tbuckley/cabot-search huggingface dataset:
The role of microsatellite instability in gastric carcinoma
Authors: J D HAYDEN, I G MARTIN, L CAWKWELL, P QUIRKE
Journal: Gut (1998)

During the past four years, the genetic basis of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome has emerged.1 2 Most HNPCC carcinomas exhibit a mutator phenotype characterised by widespread alterations in the length of repetitive DNA sequences (that is, microsatellite instability). A defect in one or more of the known DNA mismatch repair genes results in the disruption of an enzyme system which maintains the integrity of repetitive sequences which are usually stably inherited.3Germline mutations in hMLH1, hMSH2, hPMS1, hPMS2, and possibly GTBP may account for over 90% of cases of HNPCC.4-8 

A proportion of HNPCC kindreds (the so-called Lynch II families) are associated with a high frequency of extracolonic carcinomas, most commonly affecting the stomach and endometrium.9Endometrial and gastric carcinomas from HNPCC kindreds show evidence of microsatellite instability.10 The relation between microsatellite instability and gastric carcinoma has received considerable attention because of the suggestion that this mutator phenotype may also be found in sporadic carcinomas that are characteristic of the HNPCC syndrome.11 The implication is that there may be a group of sporadic gastric carcinomas which are either unrecognised HNPCC cases or a different biological subset of neoplasms, possibly requiring different clinical management.

The literature emerging from both the East and West concerning the role of microsatellite instability in gastric carcinoma is both conflicting and confusing. A number of factors have contributed to this, which include the diversity of populations studied, differences in the quantity and selection of microsatellite loci which are analysed, differences in the definition of a mutator phenotype used by various authors, and studies of small numbers of cases. It is essential to determine whether the detection of microsatellite instability in gastric carcinomas is clinically important or purely of academic interest.

Microsatellites are ubiquitous short repetitive DNA sequences …
Influence of a Pyrimidopyrimidine Derivative on Deamination of Adenosine by Blood
Authors: RUBEN D. BUNAG, C. ROBERTO DOUGLAS, SHOICHI IMAI, ROBERT M. BERNE
Journal: Circulation Research (1964)

The disappearance of exogenous adenosine from blood is principally due to its degradation into inosine and hypoxanthine by the enzymes present in the erythrocytes. In the presence of intact red cells, Persantin (RA-8 or 2,6-Bis (diethanolamino) -4,8-dipiperidinopyrimido-(5,4-d)-pyrimidine) effectively prevents the disappearance of adenosine. Although Persantin inhibits adenosine deaminase its adenosine-sparing action in whole blood is more likely due to a reduction in permeability of the red cell membrane to adenosine. This property of Persantin makes possible its use as a tool in investigation of the role of adenine nucleotide derivatives in the regulation of the coronary circulation.
FK 506 renal toxicity and lack of detectable cytochrome P-450 3A in the liver graft of a patient undergoing liver transplantation
Authors: Antoinette Lemoine, Daniel Azoulay, Ashley Dennison, Liliane Kiffel, Lydiane Pichard, Valérie Furlan, Thierry Bienvenu, Gilles Fredj, Brigitte Debuire, Patrick Maurel, Henri Bismuth, Philippe Beaune
Journal: Hepatology (1994)

Many commonly used drugs are substrates for hepatic cytochrome P-450 3A in human beings, and its role in the metabolism of potentially toxic immunosuppressants has been highlighted (cyclosporine, FK 506). One hundred fifty human liver grafts were biopsied before and after liver transplantation, and levels of cytochromes P-450 3A, 1A2, 2D6 and 2C were estimated by means of the Western-blot technique and correlated with histological appearance, glycogen content and clinical course. In 15 of the grafts, cyclosporine oxidase was also measured, and in 12 of 15 recipients, urinary 6 beta-hydroxycortisol excretion was assayed. A wide range of cytochrome P-450 3A values were observed (25 to 366 arbitrary units/mg; mean, 105 +/- 63 arbitrary units/mg). In one graft (no. 730) no cytochrome P-450 3A was detectable on immunoblotting, despite increasing homogenate concentrations. In this sample, cytochromes P-450 1A2, 2D6, and 2C were present in normal ranges. Levels of cyclosporine oxidase and 6 beta-hydroxycortisol in the urine specimens of the recipient were found to be low. The recipient of graft 730 experienced reversible complications of FK 506 therapy despite adherence to the administration protocol and drug plasma level in the normal range. The subsequent appearance of the cytochrome P-450 3A was associated with the consequent tolerance of oral FK 506. The absence of detectable amounts of P-450 3A in one biopsy from a donated human liver graft dramatically emphasizes the extreme range of this enzyme levels and has important clinical implications.
PEDIATRICS AND THE CHILD
Authors: BORDEN S. VEEDER
Journal: JAMA (1923)

The development of pediatrics in recent years has been quite remarkable. Two score years ago there were scarcely a dozen men engaged exclusively in children's work, while today there are nearly nineteen hundred physicians devoting their time to pediatrics, and nearly thirty-five hundred more who are particularly interested in our specialty. It is all the more remarkable when one considers its unique position in the field of medicine, for it differs from all other specialties in that it is not based on an anatomic part or system, as ophthalmology, or on a disease, as tuberculosis, or on a method of treatment or practice. As the name denotes, it has to do with the child. This and this alone is the<i>raison d'être</i>of considering pediatrics as a specialty, and it has seemed to me at times that we as pediatricians are not always keeping this fundamental conception clearly in the
Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing
Authors: M Ri, E Tashiro, D Oikawa, S Shinjo, M Tokuda, Y Yokouchi, T Narita, A Masaki, A Ito, J Ding, S Kusumoto, T Ishida, H Komatsu, Y Shiotsu, R Ueda, T Iwawaki, M Imoto, S Iida
Journal: Blood Cancer Journal (2012)

The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.
The centrosomal protein tax1 binding protein 2 is a novel tumor suppressor in hepatocellular carcinoma regulated by cyclin-dependent kinase 2
Authors: Wai-Lung Lai, Wing-Yan Hung, Leo Lap-Yan Wong, Yuan Zhou, Veronica Yee-Law Leong, Joyce Man-Fong Lee, Irene Oi-Lin Ng, Dong-Yan Jin, Yick-Pang Ching
Journal: Hepatology (2012)

Deregulation of cellular-signaling pathways by the inactivation of tumor-suppressor genes is one of the major causes of hepatocellular carcinoma (HCC). In this study, we identified Tax1 binding protein 2 (TAX1BP2) as a novel tumor-suppressor gene in HCC. TAX1BP2 transcript was frequently underexpressed (42.2% with T/NT <0.5; P < 0.03) in HCCs, and underexpression of TAX1BP2 was associated with poorer overall survival rates in patients after surgical resection. An effector domain (ED) for TAX1BP2 tumor-suppressor activity was mapped to the amino-acid residues 267-756. Transient or stable expression of either full-length or ED of TAX1BP2 significantly suppressed HCC cell tumorigenicity through the activation of the p38/p53/p21 pathway. In contrast, silencing of TAX1BP2 by short interfering RNA remarkably suppressed the activation of the p38/p53/p21 pathway. Finally, phosphorylation of TAX1BP2 at serine-763 by cyclin-dependent kinase (CDK)2 abolished the TAX1BP2-mediated p38 activation and tumor-suppressive activity, indicating that TAX1BP2 can adapt CDK2 signaling to the p38/p53/p21 pathway.Taken together, our data provide the first evidence that TAX1BP2 is a CDK2-regulated tumor-suppressor gene in HCC and is a novel activator of the p38/p53/p21 pathway.
Targeting Mesothelioma Using an Infectivity Enhanced Survivin-Conditionally Replicative Adenoviruses
Authors: Zeng B. Zhu, Sharmila K. Makhija, Baogen Lu, Minghui Wang, Shuyi Wang, Koichi Takayama, Gene P. Siegal, Paul N. Reynolds, David T. Curiel
Journal: Journal of Thoracic Oncology (2006)
Abstract P5-17-01: Bevacizumab (B) in the adjuvant treatment of breast cancer - first toxicity results from Eastern Cooperative Oncology Group trial E5103.
Authors: KD Miller, A O'Neill, C Dang, D Northfelt, W Gradishar, GW Sledge
Journal: Cancer Research (2012)

Abstract Background: A previous feasibility trial (E2104 – Ann Oncol 23(2):331–7,2012) suggested incorporation of B into anthracycline-containing adjuvant therapy was feasible but ongoing cardiac monitoring was required to define the true impact of B on cardiac function. Methods: Patients (pts) were assigned 1:2:2 to one of three treatment arms. In addition to doxorubicin and cyclophosphamide followed by weekly paclitaxel, patients received either placebo (Arm A – AC&amp;gt;T) or B during chemotherapy (Arm B - BAC&amp;gt;BT), or B during chemotherapy followed by B monotherapy (15 mg/kg q3wk) for an additional 10 cycles (Arm C – BAC&amp;gt;BT&amp;gt;B). Randomization was stratified and B dose adjusted for choice of AC schedule (classical q3wk − 15 mg/kg; dose dense(dd) q2 wk − 10 mg/kg). When indicated, radiation and hormonal therapy were administered concurrently with B (for Arm C pts). The primary cardiac endpoint was the incidence of clinically apparent cardiac dysfunction (CHF)defined as symptomatic decline in left ventricular ejection fraction (LVEF) to below the lower limit of normal (LLN) or symptomatic diastolic dysfunction as assessed by independent review. Cumulative toxicity data as of Jan 23, 2012 are presented. Results: From 11.07 to 2.11, 4994 pts were enrolled. Median age was 52; 80% received ddAC. Chemotherapy associated toxicities including myelosuppression (Grade 4 neutropenia 16/20/19%) and neuropathy (Grade ≥ 3 8/8/8%) were similar across all arms. Grade ≥ 3 hypertension/thrombosis/proteinuria/hemorrhage was reported by 7/3/&amp;lt;1/&amp;lt;1% of B-treated pts. 99 pts developed CHF, most commonly reported at the post-AC or post-T evaluation. After a median follow-up of 26 months, the cumulative incidence of clinical CHF at 15 months from randomization in Arm A/B/C was 1.0/1.7/2.9% respectively. Median age of CHF pts was 57; median baseline LVEF of CHF pts was 60. Conclusion: Incorporation of B into anthracycline and taxane containing adjuvant therapy results in a significant but small increase in clinical CHF. The rate of clinical CHF is similar to that predicted by E2104 (2.5–2.9%) and reported In the FDA label for anthracycline pre-treated pts(3.8%). No unexpected toxicities were encountered. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-01.
Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice
Authors: Laurens P. Kil, Marjolein J. W. de Bruijn, Menno van Nimwegen, Odilia B. J. Corneth, Jan Piet van Hamburg, Gemma M. Dingjan, Friedrich Thaiss, Guus F. Rimmelzwaan, Dirk Elewaut, Dianne Delsing, Pieter Fokko van Loo, Rudi W. Hendriks
Journal: Blood (2012)
Reduced VEGF Production, Angiogenesis, and Vascular Regrowth Contribute to the Antitumor Properties of Dual mTORC1/mTORC2 Inhibitors
Authors: Beverly L. Falcon, Sharon Barr, Prafulla C. Gokhale, Jeyling Chou, Jennifer Fogarty, Philippe Depeille, Mark Miglarese, David M. Epstein, Donald M. McDonald
Journal: Cancer Research (2011)

Abstract The mammalian target of rapamycin (mTOR) pathway is implicated widely in cancer pathophysiology. Dual inhibition of the mTOR kinase complexes mTORC1 and mTORC2 decreases tumor xenograft growth in vivo and VEGF secretion in vitro, but the relationship between these two effects are unclear. In this study, we examined the effects of mTORC1/2 dual inhibition on VEGF production, tumor angiogenesis, vascular regression, and vascular regrowth, and we compared the effects of dual inhibition to mTORC1 inhibition alone. ATP-competitive inhibitors OSI-027 and OXA-01 targeted both mTORC1 and mTORC2 signaling in vitro and in vivo, unlike rapamycin that only inhibited mTORC1 signaling. OXA-01 reduced VEGF production in tumors in a manner associated with decreased vessel sprouting but little vascular regression. In contrast, rapamycin exerted less effect on tumoral production of VEGF. Treatment with the selective VEGFR inhibitor OSI-930 reduced vessel sprouting and caused substantial vascular regression in tumors. However, following discontinuation of OSI-930 administration tumor regrowth could be slowed by OXA-01 treatment. Combining dual inhibitors of mTORC1 and mTORC2 with a VEGFR2 inhibitor decreased tumor growth more than either inhibitor alone. Together, these results indicate that dual inhibition of mTORC1/2 exerts antiangiogenic and antitumoral effects that are even more efficacious when combined with a VEGFR antagonist. Cancer Res; 71(5); 1573–83. ©2011 AACR.
Thyroid 131I Burdens in Medical and Paramedical Personnel
Authors: Manfred Blum
Journal: JAMA (1967)

IODIDE absorption is rapid and complete through the small intestine<sup>1</sup>and the pulmonary alveolar capillary interface<sup>2</sup>and incomplete through the intact skin.<sup>3</sup>After absorption, iodide is distributed to the extracellular fluid from which it is sequestered by the thyroid for hormone synthesis.<sup>1</sup>The measurement of thyroid radioactive iodine burdens, therefore, offers a simple index of contamination. Measurements were made of thyroid<sup>131</sup>I burdens in a number of medical and paramedical personnel exposed to radioactive iodine in their work, since information concerning low level activity is not available. Burdens were generally expected to be very low, and therefore, a sensitive detection system previously described was used.<sup>4</sup> <h3>Method of Measurement</h3> Thyroid<sup>131</sup>I burdens were measured in a low background steel room, with two 3 × 3-inch thallium-activated sodium iodide scintillation crystals placed in contact with the anterior surface of the neck from the sternal notch
Circulating immune complexes in coccidioidomycosis. Detection and characterization.
Authors: S Yoshinoya, R A Cox, R M Pope
Journal: Journal of Clinical Investigation (1980)

Sera of 22 patients with active and 13 with inactive coccidioidomycosis, as well as 15 healthy subjects who were skin-test positive to coccidioidin and 39 healthy subjects who were coccidioidin skin-test negative, were assayed for immune complexes. Circulating immune complexes were measured by the Clq-binding assay, the Clq-solid phase assay, the monoclonal rheumatoid factor inhibition assay, and the monoclonal rheumatoid factor solid phase assay. An increased concentration of circulating immune complexes was detected in 73% of those with active disease by at least one assay compared with 13% of the healthy controls. Significantly increased levels of immune complexes were detected in sera of patients with active coccidioidomycosis by the Clq-binding assay (P < 0.001), the Clq-solid phase assay (P < 0.001), the monoclonal rheumatoid factor inhibition assay (P < 0.005), and the monoclonal rheumatoid solid phase assay (P < 0.05) compared with the results obtained in the 54 healthy subjects. In contrast, those with inactive disease did not show significantly increased concentrations of circulating immune complexes. Sucrose density gradient ultracentrifugation of patients' sera established that the immune complexes were of intermediate size, sedimenting between the 6.6S and 19S markers. Immune complexes were shown to contain both coccidioidin antigen and anticoccidioidin antibody. In addition, a radioimmunoassay was developed to quantitate coccidioidin antigen-containing immune complexes. The latter assay proved highly sensitive in detecting immune complexes in patients with active coccidioidomycosis.
Sex and Gender Bias in Anatomy and Physical Diagnosis Text Illustrations
Authors: Kathleen D. Mendelsohn
Journal: JAMA (1994)

To examine the sex and gender distribution of illustrations in two atlases, five anatomy texts, and five physical diagnosis texts.Of 4060 illustrations that were identifiable by sex and gender in 12 commonly used anatomy and physical diagnosis textbooks, 3827 were categorized by two reviewers as female, male, or neutral.Females were represented, on average, in 21.2% of the anatomy text illustrations; males were represented, on average, in 44.3%; 34.4% of the illustrations were neutral. Of the nonreproductive anatomy illustrations, a mean of 11.1% (range, 4.6% to 23.8%) depicted women and 43.1% (range, 35.4% to 56.2%) depicted men. Of nonreproductive anatomy illustrations, a mean of 45.8% (range, 27.2% to 59.9%) were neutral. Overall, the physical diagnosis text illustrations demonstrated a more equal sex and gender distribution (21.5% female and 24.8% male). However, in the reproductive chapters of the physical diagnosis texts, females were depicted in a mean of 71.1% (range, 63.2% to 79.0%) of the illustrations, while in the nonreproductive chapters, females were depicted in 8.8% of total illustrations.In anatomy and physical diagnosis texts, women are underrepresented in illustrations of nonreproductive anatomy. The finding that males are depicted in a majority of nonreproductive anatomy illustrations may perpetuate the image of the male body as the normal or standard model for medical education.
An original technique for surgical stabilisation of traumatic flail chest.
Authors: V Beltrami, G Martinelli, P Giansante, K Gentile
Journal: Thorax (1978)

The treatment of chest wall injuries with severe paradoxical movement remains controversial. Intermittent positive-pressure respiration may be appropriate, but in some, especially those requiring exploratory thoracotomy for a visceral lesion, surgical fixation is desirable. We present a simple method using two or three stainless Kirschner wires placed in the chest wall. Results in five cases have been good.
Radiologic Estimation of Heart Volume
Authors: Maurice S. Rawlings
Journal: JAMA (1961)

<h3>To the Editor:—</h3> An article on radiologic estimation of heart volume, by Dr. John S. Hanson, appeared inThe Journal(<b>176:</b>16 [April 8] 1961). The estimation of heart volume, of course, is no more accurate than the accuracy of the heart diameters used in its measurement. This involves the 3 measurements mentioned by the author: The broad diameter requires the accurate location of the juncture of the pulmonary conus with the left ventricle. This cannot be done with an ordinary chest film and can only be done accurately with the contrapulsatile motion demonstrable by fluoroscopy. The long diameter also has innate inaccuracies since it involves measurement of the pericardial fat pad in many cases, and its upper origin at the juncture of the superior vena cava with the right atrium can only be estimated. The greastest horizontal depth of the cardiac shadow is the third diameter
Computed Tomographic Angiography Characteristics of Atherosclerotic Plaques Subsequently Resulting in Acute Coronary Syndrome
Authors: Sadako Motoyama, Masayoshi Sarai, Hiroto Harigaya, Hirofumi Anno, Kaori Inoue, Tomonori Hara, Hiroyuki Naruse, Junichi Ishii, Hitoshi Hishida, Nathan D. Wong, Renu Virmani, Takeshi Kondo, Yukio Ozaki, Jagat Narula
Journal: Journal of the American College of Cardiology (2009)
MERCUROSAL IN THE TREATMENT OF SYPHILIS
Authors: H. N. COLE
Journal: JAMA (1922)

None of the mercurial preparations used, at present, in the treatment of syphilis are perfect. In the laudable quest for better ones Parke, Davis and Company submit a new mercurial preparation for which several claims have been made. The evidence from the literature that they submit in its favor is of little or no value, since, in practically all cases reported, the patients received arsphenamin as well as Mercurosal. In the first place, they claim that they have a preparation which can be used either by the intramuscular or by the intravenous route. This, of itself, would be advantageous in certain cases in which it would be found impossible to use one of these routes. Secondly, they affirm that the drug has no deleterious effects on the vessel walls. To quote their own words, Following a long series of intravenous injections in dogs, there was no appreciable effect on the
Recombinant factor VIIa enhances deposition of platelets with congenital or acquired αIIbβ3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor–independent thrombin generation
Authors: Ton Lisman, Sultana Moschatsis, Jelle Adelmeijer, H. Karel Nieuwenhuis, Philip G. De Groot
Journal: Blood (2003)
Who should take care of children with epilepsy?
Authors: R N Chinthapalli
Journal: BMJ (2003)

One important question in the current debate in the United Kingdom about the care of children with epilepsy is who should take the lead role: the neurologist, the general paediatrician, or the paediatrician who has a special interest in epilepsy? The diagnosis of epilepsy in children is often difficult. About 30% of cases are misdiagnosed. In a similar proportion of cases children receive inappropriate drugs. About 42% of all sudden unexpected deaths among young people with epilepsy are reported to be avoidable. This is attributed to the lack of specialists. Currently the United Kingdom has fewer than 75 child neurologists, all of whom are based in tertiary centres. In 2002 the British Paediatric Neurology Association recommended that neurologists should carry out all paediatric neurology work. This goal remains unachievable at present.

42% of all sudden unexpected deaths among young people with epilepsy are …