tbuckley/cabot-search huggingface dataset:
Abstract 2390: Identification of BRCA2 genetic interactors in an ES cell-based model
Authors: Xia Ding, Shyam K. Sharan
Journal: Cancer Research (2014)

Abstract Mutations in breast cancer susceptible genes, BRCA1 and BRCA2 are the genetic factors conferring highest risk to develop breast cancer. Although BRCA proteins are known to maintain genomic stability mainly by homologous recombination-mediated DNA damage repair, detailed mechanisms of how BRCA loss induces tumorigenesis remain unclear. Interestingly, while inactivation of both alleles of BRCA1 or BRCA2 genes is necessary for tumor development, their loss in normal cells affects cell viability, indicating that cells lacking BRCA1 or 2 are able to survive and predisposed to tumorigenesis due to mutations in other genes such as those involved in cell cycle regulation or DNA damage response. In the current study, we identified some of the candidate genes using a mouse embryonic stem (mES) cell-based insertional mutagenesis screening. Overexpression of these genes rescued BRCA2 loss-induced lethality in mES cells. One candidate encodes a PDZ domain-containing protein, GIPC3. While overexpression of GIPC3 rescued BRCA2 loss efficiently, overexpression of its close homolog GIPC1 rescued much less efficiently. The GIPC3-rescued cells were hypersensitive to DNA damaging agents and exhibited an overall increase in genomic instability. Point mutation analysis showed several amino acids in the PDZ domain was critical for rescuing BRCA2 lethality, suggesting protein-protein interaction is responsible for the rescuing. We therefore performed IP-MS analysis and found that GIPC3 can interact with APPL1 and APPL2, two important mediators in AKT-mediated survival signal transduction pathway. We are now analyzing if these two molecules are potential down-stream factors of GIPC3 in rescuing BRCA2 loss-induced lethality. Meanwhile, we found that Gipc3 overxpression can partially rescue the lethality of Brca2ko/ko embryos. We are now also examining the expression of GIPC3 in human BRCA2-deficient tumors and we are monitoring tumorigenesis of GIPC3 transgenic mice in a K14-Cre;Brca2cko/cko mammary tumor model. Citation Format: Xia Ding, Shyam K. Sharan. Identification of BRCA2 genetic interactors in an ES cell-based model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2390. doi:10.1158/1538-7445.AM2014-2390
Bombesin-like peptide mediates lung injury in a baboon model of bronchopulmonary dysplasia.
Authors: M E Sunday, B A Yoder, F Cuttitta, K J Haley, R L Emanuel
Journal: Journal of Clinical Investigation (1998)

The etiology of bronchopulmonary dysplasia (BPD), a chronic lung disease of infants surviving respiratory distress syndrome, remains fundamentally enigmatic. BPD is decreasing in severity but continues to be a major problem in pediatric medicine, being especially prevalent among very premature infants. Increased numbers of pulmonary neuroendocrine cells containing bombesin-like peptide (BLP) have been reported to occur in human infants with BPD. We tested the hypothesis that BLP mediates BPD using the hyperoxic baboon model. Urine BLP levels increased soon after birth only in 100% O2-treated 140-d animals which developed BPD, correlating closely with severity of subsequent chronic lung disease. Similar elevations in urine BLP were observed in the 125-d baboon "interrupted gestation" model of BPD. Postnatal administration of anti-BLP antibody attenuated clinical and pathological evidence of chronic lung disease in the hyperoxic baboon model. Urine BLP could be a biological predictor of infants at risk for BPD, and blocking BLP postnatally could be useful for BPD prevention.
The Mixed Lineage Leukemia (MLL) Fusion–Associated Gene <i>AF4</i> Promotes CD133 Transcription
Authors: Anthony B. Mak, Allison M.L. Nixon, Jason Moffat
Journal: Cancer Research (2012)

Abstract The AC133 epitope has been used as a marker for both normal and cancer stem cells from multiple tissue lineages. To identify transcription factors that regulate CD133 expression, we conducted parallel large-scale RNA interference screens in Caco-2 cancer cells that endogenously express CD133 and in engineered HEK293 cells that express CD133 from a heterologous promoter. The transcription factor AF4 was identified following a comparative analysis between the two screens. We then showed that AF4 is a promoter of CD133 transcription in multiple cancer cell lines. Knockdown of AF4 resulted in a dramatic reduction in CD133 transcript levels. Importantly, a subset of pediatric acute lymphoblastic leukemias (ALL) harbor a fusion oncogene results from a chromosomal translocation that juxtaposes the mixed-lineage leukemia (MLL) gene and the AF4 gene. An investigation of the functional role of CD133 in the MLL-AF4–dependent ALL cells revealed that CD133 was required for leukemia cell survival. Together, our findings show AF4-dependent regulation of CD133 expression, which is required for the growth of ALL cells. CD133 may therefore represent a therapeutic target in a subset of cancers. Cancer Res; 72(8); 1929–34. ©2012 AACR.
Humanitarian corridor set up in Egypt as Libyan casualties escalate
Authors: J. Zarocostas
Journal: BMJ (2011)

The World Health Organization has negotiated the establishment of a humanitarian corridor with authorities in Egypt at the Salloum border with Libya to allow access to supplies as hundreds of thousands of Libyans flee violent clashes with supporters of Muammar Gaddafi’s government. Support from Egypt includes three field hospitals in the Salloum border crossing area.

According to the UN refugee agency, UNHCR, close to 100 000 people have fled the violence in Libya—50 000 crossing into Tunisia since 20 February …
The Effect of Oral Sulfonamide Diuretics on Carbohydrate Metabolism.
Authors: Stanley Green
Journal: Annals of Internal Medicine (1964)

s1 October 1964The Effect of Oral Sulfonamide Diuretics on Carbohydrate Metabolism.Stanley Green, M.D., F.A.C.P.Stanley Green, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-61-4-812_4 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe widespread use of oral sulfonamide diuretics has stimulated an increasing awareness of their metabolic side effects, namely, hyperglycemia, and hypokalemia. The mechanism of hyperglycemia has not been satisfactorily explained.Twenty-three well controlled diabetic patients were studied during a control period and for a prolonged period while on Chlorthalidone. The following data were collected: weight, blood pressure, blood sugar, serum potassium, uric acid, and urea nitrogen, 24-hr urinary 17-ketosteroids, 17-hydroxycorticosteroids, and aldosterone. During treatment approximately one half of the patients showed a significant rise in blood sugar and adrenal steroid excretion above control levels. The hyperglycemic response was inconsistent, occurring... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Philadelphia, Pa. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1964Volume 61, Issue 4Page: 812-812KeywordsBlood pressureBlood sugarCarbohydrate metabolismDiureticsExcretionHyperglycemiaPotassiumSulfonamideUreaUric acid Issue Published: 1 October 1964 PDF DownloadLoading ...
Unicef comes under attack for Big Mac funding deal
Authors: O. Dyer
Journal: BMJ (2002)

Unicef, the United Nations Children's Fund, has come under fire from children's advocates for concluding a fundraising alliance with the McDonald's chain of fast food restaurants.

A petition signed by delegates from the World Alliance for Breastfeeding Action accuses Unicef of compromising its mission to promote good nutrition by associating with the giant American corporation.

A letter accompanying the petition said that news of the alliance had shocked participants at a colloquium on HIV and infant feeding in Tanzania. “Discussions here with Unicef staff from regional and country offices lead us …
Addendum: Defective Dock2 expression in a subset of ASC-deficient mouse lines
Authors: Sirish K Ippagunta, R K Subbarao Malireddi, Patrick J Shaw, Geoffrey A Neale, Lieselotte Vande Walle, Yoshinori Fukui, Douglas R Green, Mohamed Lamkanfi, Thirumala-Devi Kanneganti
Journal: Nature Immunology (2012)
Competitive swimmers with allergic asthma show a mixed type of airway inflammation
Authors: A. Moreira, L. Delgado, C. Palmares, C. Lopes, T. Jacinto, P. Rytila, J. A. Silva, M. G. Castel-Branco, T. Haahtela
Journal: European Respiratory Journal (2008)

pneumonia has been also commented upon by other experts in the field [5, 6].Thus, the present authors believe that the prophylactic administration of antimicrobials via the respiratory tract for ventilator-associated pneumonia deserves the attention of investigators.However, future studies should focus not only on the effectiveness of this strategy but also on safety and the issue of emergence of antimicrobial resistance.
The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP
Authors: Thomas J. Sayers, Alan D. Brooks, Crystal Y. Koh, Weihong Ma, Naoko Seki, Arati Raziuddin, Bruce R. Blazar, Xia Zhang, Peter J. Elliott, William J. Murphy
Journal: Blood (2003)
German government shortens medical training
Authors: A. Tuffs
Journal: BMJ (2003)

The German government has decided to abolish the final practical phase of medical education, the so called “Arzt im praktikum” or prequalifying medical placement.

Before fully qualifying as doctor, medical students have had to work in this houseman-like position for one and a half years on low pay but with similar duties to those of a junior doctor.

The scheme was introduced in 1988 because it was felt that medical students needed to acquire more practical skills before they were accepted as fully qualified doctors. Doctors …
Gallium-67 Imaging Cephalohematoma
Authors: JOHN R. STY, ROBERT G. WELLS, DAVID C. GREGG, JOAN A. von ARRAS
Journal: Clinical Nuclear Medicine (1987)

Localized uptake of Ga-67 in a child with a mature cephalohematoma is demonstrated. Cephalohematoma should be considered in the differential diagnosis of calvarial gallium uptake in infants.
Down-regulation of the Na + /taurocholate cotransporting polypeptide during pregnancy in the rat
Authors: Marco Arrese, Michael Trauner, Meenakshisundaram Ananthanarayanan, Margarita Pizarro, Nancy Solı́s, Luigi Accatino, Carol Soroka, James L Boyer, Saul J Karpen, Juan Francisco Miquel, Frederick J Suchy
Journal: Journal of Hepatology (2003)
L-Arginine, nitric oxide, and intestinal secretion: studies in rat jejunum in vivo.
Authors: F H Mourad, L J O'Donnell, E A Andre, C P Bearcroft, R A Owen, M L Clark, M J Farthing
Journal: Gut (1996)

BACKGROUND: L-Arginine has been shown to induce fluid secretion in human jejunum. Nitric oxide, a derivative of L-arginine is thought to have an important role as an intestinal secretagogue. AIM: To determine the effect of L-arginine and the nitric oxide synthase inhibitor, nitro L-arginine methyl ester (L-NAME), on fluid and electrolyte movement in rat jejunum. METHODS: A 25 cm segment of rat jejunum was perfused in situ with iso-osmotic solutions containing either (1) saline, (2) D-arginine 20, (3) L-arginine 20, (4) L-NAME 0.1, 1, or 20 mmol/l, or (5) a combination of L-arginine 20 and L-NAME 0.1, 1, or 20 mmol/l. In further groups the effect of a subcutaneous injection of L-NAME 100 mg/kg was examined in rats pretreated with either D-or L-arginine 500 mg/kg. RESULTS: L-Arginine, unlike D-arginine, induced fluid secretion despite being better absorbed (mean -7.3 v 17.0 microliters/min/g; p &lt; 0.01). L-NAME at 0.1 mmol/l had no effect on basal fluid movement but reversed L-arginine induced secretion (7.8; p &lt; 0.05). L-NAME at 1 and 20 mmol/l induced fluid secretion (-15.4 and -28.4, respectively), which was enhanced by the addition of L-arginine (-30.0 and -41.0, respectively; both p &lt; 0.05). A subcutaneous injection of L-NAME resulted in marked fluid secretion (-39.9) and histological evidence of intestinal ischaemia. These changes were attenuated or reversed by pretreatment with subcutaneous L- but not D-arginine. CONCLUSIONS: L-arginine induces intestinal fluid secretion through production of nitric oxide. There is a delicate balance between the effect of nitric oxide as a secretagogue and its effect on maintaining blood flow and thus preventing intestinal ischaemia.
The Lost Art of Healing
Authors: Lois DeBakey
Journal: JAMA (1996)

Dr Bernard Lown has made major contributions to medical science. A pioneer in the study of the relation of potassium to digitalis toxicity, he also introduced direct-current cardioversion for the treatment of cardiac arrhythmias, was a major developer of the coronary care unit, and helped put the study of sudden death on the medical agenda. With Dr Samuel A. Levine, he fostered the early mobilization of patients recovering from a myocardial infarction, advocating that the patient sit in an armchair soon after the attack, and with Russian cardiologist Evegeni Chazof, he organized the International Physicians for Prevention of Nuclear War, for which they won the Nobel Peace Prize. In<i>The Lost Art of Healing</i>, Dr Lown devotes five chapters to his research activities, but most of the book focuses on his passion for the art of medicine, the importance of the doctor-patient relationship, caring for patients, and the need for
Valve Replacement for Bacterial and Fungal Endocarditis
Authors: JOE R. UTLEY, JOHN MILLS, JOHN C. HUTCHINSON, L. HENRY EDMUNDS, RICHARD G. SANDERSON, BENSON B. ROE
Journal: Circulation (1973)

Twenty-eight of 143 patients treated for infective endocarditis had replacement of one or more cardiac valves within six months after the diagnosis was made. Twenty-two patients (16%) with bacterial endocarditis had operation, and six died in hospital. All six patients with fungal endocarditis required vale replacement, and one died in hospital. Uncontrolled or progressive heart failure was the indication for operation in all patients with bacterial endocarditis. When severe heart failure was present, 5 of 11 patients with bacterial endocarditis died in hospital, and only 1 of 3 patients with associated bacteremia survived. If blood cultures were sterile, the duration of preoperative antibiotic therapy did not correlate with hospital survival. None of the patients with bacterial endocarditis developed prosthetic infections, but two developed paravalvular leak. Massive emboli or persistent mycotic septicemia were the indications for valve replacement in patients with fungal endocarditis. Viable organisms were cultured from the excised valves in all of these patients in spite of preoperative amphotericin B for 30 to 140 days and negative blood cultures. Excision of the infected valve cured the infection in all patients. Five patients died 6 weeks to 36 months after operation. At the present time 16 patients remain alive 14 to 47 months after operation. Six of nine drug addicts are alive 15 to 27 months postoperatively.
Abstract 4942: Metastatic tumor migration in lymphatic vessels revealed by real-time intravital imaging
Authors: Darci M. Fink, Alicia L. Connor, Philip M. Kelley, Richard M. Tempero, Michael A. Hollingsworth
Journal: Cancer Research (2014)

Abstract Distant tumor metastases and their confounding symptoms are often responsible for reduced patient quality-of-life and decreased overall survival. The main route of metastasis for many solid tumors is the lymphatic vasculature. The mechanisms of metastatic spread of tumor cells through the lymphatic vessels remain poorly understood. We have developed a novel transgenic mouse model and customized real-time intravital microscopy platforms to study the migration of tumor cells into lymphatic vessels in live animals over the course of several days. TdTomato fluorescent protein was expressed in lymphatic endothelial cells using an inductive CRE recombinase approach. This transgenic system coupled with the use of fluorescent stereomicroscopy techniques allowed us to visualize the cutaneous lymphatic vessel network with remarkable anatomic detail in living mice. We tracked the fate of CFSE-labeled B16 tumor cells administered cutaneously using two-color intravital fluorescence microscopy. This strategy allowed us to simultaneously visualize the lymphatic vessel network (red) and the B16 tumor cells (green) at single-cell resolution. We clearly visualized and documented several key behaviors of metastasizing tumor cells including single-cell intravasation, movement of tumor cells within vessels, clearing from vessels, and the accumulation of tumor cells in regional lymph nodes. These events occurred at a low frequency over the course of days in conditions of tissue homeostasis. Current studies are designed to define the anatomic site of tumor intravasation into lymphatic vessels and investigate how the inflamed tumor microenvironment affects tumor migration into the lymphatic vasculature. Citation Format: Darci M. Fink, Alicia L. Connor, Philip M. Kelley, Richard M. Tempero, Michael A. Hollingsworth. Metastatic tumor migration in lymphatic vessels revealed by real-time intravital imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4942. doi:10.1158/1538-7445.AM2014-4942
The full induction of human apoprotein A-I gene expression by the experimental nephrotic syndrome in transgenic mice depends on cis-acting elements in the proximal 256 base-pair promoter region and the trans-acting factor early growth response factor 1.
Authors: M Zaiou, N Azrolan, T Hayek, H Wang, L Wu, M Haghpassand, B Cizman, M P Madaio, J Milbrandt, J B Marsh, J L Breslow, E A Fisher
Journal: Journal of Clinical Investigation (1998)

To identify molecular factors regulating apo A-I production in vivo, we induced in transgenic mice the experimental nephrotic syndrome, which results in elevated levels of HDL cholesterol (HDL-C), plasma apo A-I, and hepatic apo A-I mRNA. Human (h) apo A-I transgenic mice with different length 5' flanking sequences (5.5 or 0.256 kb, the core promoter for hepatic-specific basal expression) were injected with nephrotoxic (NTS) or control serum. With nephrosis, there were comparable (greater than twofold) increases in both lines of HDL-C, h-apo A-I, and hepatic h-apo A-I mRNA, suggesting that cis-acting elements regulating induced apo A-I gene expression were within its core promoter. Hepatic nuclear extracts from control and nephrotic mice footprinted the core promoter similarly, implying that the same elements regulated basal and induced expression. Hepatic mRNA levels for hepatocyte nuclear factor (HNF) 4 and early growth response factor (EGR) 1, trans-acting factors that bind to the core promoter, were measured: HNF4 mRNA was not affected, but that of EGR-1 was elevated approximately fivefold in the nephrotic group. EGR-1 knockout (EGR1-KO) mice or mice expressing EGR-1 were injected with either NTS or control serum. Levels of HDL-C, apo A-I, and hepatic apo A-I mRNA were lowest in nonnephrotic EGR1-KO mice and highest in nephrotic mice expressing EGR-1. Although in EGR1-KO mice HDL-C, apo A-I, and apo A-I mRNA levels also increased after NTS injection, they were approximately half of those in the nephrotic EGR-1-expressing mice. We conclude that in this model, basal and induced apo A-I gene expression in vivo are regulated by the trans-acting factor EGR-1 and require the same cis-acting elements in the core promoter.
BENEFICIAL OUTCOMES AFTER PCV PLUS RT IN OLIGODENDROGLIAL TUMORS ARE ASSOCIATED WITH DETECTION OR RISK OF AN IDH MUTATION
Authors: G. Cairncross, M. Wang, R. Jenkins, E. Shaw, C. Giannini, D. Brachman, J. Buckner, K. Fink, L. Souhami, N. Laperriere, J. T. Huse, M. Mehta
Journal: Neuro-Oncology (2014)

BACKGROUND: Oligodendroglial tumors harbor IDH mutations and risk of this type of cancer is associated with a germ-line polymorphism at 8q. In addition, when these tumors harbor a co-deletion of 1p19q, they can be highly chemo-sensitive. Indeed, patients with anaplastic tumors (i.e., AO/AOA) with 1p19q co-deletion lived nearly twice as long after chemotherapy and radiation (CRT; 14-16 years) as radiotherapy alone (RT; 7-9 years) in two large randomized trials. In RTOG 9402, some patients with non-co-deleted AO/AOA also lived longer after CRT: for these participants, the survival curves separated after the median had been reached, and significantly more lived 10 years or longer after CRT than RT (25% vs. 10%). Since co-deletion status did not identify all patients benefiting from CRT, we asked whether other molecular hallmarks of AO/AOA – IDH or G-allele status – might be more inclusive markers of benefit from CRT. METHODS: We used tissues and data from RTOG 9402 to explore this hypothesis. RESULTS: IDH status was evaluable in 210 of 291 participants: 156 (74%) had a mutation of IDH1/2. The G allele of rs55705857 was evaluable in 245 of 291 participants: 76 (31%) carried the risk-allele in their germ-line. Presence of either an IDH mutation or the G risk-allele was associated with significantly longer progression-free survival after CRT, and an IDH mutation with much longer overall survival [9.4 vs. 5.7 years, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.40, 0.86), P = 0.006]. For cases in which IDH was intact, CRT did not prolong median survival time [1.3 vs. 1.8 years, HR 1.14, CI (0.63, 2.04), P = 0.67] or 10-year survival rates (CRT 6% vs. RT 4%). As expected, patients with mutated, co-deleted AO/AOA lived longer after CRT than RT (14.7 vs. 6.8 years, HR 0.49, CI (0.28, 0.85), P = 0.01], but so too did those with mutated, non-co-deleted AO/AOA [5.5 vs. 3.3 years, HR 0.56, CI (0.32, 0.99), P < 0.05]. Among the latter, ATRX positive and negative cases had longer overall survival after CRT than RT, but these differences were not significant. CONCLUSIONS: In AO/AOA cases in RTOG 9402, the presence or risk of an IDH mutation was associated with ‘benefit’ from CRT. Wild-type IDH was associated with poor overall and long-term survival, and absence of benefit from CRT. IDH mutation status identified more patients who benefited from CRT than did 1p/19q co-deletion status, but patients with co-deleted AO/AOA lived much longer.