. To understand the evolution of the triplicate Adh structure, we have cloned and sequenced the Adh locus of D. mettleri. This region consists of a 5' pseudogene and a 3' functional Adh gene. On the basis of the structure and nucleotide sequence comparisons of Adh genes of D. mettleri and other species, we propose that an initial duplication of the ancestral Adh gene generated two Adh genes arranged in tandem. The more 5' Adh gene became a pseudogene, while the more 3' gene remained functional through all the developmental stages. A second duplication of this 3' gene resulted in Adh regions with three genes--a pseudogene, Adh-2, and Adh-1.
A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A
Authors: Giuseppina Giglia-Mari, Frederic Coin, Jeffrey A Ranish, Deborah Hoogstraten, Arjan Theil, Nils Wijgers, Nicolaas G J Jaspers, Anja Raams, Manuela Argentini, P J van der Spek, Elena Botta, Miria Stefanini, Jean-Marc Egly, Ruedi Aebersold, Jan H J Hoeijmakers, Wim Vermeulen
Journal: Nature Genetics (2004)
Injuries by Venomous Animals.
Authors: Findlay E. Russel
Journal: Annals of Internal Medicine (1964)

s1 October 1964Injuries by Venomous Animals.Findlay E. Russel, M.D., F.A.C.P.Findlay E. Russel, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-61-4-803_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptInjuries inflicted by venous animals are medical emergencies requiring immediate attention and considerable clinical judgment. Approximately 2,200 persons a year in the United States are bitten by venomous reptiles. Venomous fishes, coelenterates, and certain other marine forms are responsible for about 1,800 injuries annually. The number of envenomations by venomous arthropods is not known, but it must exceed 500,000 each year. Fortunately, deaths from these various poisonings are relatively uncommon in this country: less than 50 fatalities are reported each year.The toxins of the venomous animals vary considerably in their composition and modes of action. The arbitrary division of... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Los Angeles, Calif. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1964Volume 61, Issue 4Page: 803-803KeywordsArmed forcesPoisoningToxins Issue Published: 1 October 1964 PDF DownloadLoading ...
Evelyn Witkin and Stephen Elledge share the 2015 Lasker Basic Medical Award
Authors: Sarah Jackson
Journal: Journal of Clinical Investigation (2015)

How do cells cope with damage to genet- ic material?This year's Albert Lasker Basic Medical Research Award honors two distinct leaders in the field, Evelyn Witkin and Stephen Elledge, for their groundbreaking work to answer this question and uncover the cellular responses to DNA damage (Figure 1).Early in her career, Witkin isolated strains of UV-resistant bacteria and subsequently played a pivotal role in developing the SOS model of bacterial DNA damage response.A generation later, Elledge identified a number of key components of the signal transduction cascades that are critical for eukaryotic cells to sense and respond to damaged DNA and blocked DNA replication forks.Collectively, their work sheds light on multiple pathways that enable cells across the evolutionary spectrum to maintain genomic integrity.
Recurrent Testicular Germ Cell Tumors in a Family With MYH-Associated Polyposis
Authors: Adela Castillejo, Ana Beatriz Sanchez-Heras, Rodrigo Jover, Maria Isabel Castillejo, Carla Guarinos, Silvestre Oltra, Ana Martínez-Canto, Victor Manuel Barbera, Juan Laforga, Artemio Paya, Cristina Alenda, Jose Luis Soto
Journal: Journal of Clinical Oncology (2012)

Case ReportWe report a family with a genetic diagnosis of MYH-associated polyposis (MAP; Mendelian Inheritance in Man [MIM] No. 608456), resulting from a combination of rare pathogenic variants at MUTYH (MIM No. 604933) and a testicular germ cell tumor (TGCT) in two siblings with the same MUTYH genotype.Extraintestinal neoplasias of breast, gastric, thyroid, and hematologic origin have been described in MAP syndrome.Testicular cancer may be a previously unreported extraintestinal manifestation of this syndrome.The index patient (III-2; Fig 1; Dx, diagnosis; [ †] indicates age of death) was referred to our Genetic Counseling in Cancer consultancy with suspected Lynch or MAP syndrome because, at the age of 44 years, he was diagnosed with rectal cancer and eight adenomatous polyps in the right colon.He had been previously diagnosed with TGCT at the age of 32 years.At that time, the patient detected a testicular mass on self-examination, and he consulted his physician.Scrotal examination revealed a nontender induration in the lower pole of the right testis and a normal left testis.The rest of the physical examination was normal.Laboratory investigations were within the normal ranges except for ␣-fetoprotein, beta human chorionic gonadotropin hormone, and lactate dehydrogenase, which were at higher than normal levels.Scrotal ultrasonography revealed a normal left testis and a hypoechoic solid mass 32 to 37 mm in diameter in the right testis.Thoracic, abdominal, and pelvic computed tomography (CT) scans did not reveal any metastases.A right radical orchiectomy was performed.Histopathology showed stage I pT1N0M0 disease.
Serotonin selectively aggravates subendocardial ischemia distal to a coronary artery stenosis during exercise.
Authors: R J Bache, R P Stark, D J Duncker
Journal: Circulation (1992)

BACKGROUND The coronary circulation has been shown to remain responsive to vasodilator and vasoconstrictor stimuli during myocardial ischemia. Because serotonin possesses both vasodilator and vasoconstrictor properties, we examined its effect in the coronary circulation distal to an arterial stenosis that resulted in myocardial hypoperfusion during exercise. METHODS AND RESULTS Seven chronically instrumented dogs were studied during treadmill exercise in the presence of a stenosis that reduced distal left circumflex coronary artery perfusion pressure to 42 +/- 1 mm Hg. Myocardial blood flow was assessed with radioactive microspheres during exercise before and during intracoronary infusion of 0.4 and 2.0 micrograms/kg-1.min-1 serotonin. The stenosis was adjusted to maintain distal coronary pressure constant during control exercise and with the two doses of serotonin. In seven dogs, the effect of serotonin (2.0 micrograms/kg-1.min-1) was also studied during exercise with normal arterial inflow. During control exercise, the stenosis decreased mean myocardial blood flow to 45% of flow in the normally perfused region. This decrease was most pronounced in the subendocardium (endocardial/epicardial ratio 0.36 +/- 0.06 versus 1.46 +/- 0.14 in the control region; p &lt; 0.01). With no change in pressure distal to the stenosis, serotonin decreased subendocardial flow from 0.51 +/- 0.09 ml/min-1.g-1 to 0.41 +/- 0.12 (p &lt; 0.05) and then to 0.35 +/- 0.08 ml/min-1.g-1 (p &lt; 0.05) and tended to increase subepicardial flow from 1.47 +/- 0.17 to 1.91 +/- 0.23 and 1.85 +/- 0.21 ml/min-1.g-1 (p = 0.08) during infusions of 0.5 and 2.0 micrograms/kg-1.min-1, respectively, with no change in total arterial inflow. In contrast, in the absence of a stenosis, serotonin (2.0 micrograms/kg-1.min-1) increased subendocardial flow from 2.43 +/- 0.25 to 3.73 +/- 0.25 ml/min-1.g-1 (p &lt; 0.01) and subepicardial flow from 1.88 +/- 0.20 to 5.29 +/- 0.38 ml/min-1.g-1 (p &lt; 0.01). CONCLUSIONS During normal arterial inflow, serotonin dilated coronary resistance vessels and increased flow to all myocardial layers. During hypoperfusion, a vasodilator response was still present in the subepicardium, but vasoconstriction was then observed in the subendocardium. Our data suggest that serotonin constricts the intramural penetrating arteries, thereby selectively increasing resistance to subendocardial blood flow.
Urinary Tract Effects of HPSE2 Mutations
Authors: Helen M. Stuart, Neil A. Roberts, Emma N. Hilton, Edward A. McKenzie, Sarah B. Daly, Kristen D. Hadfield, Jeffery S. Rahal, Natalie J. Gardiner, Simon W. Tanley, Malcolm A. Lewis, Emily Sites, Brad Angle, Cláudia Alves, Teresa Lourenço, Márcia Rodrigues, Angelina Calado, Marta Amado, Nancy Guerreiro, Inês Serras, Christian Beetz, Rita-Eva Varga, Mesrur Selcuk Silay, John M. Darlow, Mark G. Dobson, David E. Barton, Manuela Hunziker, Prem Puri, Sally A. Feather, Judith A. Goodship, Timothy H.J. Goodship, Heather J. Lambert, Heather J. Cordell, Anand Saggar, Maria Kinali, Christian Lorenz, Kristina Moeller, Franz Schaefer, Aysun K. Bayazit, Stefanie Weber, William G. Newman, Adrian S. Woolf
Journal: Journal of the American Society of Nephrology (2014)

Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS.
Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model
Authors: Olympia Bikou, Dierk Thomas, Kerstin Trappe, Patrick Lugenbiel, Kamilla Kelemen, Martin Koch, Radim Soucek, Frederik Voss, Rüdiger Becker, Hugo A. Katus, Alexander Bauer
Journal: Cardiovascular Research (2011)

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and effective treatment of AF still remains an unmet medical need. AF is associated with atrial conduction disturbances caused by electrical and/or structural remodelling. We hypothesized that AF suppresses expression of the gap junction protein connexin (Cx) 43 and that Cx43 gene transfer to both atria would prevent persistent AF. The first aim of this study was to assess whether AF is associated with connexin remodelling in a porcine model. A strategy to suppress persistent AF by gene therapy was then developed and evaluated in vivo. AF was induced in domestic pigs via atrial burst pacing, causing a 62.4% reduction in atrial Cx43 protein. Adenoviruses encoding for Cx43 (AdCx43) or green fluorescent protein (AdGFP) were injected into both atria, followed by epicardial electroporation to enhance transgene expression. Combining direct injection of adenoviruses with electroporation achieved GFP reporter gene expression in ∼50% of atrial cells in vivo. AdCx43-treated animals exhibited a 2.5-fold increase in atrial Cx43 protein content and did not develop persistent AF during the observation period of 14 days. In contrast, control animals developed persistent AF within 7.4 ± 0.5 days. Rapid ventricular heart rates during AF led to deterioration of cardiac function in control pigs but not in pigs treated with AdCx43. Our results highlight the contribution of Cx43 to the pathophysiology of AF and demonstrate the viability of gene therapy for prevention of atrial arrhythmias.
Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease
Authors: Gregory J. Kato, Vicki McGowan, Roberto F. Machado, Jane A. Little, James Taylor, Claudia R. Morris, James S. Nichols, Xunde Wang, Mirjana Poljakovic, Sidney M. Morris, Mark T. Gladwin
Journal: Blood (2005)
Prevalence of spondyloarthritis in Terceira, Azores: a population based study
Authors: J Bruges-Armas
Journal: Annals of the Rheumatic Diseases (2002)

Objective: To determine the prevalence of spondyloarthritis (SpA) in the Caucasian population of Terceira Island, Azores. Methods: Study subjects were recruited from people over the age of 50 years from one half of the island of Terceira (n=24 561). Seventy eight men and 78 women from each five year age group were selected, giving a total of 468 men and 468 women available for study, of whom 490 agreed to take part. These subjects were assessed by dorsal, lumbar, and pelvic radiography. Radiological sacroiliitis was identified in eight patients on whom sacroiliac computed tomography scans were performed. HLA class I typing by polymerase chain reaction with sequence-specific primers was carried out in seven cases. Results: SpA was present in eight subjects (1.6%, 95% CI 0.8 to 2.7%), including seven men (2.7%) and one woman (0.4%). Three (1.2% ) male patients with definite ankylosing spondylitis were HLA-B27 positive. Only one person had a previous diagnosis of SpA. Conclusion: These data complement previous studies in European countries on SpA prevalence and establish an estimate of the overall prevalence of SpA in a southern European population.
In This Issue
Authors: E Jane Costello, William Copeland, Alexander Cowell, Gordon Keeler
Journal: American Journal of Psychiatry (2007)

Costs of treating child psychiatric disorders fall on educational, primary care, juvenile justice, and social service agencies as well as on psychiatric services. The authors estimated multiagency mental health costs by integrating service unit costs with utilization rates in an 11-county area. Using psychiatric diagnoses made independently of service use records, the authors calculated costs across agencies as well as the extent of unmet need for psychiatric care.Annual parent and child reports were used to measure mental health care needs and units of service across 21 types of settings for the population-based Great Smoky Mountain Study sample of 1,420 adolescents from ages 13 to 16. Unit costs for services were generated from information from service providers and records. The authors calculated costs overall, costs by type of service, and costs by diagnosis.Average annual costs per adolescent treated were $3,146. Juvenile justice and inpatient/residential facilities accounted for well over half of the total costs. Costs for youths with two or more diagnoses were twice as much as costs of those with a single disorder. Among adolescents with service needs, 66.9% received no services. Public health insurance was associated with higher rates of specialty mental health care than either private insurance or no insurance.Annual costs across all services were three to four times greater than recent health insurance estimates alone. Many costs for adolescents with mental health problems were borne by agencies not designed primarily to provide psychiatric or psychological services. Only one in three adolescents needing psychiatric care received any mental health services.
Humanization of the Bispecific Epidermal Growth Factor Receptor × CD3 Diabody and Its Efficacy as a Potential Clinical Reagent
Authors: Ryutaro Asano, Yukiko Sone, Koki Makabe, Kouhei Tsumoto, Hiroki Hayashi, Yu Katayose, Michiaki Unno, Toshio Kudo, Izumi Kumagai
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Bispecific antibodies (BsAb) have been exploited as both cancer immunodiagnostics and cancer therapeutics and show promise in clinical trials of cancer imaging and therapy. For development of BsAbs as clinical reagents, we have focused on construction of small recombinant BsAbs, called bispecific diabodies. Here, we constructed and characterized a humanized bispecific diabody. Experimental Design: We have reported significant antitumor activity of an anti-epidermal growth factor receptor (EGFR) × anti-CD3 bispecific diabody (Ex3) in in vitro cytotoxicity assays and in vivo. We humanized the Ex3 diabody (hEx3) by grafting the complementarity-determining region and compared its biological properties with those of Ex3. We also tested its physiologic stability and ability to alter survival in xenografted mice. Results: The final yield of hEx3 was 10 times that of Ex3, and refolded hEx3 and Ex3 showed identical binding profiles in EGFR-positive cell lines and EGFR-transfected Chinese hamster ovary cells. hEx3 showed dose-dependent cytotoxicity to EGFR-positive cell lines, which could be specifically inhibited by parental monoclonal antibody IgGs against EGFR or CD3 antigens. The heterodimeric structure was retained in PBS for 6 months, and growth inhibition was maintained after incubation under physiologic conditions. Coadministration of hEx3 with T-LAK cells and interleukin-2 prolonged the survival of nude mice with human colon carcinoma. Conclusions: The humanized diabody hEx3 is an attractive molecule for cancer therapy and may provide important insights into the development of EGFR-based cancer-targeting reagents.
Molecular Diagnosis of Surgical Margins and Local Recurrence in Head and Neck Cancer Patients
Authors: Viola M. M. van Houten, C. René Leemans, J. Alain Kummer, Janny Dijkstra, Dirk J. Kuik, Michiel W. M. van den Brekel, Gordon B. Snow, Ruud H. Brakenhoff
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Approximately 10–30% of surgically treated head and neck cancer patients develop local recurrences while the resection margins are histologically tumor free. These recurrences may arise from cancer cells left behind but not detected by the pathologist, or they may develop from precursor lesions adjacent to the tumor that were not completely resected. We have investigated whether TP53-mutated DNA in the surgical margins is suitable to identify patients with head and neck squamous cell carcinoma at risk for local and locoregional recurrence. Experimental Design: In a prospective cohort study of 76 patients with histologically tumor-free margins, the presence of TP53-mutated DNA was determined in the surgical margins using the phage plaque assay and correlated to clinical outcome. Immunostaining of the molecular-positive margins for mutated p53 protein was used to identify whether unresected precursor lesions or residual tumor cells were left behind. Results: The absence of TP53-mutated DNA in surgical margins was significantly associated with remaining free of local and locoregional recurrence (P = 0.027 and P = 0.028, respectively). Moreover, the presence of TP53-mutated DNA in the surgical margins was an independent prognosticator for locoregional recurrence (relative risk = 7.1; P = 0.021; 95% confidence interval, 0.9–56). In 20% of the cases, the presence of TP53-mutated DNA in the surgical margins was found to be related to the presence of tumor-related precursor lesions. Conclusions: This study shows the value of TP53-mutated DNA as a molecular marker to predict locally recurrent head and neck squamous cell carcinoma. The observation that all patients who were negative for TP53-mutated DNA in the surgical margins remained free of local recurrence raises hope that molecular analysis of histologically tumor-free surgical margins can be exploited to decide on postoperative radiotherapy. Furthermore, our data provide evidence that local recurrences originate mainly from tumor cells left behind but also originate, in part, from unresected precursor lesions.
GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice
Authors: Irene Delgado, Manuel Carrasco, Elena Cano, Rita Carmona, Rocío García-Carbonero, Luis M. Marín-Gómez, Bernat Soria, Francisco Martín, David A. Cano, Ramón Muñoz-Chápuli, Anabel Rojas
Journal: Hepatology (2014)

The zinc finger transcription factor GATA4 controls specification and differentiation of multiple cell types during embryonic development. In mouse embryonic liver, Gata4 is expressed in the endodermal hepatic bud and in the adjacent mesenchyme of the septum transversum. Previous studies have shown that Gata4 inactivation impairs liver formation. However, whether these defects are caused by loss of Gata4 in the hepatic endoderm or in the septum transversum mesenchyme remains to be determined. In this study, we have investigated the role of mesenchymal GATA4 activity in liver formation. We have conditionally inactivated Gata4 in the septum transversum mesenchyme and its derivatives by using Cre/loxP technology. We have generated a mouse transgenic Cre line, in which expression of Cre recombinase is controlled by a previously identified distal Gata4 enhancer. Conditional inactivation of Gata4 in hepatic mesenchymal cells led to embryonic lethality around mouse embryonic stage 13.5, likely as a consequence of fetal anemia. Gata4 knockout fetal livers exhibited reduced size, advanced fibrosis, accumulation of extracellular matrix components and hepatic stellate cell (HSC) activation. Haploinsufficiency of Gata4 accelerated CCl 4 -induced liver fibrosis in adult mice. Moreover, Gata4 expression was dramatically reduced in advanced hepatic fibrosis and cirrhosis in humans. Conclusions : Our data demonstrate that mesenchymal GATA4 activity regulates HSC activation and inhibits the liver fibrogenic process. (Hepatology 2014;59:2358–2370)
Reply to: “Virtual portal pressure from anatomic CT angiography”
Authors: Pouya Iranmanesh, Antoine Poncet, Christian Toso
Journal: Journal of Hepatology (2014)

We thank Qi et al. [1] for their interest in our study proposing a non-invasive computed tomography (CT)-based model predicting the level of hepatic venous pressure gradient (HVPG): HVPG score=17.37–4.91*ln(Liver/Spleen ratio)+3.8 [if presence of peri-hepatic ascites], entitled “Accurate computed tomography-based portal pressure assessment in patients with hepatocellular carcinoma” [2].