tbuckley/cabot-search huggingface dataset:
Abstract 2761: Germline polymorphism discovered via a cell-based genome-wide approach predicts platinum response in ovarian and head and neck cancers
Authors: Rong Stephanie Huang, Sharon E. Johnatty, Eric Gamazon, Hae Kyung Im, Dana Ziliak, Wei Zhang, Peixian Chen, Jonathan Beesley, Peter H. O'Donnell, Soma Das, Nancy J. Cox, Everett E. Vokes, Anna deFazio, Georgia Chenevix-Trench, Ezra E.W. Cohen, M. Eileen Dolan
Journal: Cancer Research (2010)

Abstract Identifying patients prior to treatment that are less likely to benefit from or most likely to experience adverse events from chemotherapeutic agents is essential. Even though humans are the most relevant system, pharmacogenomic discovery in the field of oncology is plagued by difficulties in executing large clinical trials and confounding factors such as co-morbidities, dosage, and concomitant medications. Therefore, we developed a genome-wide cell-based approach evaluating single nucleotide polymorphisms (SNPs) and gene expression to predict chemotherapy-induced response and toxicity and then validated our findings in clinically relevant patient cohorts. Our model utilizes the International HapMap lymphoblastoid cell lines (LCLs). Genome-wide association studies were performed to identify SNPs significantly associated with carboplatin sensitivity through their effects on mRNA expression. The significant findings were evaluated in an independent LCL replication set and in patient samples obtained from the Australian Ovarian Cancer Study (AOCS) and two Phase II head and neck clinical trials (UC12019 and UC13881) conducted at the University of Chicago. Four hundred and nine ovarian cancer patients receiving carboplatin and paclitaxel were analyzed in AOCS; while 60 and 32 head and neck cancer patients were evaluated in UC12019 and UC13881 trials. Carboplatin was used as induction and concomitant chemo-radiation therapy in UC12019 and UC13881 trials, respectively. Using LCLs, our genome-wide model identified 65 SNPs that are associated with at least one carboplatin sensitivity phenotype through the expression of 61 genes. Five of them were replicated in a separate set of LCLs. In AOCS, SNP (rs1649942) was significantly associated with progression-free survival (Plog-rank=0.009) and overall survival (Plog-rank=0.03). In the head and neck cancer trials, 2 other SNP-phenotype associations were identified and replicated in both trials, including the association between SNP (rs4946514) and overall response to carboplatin, and the association between SNP (rs7134205) and post treatment platelet changes. Given the obstacles to performing large, replicable pharmacogenomic studies in patients, the cell-based model is proven to be an effective alternative in novel pharmaco-SNP discovery. We demonstrate germline SNPs identified through the cell-based genome-wide approach are clinically important predictors of chemotherapy response and toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2761.
GMC's case against fertility doctor collapses
Authors: O. Dyer
Journal: BMJ (2008)

The General Medical Council’s case against a UK fertility specialist collapsed on 24 October, when a GMC fitness to practise panel ruled that the evidence against Mohamed Taranissi could not sustain a misconduct charge.

Mr Taranissi, founder of the Assisted Reproduction and Gynaecology Centre, London, was accused of inappropriately pressuring one patient to take adalimumab, a drug not licensed for fertility treatment. He was also accused of failing to adequately treat a patient who attended his clinic distressed and nauseous and who later collapsed and was admitted to intensive care with severe hyponatraemia ( BMJ 2008;337:a1995, 6 Oct, doi:10.1136/bmj.a1995).

The panel’s chairman, Harvey Marcovitch, …
Abstract 4038: Aspirin acetylates p53 in colon cancer cells and induces the expression of p21 and Bax: Identification of aspirin acetylated sites on rp53
Authors: Raghavender Chivukula, Srinivasan Marimuthu, Lloyd Alfonso, Fred Hagen, Jayarama B. Gunaje
Journal: Cancer Research (2011)

Abstract Several studies over the past decade have shown that regular use of aspirin reduces the risk of cancers of various organs such as colon, breast, lung and prostate tissue. The mechanism by which aspirin exerts its anti-cancer effects is not clearly understood. Previous studies from our laboratory showed that aspirin acetylates the tumor suppressor protein p53 and modulates target gene expression in MDA-MB-231 breast cancer cells. We now have extended these studies to include HCT116 (wt-type p53) and HT-29 (mutant p53) colon cancer cells. Using anti-acetyl p53 antibody, we show in the present study that aspirin acetylated p53 at lysine 382 in both cell types. It also detected two other proteins of size 63 kDA and 35 kDa, which are likely to represent other isoforms of p53. Aspirin also acetylated recombinant p53 (rp53) in vitro, suggesting that the mechanism of cellular acetylation may be through a direct non-enzymatic chemical reaction. Mass spectrometry analysis of the aspirin-treated rp53 identified 7 acetylate lysine residues. In HCT116 and HT-29 cells, aspirin-induced acetylation of p53 was observed in a concentration dependent manner. The acetylated p53 was localized to the nucleus. Consistent with these observations, aspirin transiently increased p21, a protein involved in cell cycle arrest; however, the expression of the proapoptotic protein, Bax, was sustained. Treatment of cells with the anti-cancer drug, camptothecin, induced sustained induction of p21. Co-treatment with both camptothecin and aspirin decreased the expression of p21. Aspirin also potentiated camptothecin-induced cell death as measured by MTT assay, clonogenic cell survival assay and annexin V binding assay. Our results suggest that p53 pathway may contribute to the anti-cancer properties of aspirin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4038. doi:10.1158/1538-7445.AM2011-4038
IS PEMPHIGUS AN AUTOIMMUNE DISEASE?
Authors: H.-W. KREYSEL, A. R. MEMMESHEIMER
Journal: British Journal of Dermatology (1971)

Summary.— This paper deals with the pathogenesis and the microscopic and cytological features of the pemphigus group of diseases. The immunological aspects of acantholysis are discussed. The statement by several authors that pemphigus is an autoimmune disease is questioned and evidence from the literature against this hypothesis is cited.
Retinoic acids up‐regulate functional eosinophil‐driving receptor <scp>CCR</scp>3
Authors: S. Ueki, J. Nishikawa, Y. Yamauchi, Y. Konno, M. Tamaki, M. Itoga, Y. Kobayashi, M. Takeda, Y. Moritoki, W. Ito, J. Chihara
Journal: Allergy (2013)

Abstract Eotaxins and their receptor CCR 3 have a definitive role for tissue accumulation of eosinophils both under homeostatic and pathologic conditions. However, physiological stimuli that can up‐regulate CCR 3 in blood‐derived human eosinophils have not been recognized. As a prior gene microarray study revealed up‐regulation of CCR 3 in eosinophils stimulated with retinoic acids ( RA s), the expression of functional CCR 3 was examined. We found that 9‐cis RA and all‐trans RA ( ATRA ) significantly induced surface CCR 3 expression regardless of the presence of IL ‐3 or IL ‐5. Pharmacological manipulations with receptor‐specific agonists and antagonists indicated that retinoic acid receptor‐α activation is critical for CCR 3 up‐regulation. RA ‐induced CCR 3 was associated with its functional capacity, in terms of the calcium mobilization and chemotactic response to eotaxin‐1 ( CCL 11). Our study suggests an important role of vitamin A derivatives in the tissue accumulation of eosinophils.
Abstract 5471: Pharmacokinetic investigation of vandetanib in patients with medullary thyroid carcinoma using liquid chromatography-tandem mass spectrometry
Authors: Sophie Broutin, Alain Deroussent, Angelo Paci, Anderson Joseph Ryan, Martin Schlumberger, Jean-Michel Bidart
Journal: Cancer Research (2011)

Abstract Introduction: Vandetanib is a once-daily oral multikinase inhibitor with antitumoral activity in patients with advanced medullary thyroid carcinoma (MTC). The aim of this study was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of serum vandetanib levels and to investigate the pharmacokinetic/pharmacodynamic relationship in MTC patients. Materials and Methods: A LC-MS/MS method was developed using acetonitrile/water 0.1% acetic acid (80:20, v/v). Serum proteins were precipitated with cold acetonitrile after addition of trazodone used as internal standard (IS). Vandetanib was detected and quantitated by multiple reactions monitoring of the ion transitions m/z 475–&amp;gt;112 (vandetanib) and m/z 372–&amp;gt;176 (IS). Serum from 28 MTC patients (clinical study D4200C00058) was collected during each course of vandetanib treatment (initial dosing 300 mg/day) from 1 week to 36 months and stored at -20°C before analysis. Exposure monitoring was investigated retrospectively on 121 samples. Results: Mean extraction recoveries from human serum were 103±3% and 94±2 % for vandetanib and IS, respectively. The calibration curve was linear for a range spanning 2.5-5,000 ng/mL. The accuracy was 92% at the lower limit of quantitation of 2.5 ng/mL with good precision (CV &amp;lt;10%). Intra-day and inter-day quality control accuracies ranged from 90 to 97% (CV &amp;lt;5%) and from 90 to 99% (CV&amp;lt; 6%). Median vandetanib serum levels evaluated in MTC patients indicated a progressive rise from ∼400 ng/ml (at 1 week) to ∼800 ng/ml (at 3 months) that persisted over time. Half of patients (n=14) presented serious toxicity that required treatment interruption and/or dose reduction. Interestingly, most patients with serious toxicity (n=11/14) had a maximal vandetanib level greater than 20% above the median level versus only one patient in the non-serious toxicity group (n=14). Conclusion: We developed and validated a fast and sensitive LC-MS/MS method allowing the quantitation of vandetanib levels in human serum. Results indicated that MTC patients display different vandetanib pharmacokinetic profiles. The relationships between these profiles and toxic side-effects and/or efficacy deserve further investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5471. doi:10.1158/1538-7445.AM2011-5471
Deficiency of Src homology 2 domain–containing inositol 5-phosphatase 1 affects platelet responses and thrombus growth
Authors: Sonia Séverin, Marie-Pierre Gratacap, Nadège Lenain, Laetitia Alvarez, Etienne Hollande, Josef M. Penninger, Christian Gachet, Monique Plantavid, Bernard Payrastre
Journal: Journal of Clinical Investigation (2007)

Platelets are critical for normal hemostasis. Their deregulation can lead to bleeding or to arterial thrombosis, a primary cause of heart attack and ischemic stroke. Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) is a 5-phosphatase capable of dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate second messenger into phosphatidylinositol 3,4-bisphosphate. SHIP1 plays a critical role in regulating the level of these 2 lipids in platelets. Using SHIP1-deficient mice, we found that its loss affects platelet aggregation in response to several agonists with minor effects on fibrinogen binding and beta(3) integrin tyrosine phosphorylation. Accordingly, SHIP1-null mice showed defects in arterial thrombus formation in response to a localized laser-induced injury. Moreover, these mice had a prolonged tail bleeding time. Upon stimulation, SHIP1-deficient platelets showed large membrane extensions, abnormalities in the open canalicular system, and a dramatic decrease in close cell-cell contacts. Interestingly, SHIP1 appeared to be required for platelet contractility, thrombus organization, and fibrin clot retraction. These data indicate that SHIP1 is an important element of the platelet signaling machinery to support normal hemostasis. To our knowledge, this is the first report unraveling an important function of SHIP1 in the activation of hematopoietic cells, in contrast to its well-documented role in the negative regulation of lymphocytes.
Operations in Ireland cancelled because of blood shortages
Authors: D. Payne
Journal: BMJ (2002)

Citing an “acute shortage of blood,” the Irish Blood Transfusion Service last week wrote to hospitals to advise them to postpone elective surgery. The situation was returning to normal this week after a widespread public response to appeals for donations, but at the time of the advisory notice there were shortages of as much as half the required amount in some cases in seven of the eight blood categories.

Worst hit were acute care hospitals in Dublin. Some blood transfusions for children were also cancelled, said haematologist Owen Smith from St James's and Tallaght hospitals, and …
Rifapentine and Isoniazid in the Continuation Phase of Treating Pulmonary Tuberculosis
Authors: C. M. TAM, S. L. CHAN, C. W. LAM, C. C. LEUNG, K. M. KAM, J. S. MORRIS, D. A. MITCHISON
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

A randomized comparison has been made of three times weekly rifampin plus isoniazid (HR3) with rifapentine plus isoniazid given once weekly (HRp1) or on 2 of 3 wk (HRp1.2/3) in the continuation phase of 6-mo regimens (each starting with an initial 2 mo of 4-drug therapy) for the treatment of pulmonary tuberculosis in 672 Chinese patients in Hong Kong. Because of poor bioavailability of the rifapentine used (produced in China), its dose size was increased from 600 mg initially to about 750 mg in the last third of patients to obtain serum concentrations similar to those with rifapentine of Western origin; all doses were given after a meal promoting absorption. After initial exclusions, an intent to treat analysis, done on the remaining 592 patients, showed 45 adverse treatment events in 7 of 190 HR3 patients, in 17 of 199 HRp1 patients, and in 21 of 203 HRp1.2/3 patients; of these, 42 were bacteriological or radiographic relapses after the end of treatment (HR3 versus HRp1, p = 0.04; HR3 versus HRp1.2/3, p = 0.01). Patients with organisms initially sensitive or resistant to isoniazid or streptomycin had similar relapse rates. The high relapse rate in the HRp1 regimen suggests that the rifapentine dose should be increased. Similarity of relapse rates, 8.9% and 10.4%, after the HRp1 and HRp1.2/3 regimens, respectively, indicates that irregularity in taking rifapentine/isoniazid could be tolerated. The few adverse side effects in the continuation phase in the rifapentine regimens were less frequent than in the HR3 regimen.
Expression of e-cadherin, ?-catenin, ?-catenin, and CD44 (standard and variant isoforms) in human cholangiocarcinoma: An immunohistochemical study
Authors: Keigo Ashida, Tadashi Terada, Yukisato Kitamura, Nobuaki Kaibara
Journal: Hepatology (1998)

Immunolocalization of E-cadherin (E-cad), alpha-catenin, beta-catenin, and CD44 has rarely been investigated in human cholangiocarcinoma (CC). We, therefore, immunohistochemically examined the expression of E-cad, alpha-catenin, beta-catenin, CD44 standard (CD44s), and CD44 variants (CD44v) including CD44v5, CD44v6, CD44v7-8, and CD44v10 in normal adult livers and in 47 cases of CC; and the results were then correlated with tumor grade, vascular invasion, metastasis, p53 expression, proliferative fraction (Ki-67 labeling), and c-erbB2 expression. In normal livers, E-cad, alpha-catenin and beta-catenin, but not CD44s, CD44v5, CD44v6, CD44v7-8, and CD44v10, were expressed at the cell membrane of normal intrahepatic bile ducts. In CC, membranous expression of E-cad, alpha-catenin, and beta-catenin was the same or reduced when compared with non-cancerous bile ducts in the majority of CC. We found that the down-regulation of E-cad, alpha-catenin, and beta-catenin expression significantly correlated with tumor high grade, but not with vascular invasion, metastasis, p53 expression, Ki-67 labeling, or c-erbB2 expression, except for beta-catenin, the down-regulation of which was associated with c-erbB2 down-regulation. CD44s, CD44v5, CD44v6, CD44v7-8 and CD44v10 were frequently expressed at the membrane of CC cells. There were, however, no significant correlations between these aberrant CD44 expression and tumor grade, metastasis, vascular invasion, p53 expression, Ki-67 labeling, or c-erbB2 expression, with a few exceptions of CD44s and CD44v5. We found that CD44s aberrant expression significantly correlated with absence of metastasis and vascular invasion, and that CD44v5 aberrant expression significantly correlated with p53 under-expression. These results suggest that membranous expression of E-cad, alpha-catenin, and beta-catenin is reduced in a majority of CC and this down-regulation correlates with CC high grade, and that beta-catenin down-regulation is associated with c-erbB2 down-regulation. The data also suggested that CD44s, CD44v5, CD44v6, CD44v7-8, and CD44v10 may be neoexpressed during carcinogenesis of CC but this neoexpression does not correlate with tumor progression in CC, with the exception of CD44s and CD44v5.
Carcinogenicity of Halo Ethers
Authors: Norton Nelson
Journal: New England Journal of Medicine (1973)

The report by Figueroa et al. in this issue concerning the occurrence of lung cancer in workers exposed to chloromethyl methyl ether (CMME) represents another step in apparently parallel efforts that have been under way in several centers. A paper from the New York University Institute of Environmental Medicine, "Tumors of the Respiratory Tract Induced by Inhalation of Bis (Chloromethyl) Ether" (BCME) by Laskin et al.1 opened the door to such findings by reporting the very high potency of BCME for the production of bronchogenic carcinoma and esthesioneuroepitheliomas in the rat. These tumors were produced at relatively high incidence levels . . .
HEREDITARY ICTERUS, OR FAMILIAL ACHOLURIC JAUNDICE
Authors: J. S. Manson
Journal: BMJ (1928)

THE fosllowillg is a descrip)tion of a family Rome memoens of wlich show very distiiictlv an icteiic tinge i me t meskii aif( conjunctivae.The title " hereditary icterotis ' w ouildI seemli to he imiore iacurate than the alternative " familial achohlric
Risk of AIDS related complex and AIDS in homosexual men with persistent HIV antigenaemia.
Authors: F de Wolf, J Goudsmit, D A Paul, J M Lange, C Hooijkaas, P Schellekens, R A Coutinho, J van der Noordaa
Journal: BMJ (1987)

One hundred and ninety eight men seropositive for human immunodeficiency virus (HIV) antibody and 58 HIV antibody seroconverters were studied for an average of 19.3 (SEM 0.5) months to assess the relation between HIV antigenaemia and the risk of developing the acquired immune deficiency syndrome (AIDS) and AIDS related complex. Forty (20.2%) of the 198 HIV antibody seropositive men were antigen positive at entry and remained so during follow up. Eight (13.8%) of the 58 HIV antibody seroconverters and 20 (12.7%) of the remaining 158 HIV antibody seropositive men became antigen positive during follow up, resulting in an end point attack rate for HIV antigenaemia of 14.3%. AIDS related complex was diagnosed in 25 (15.8%) of the HIV antigen negative men and in 14 (20.7%) of the HIV antigen positive men. AIDS was diagnosed in 15 men, resulting in an end point attack rate for AIDS of 23.9% in the HIV antigen positive group and 1.3% in the antigen negative group. HIV antibody seropositive men without symptoms but with persistent HIV antigenaemia are at increased risk of developing AIDS and AIDS related complex.
A CASE OF PRIMARY ARTERIAL THROMBOSIS OF THE EXTERNAL ILIAC ARTERY, WITH SECONDARY EMBOLTJS.
Authors: M. THORNER
Journal: JAMA (1906)

Primary or autochthonous arterial thrombosis of the large vessels, other than the aorta with sequelæ, affords a sufficient incentive to a most careful analysis of each case from a clinic as well as from a histologic standpoint, as the gravity of the subsequent conditions is of paramount importance. The occurrence of secondary emboli from thrombosis in arteries other than the aorta and pulmonary arteries gives the following case an especial significance. To Virchow is given the credit of first actually proving anatomically and clinically, as well as of having first recognized that not all intravascular and antemortem clots are formed at the place where they are found. but are the result of emboli. It is a well-known fact that embolus with secondary thrombosis plays a greater rôle in arterial occlusion than primary thrombi, yet the close relation of the latter to the former, as in this case, accentuates the necessity
Monocyte activation in early onset rheumatoid arthritis.
Authors: I Fujii, M Shingu, M Nobunaga
Journal: Annals of the Rheumatic Diseases (1990)

Monocytes from peripheral blood and synovial fluid of patients with definite and classic rheumatoid arthritis spontaneously produced significantly greater amounts of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and interleukin-1 beta (IL-1 beta) than samples of peripheral blood from normal controls. Peripheral blood monocytes from patients with rheumatoid arthritis produced significantly greater amounts of PGE2 than control samples when stimulated with lipopolysaccharide. There were no significant differences in the spontaneous release of superoxide or N-acetyl-beta-D-glucosaminidase by peripheral blood monocytes between patients and healthy controls. Both stimulated and unstimulated peripheral blood monocytes from patients with definite or classic rheumatoid arthritis produced significantly greater amounts of PGE2 than samples from normal controls. This was true, regardless of the stage of disease and the presence or absence of roentgenological joint abnormalities. Amounts of N-acetyl-beta-D-glucosaminidase released by peripheral blood monocytes from patients correlated positively with the erythrocyte sedimentation rate (ESR) and negatively with duration of disease. Amounts of IL-1 beta and N-acetyl-beta-D-glucosaminidase released from the peripheral blood monocytes of patients who had had their disease for less than one year were significantly higher than those of normal controls. There were no significant correlations between the types of treatment and the amounts of PGE2, LTB4, IL-1 beta or N-acetyl-beta-D-glucosaminidase released by peripheral blood monocytes in patients with rheumatoid arthritis. The findings suggest that monocytes are activated in patients with rheumatoid arthritis both at the onset of disease and during its chronic phase, and that they produce large amounts of mediators which may have a role in the induction and extension of the inflammatory process which leads to tissue damage.